Baier, A., B. Wittek, et al. (2002). "Drosophila as a new model organism for the neurobiology of aggression?" J Exp Biol 205(Pt 9): 1233-40.
We report here the effects of several neurobiological determinants on aggressive behaviour in the fruitfly Drosophila melanogaster. This study combines behavioural, transgenic, genetic and pharmacological techniques that are well established in the fruitfly, in the novel context of the neurobiology of aggression. We find that octopamine, dopamine and a region in the Drosophila brain called the mushroom bodies, all profoundly influence the expression of aggressive behaviour. Serotonin had no effect. We conclude that Drosophila, with its advanced set of molecular tools and its behavioural richness, has the potential to develop into a new model organism for the study of the neurobiology of aggression.

Cabib, S., S. Puglisi-Allegra, et al. (2002). "The contribution of comparative studies in inbred strains of mice to the understanding of the hyperactive phenotype." Behav Brain Res 130(1-2): 103-9.
Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity and impulsivity. Converging evidence, suggests a primary role of disturbances in brain dopamine (DA) transmission and a role of genetic factors in its pathology. Inbred provide a well-defined and stable genotype for analysis. C57BL/6 (C57) and DBA/2 (DBA) mice are amongst the most studied inbred strains in the behavioral pharmacology of DA, and they differ in several parameters of the DA system that relate directly to behavioral differences. These strains also exhibit several qualitatively different behavior patterns that rely on separate DA networks (e.g. mesoaccumbens vs. nigrostriatal) and on different modes of inheritance. C57 mice are good learners in most tasks also involving associative learning but are totally unable to learn active avoidance although being very active. Moreover, C57 mice show greater novelty-induced locomotor activity than DBA, which is modulated strongly by DA neurons in the ventral tegmental area (VTA) region. Pharmacological studies also indicate a facilitated mesoaccumbens DA transmission in C57 mice when compared to DBAs. Increased density of D2 autoreceptors located on VTA neurons, and lower D2 postsynaptic receptors in the NAS were observed in DBA relative to C57. Activation of D2 autoreceptors inhibits impluse flow, synthesis, and release rates of DA neurons. As would be predicted from their higher D2 autoreceptor: DBA compared to C57 mice show reduced DA synthesis and release within the mesoaccumbens DA system when challenged with DA direct agonists. However, DBA mice are by fare more susceptible than C57s to stress-induced enhanced mesoaccumbens DA release and in stressful situation, they show sustained active behavioral responses whilst C57 adopt extremely passive responses (behavioral despair). Finally, chronic or repeated stress promote opposite adaptation of VTA DA autoreceptors in the two strains and render the hypoactive DBAs as active as the C57 mice. These results indicate that a complex interaction between genetic and environmental factors controls, mesoaccumbens DA functioning and hyperactive phenotype.

Cagiano, R., T. Cassano, et al. (2002). "Genetic factors involved in the effects of developmental low-level alcohol induced behavioral alterations in rats." Neuropsychopharmacology 26(2): 191-203.
Behavioral and neurochemical effects of perinatal alcohol exposure (3% v/v solution from Day 15 of gestation to Day 7 after parturition) have been investigated in Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rat lines, selectively bred for opposite alcohol preference and consumption. In an elevated zero-maze model of anxiety, sucrose-exposed sP rats (sP-S): (i) spent significantly less time on the open arms (TO); (ii) exhibited a significantly lower number of head dips (HDIPS); and (iii) showed a higher number of stretched attend-postures (SAP) than sucrose-exposed sNP rats (sNP-S) at 90 and 180 days of age. The two rat lines displayed different emotional reactivity in response to alcohol exposure. Subtle differences in sexual behavior and ultrasonic emission (latency to the first intromission and to the first 50 kHz call) were observed between sP-S and sNP-S rats. sP-alcohol exposed (sP-A) offspring exhibited a higher latency to the first intromission than sNP-alcohol (sNP-A) treated rats. Moreover, a lower number of sP-A rats exhibited both intromission and ejaculation with respect to sNP-A animals. sP-S rats were significantly slower in recover of the righting reflex than sNP-S animals after a challenge dose of alcohol (3 g/kg, i.p.). Perinatal alcohol did not affect either onset or duration of sleep time in either line. Neurochemical experiments have shown that perinatal alcohol did not influence basal dopamine levels or amphetamine-induced dopamine increase in the prefrontal cortex of either sP or sNP offspring. These results, showing an endpoint-specific differential sensitivity of sP and sNP lines to perinatal low alcohol exposure, indicate that genetic factors could be responsible for selective susceptibility to behavioral alterations induced by developmental treatment with this drug of abuse.

Caine, S. B., S. S. Negus, et al. (2002). "Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists." J Neurosci 22(7): 2977-88.
Dopamine receptor subtypes have been classified generally as D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence suggests that D2-like receptors may be especially important in mediating the abuse-related effects of cocaine. However, it has been difficult to differentiate the roles of the D2-like receptor subtypes in the behavioral effects of cocaine because of the relatively low selectivity of drugs for D2, D3, and D4 receptors in vivo. The goal of the present series of studies was to investigate the contributions of D2-like receptor subtypes in the reinforcing effects of cocaine using new genetic and pharmacological tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack the D2 receptor but express D3 and D4 receptors. When high doses of cocaine on the descending limb of the cocaine dose-effect function were available, D2 mutant mice self-administered at higher rates than their heterozygous or wild-type littermates, but the ascending limb of the cocaine dose-effect function did not differ between genotypes. Elevated rates of drug intake were not attributable to nonspecific increases in response rate, because response rates maintained by presentation of a range of food concentrations were significantly lower in D2 mutant mice than in wild-type mice. In wild-type mice, pretreatment with the D2-like antagonist eticlopride increased rates of self-administration of high doses of cocaine, and the D2-like agonist quinelorane served as a positive reinforcer when substituted for cocaine. However, these effects of eticlopride and quinelorane were not observed in mice that lacked the D2 receptor. Next, we compared the effects of novel antagonists selective for different D2 receptor subtypes on cocaine self-administration behavior in outbred rats. In rats, a D2 selective antagonist increased rates of self-administration of high doses of cocaine and also combinations of cocaine and the D2-like agonist quinelorane, whereas D3/D4 antagonists were ineffective. Collectively, these findings suggest that the D2 receptor is not necessary for cocaine self-administration, but this receptor subtype is involved in mechanisms that limit rates of high-dose cocaine self-administration. Our results also suggest that D3 and D4 receptors do not play major roles in the modulation of cocaine self-administration by D2-like drugs.

Carson, R. P. and D. Robertson (2002). "Genetic manipulation of noradrenergic neurons." J Pharmacol Exp Ther 301(2): 410-7.
The neurotransmitter norepinephrine has been the focus of intense investigation for nearly a century. With advances in technology come novel approaches for testing hypotheses about the physiological roles of norepinephrine and the genes involved in norepinephrine (NE) biosynthesis, metabolism, and noradrenergic signaling. Homologous recombination techniques, which generate mice deficient in specific gene products, aid the integrated physiologist and pharmacologist in the evaluation of protein function. Mouse models lacking proteins involved in NE biosynthesis or metabolism provide tools to expand the knowledge previously gleaned from pharmacologic studies. Removal of the biosynthetic enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase yield animals deficient in norepinephrine and have been used to further examine the role of NE in diverse physiologic roles. Complete removal of the vesicular monoamine transporter has demonstrated that mobilizing neurotransmitters to vesicles is required for animal survival. Lastly, the generation of animals in which the ability to remove NE from the synapse is impaired (norepinephrine transporter deficiency and extraneuronal monoamine transporter deficiency) and in which the enzymes responsible for the metabolism of NE have been removed (catechol-O-methyltransferase and monoamine oxidase) has facilitated the study of the long-term physiological consequences of altered NE homeostasis.

Catalina, F., L. Milewich, et al. (2002). "Decrease of core body temperature in mice by dehydroepiandrosterone." Exp Biol Med (Maywood) 227(6): 382-8.
Dietary dehydroepiandrosterone (DHEA) reduces food intake in mice, and this response is under genetic control. Moreover, both food restriction and DHEA can prevent or ameliorate certain diseases and mediate other biological effects. Mice fed DHEA (0.45% w/w of food) and mice pair-fed to these mice (food restricted) for 8 weeks were tested for changes in body temperature. DHEA was more efficient than food restriction alone in causing hypothermia. DHEA injected intraperitoneally also induced hypothermia that reached a nadir at 1 to 2 hr, and slowly recovered by 20 to 24 hr. This effect was dose dependent (0.5-50 mg). Each mouse strain tested (four) was susceptible to this effect, suggesting that the genetics differ for induction of hypophagia and induction of hypothermia. Because serotonin and dopamine can regulate (decrease) body temperature, we treated mice with haloperidol (dopamine receptor antagonist), 5,7-dihydroxytryptamine (serotonin production inhibitor), or ritanserin (serotonin receptor antagonist) prior to injection of DHEA. All of these agents increased rather than decreased the hypothermic effects of DHEA. DHEA metabolites that are proximate (5-androstene-3beta, 17beta-diol and androstenedione) or further downstream (estradiol-17beta) were much less effective than DHEA in inducing hypothermia. However, the DHEA analog, 16alpha-chloroepiandrosterone, was as active as DHEA. Thus, DHEA administered parentally seems to act directly on temperature-regulating sites in the body. These results suggest that DHEA induces hypothermia independent of its ability to cause food restriction, to affect serotonin or dopamine functions, or to act via its downstream steroid metabolites.

Chauveau, D., C. Burckle, et al. (2002). "Diagnosis of pheochromocytoma and laparoscopic adrenalectomy in two anephric patients with von Hippel-Lindau disease." Am J Kidney Dis 39(2): E6.
This study reports the first two cases of laparoscopic treatment of functional pheochromocytomas in patients with von Hippel-Lindau (VHL) disease receiving regular dialysis treatment. The genetic changes predisposing to pheochromocytoma, diagnostic procedures, and surgical management were analyzed. Both patients were considered at low risk of developing pheochromocytoma because they belonged to VHL families with 10 and 25 affected relatives without pheochromocytoma (VHL type 1 families). The mutation responsible for the disease was a stop codon in one case and a missense change in the other. Multiple renal cell carcinomas had required removal of the kidneys at age 37 in one patient and age 25 in the other patient. Computed tomography scan was crucial for diagnosis, showing a unilateral enlarged adrenal gland after 3 and 6 years on regular dialysis. No change in blood pressure was observed. MIBG scintigraphy was negative. Plasma epinephrine in one case and dopamine in the other were increased compared with patients on hemodialysis without pheochromocytoma. Pheochromocytomas were removed successfully by laparoscopic adrenalectomy. Lifelong follow-up of all affected tissues is required in all VHL patients, and pheochromocytoma should be screened for even in the absence of family history in large kindreds. Computed tomography scan allows early recognition, and patients on hemodialysis are responsive to laparoscopic adrenalectomy.

Cubells, J. F., L. H. Price, et al. (2002). "Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression." Biol Psychiatry 51(5): 358-64.
BACKGROUND: Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine, is reportedly lower in patients with unipolar major depression with psychotic features (UDPF) than in those with nonpsychotic unipolar major depression (UD). Plasma DbetaH is under genetic control by the structural locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific allelic variation at DBH accounts for lower plasma DbetaH in UDPF. METHODS: Plasma DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD (n = 45). Genotypes were determined at several functional DBH polymorphisms, including C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that associates with variation in plasma DbetaH activity. RESULTS: Mean plasma DbetaH activity was significantly lower in UDPF than in UD. Genotyping at DBH did not reveal genetic associations distinguishing UDPF from UD. A two-way analysis of variance showed significant effects of genotype and diagnostic group but no significant interaction. CONCLUSIONS: Although the effects of the diagnosis of UDPF, and of DBH allele status, on plasma DbetaH activity were replicated, the lower plasma DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations for this result are possible. First, other variants at DBH, or at other loci, could account for the findings. Second, nongenetic factors could account for the differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH protein, which could in turn alter the ratio of dopamine and norepinephrine in noradrenergic neurons, thereby promoting development of psychotic symptoms.

Cunningham, L. A. and C. Su (2002). "Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease." Exp Neurol 174(2): 230-42.
Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease. A replication-defective retrovirus was constructed, which contained the rat GDNF sequence and a sequence encoding a beta-galactosidase (beta-gal)/neomycin phosphotransferase fusion protein, linked via an internal ribosomal entry site. Murine astrocytes transduced with this vector secreted GDNF into the culture media at the rate of 115 +/- 34 pg/24 h/10(5) cells and expressed cytoplasmic beta-gal, whereas control nontransduced astrocytes were negative for GDNF production and cytoplasmic beta-gal expression. Mice that received implants of GDNF-producing astrocytes into the striatum or nigra displayed elevated levels of GDNF compared to mice that received control nontransduced astrocytes. In addition, tissue content of GDNF was increased bilaterally and in brain regions both proximal and distal to the graft, even though astrocyte migration away from the graft site did not occur. Importantly, GDNF-producing astrocytes provided marked neuroprotection of nigral dopaminergic perikarya, and partial protection of striatal dopaminergic fibers, when implanted into the midbrain 6 days prior to a retrograde 6-OHDA lesion, as assessed by tyrosine hydroxylase immunohistochemistry. Similarly, GDNF-producing astrocytes prevented the acquisition of amphetamine-induced rotational behavior in 6-OHDA-treated mice and completely prevented dopamine depletion within the substantia nigra, as assessed by high-performance liquid chromatography. These results indicate that continuous exposure to low levels of GDNF provided by transgenic astrocytes provides marked neuroprotection of nigral dopaminergic neurons. (c)2002 Elsevier Science (USA).

Cusin, C., A. Serretti, et al. (2002). "Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders." Am J Med Genet 114(4): 380-90.
The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.

D'Aquila, P. S., A. T. Peana, et al. (2002). "Different sensitivity to the motor-stimulating effect of amphetamine in Sardinian alcohol-preferring and non-preferring rats." Eur J Pharmacol 435(1): 67-71.
The selective breeding of rodents on the basis of ethanol intake and preference has led to the development of lines of alcohol-preferring and non-preferring animals. The divergent degree of alcohol preference and consumption displayed by these lines of animals appears to be related, among other factors, to the genetic differences in dopaminergic neurotransmission. Moreover, in genetically unselected rats, a positive correlation has been found between alcohol preference and several amphetamine effects, including the stimulation of motor hyperactivity, thus suggesting the hypothesis that a common neural pathway might underlie some aspects in both of the amphetamine-induced hypermotility and alcohol preference. In the present study, we compared the motor-stimulating effect of amphetamine, which is mediated by the release of dopamine in the nucleus accumbens and in the corpus striatum in two lines of rats selectively bred for high and low ethanol preference, the Sardinian alcohol-preferring (sP) and the Sardinian alcohol-non-preferring (sNP) rats, respectively. The results show that sP rats are less sensitive to the motor-stimulant effect of amphetamine with respect to sNP rats, thus suggesting a negative correlation between this behavioural response and alcohol preference. The present results might be explained by the previously reported reduced density of dopamine receptors in the nucleus accumbens of sP rats and are consistent with the view that alcohol preference is associated with a deficient dopaminergic transmission. Moreover, they are consistent with the hypothesis that alcohol preference and amphetamine motor effect share a common neural substrate and that hereditary factors determine individual variations in its sensitivity.

D'Souza, U. M., C. H. Lammers, et al. (2002). "Developmental expression of the zinc finger transcription factor DRRF (dopamine receptor regulating factor)." Mech Dev 110(1-2): 197-201.
Dopamine receptor regulating factor (DRRF) is a novel transcription factor with unique anatomical distribution and functional properties, suggesting its importance in regulating dopaminergic neurotransmission. To gain insight into the in vivo function of this factor during embryogenesis, we studied its distribution at embryonic days E8-E16 in the mouse using in situ hybridization. DRRF mRNA is expressed uniquely during development at all time points tested with high levels observed at E12, E14 and E16 in various tissues. DRRF expression is also found in particular brain regions, such as the neopallial cortex, olfactory lobe and corpus striatum. This pattern of DRRF distribution during embryogenesis overlaps with that found in the adult brain, and with the expression profile of dopamine receptors both in the adult and during development.

de Almeida, L. P., C. A. Ross, et al. (2002). "Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length." J Neurosci 22(9): 3473-83.
A new strategy based on lentiviral-mediated delivery of mutant huntingtin (htt) was used to create a genetic model of Huntington's disease (HD) in rats and to assess the relative contribution of polyglutamine (CAG) repeat size, htt expression levels, and protein length on the onset and specificity of the pathology. Lentiviral vectors coding for the first 171, 853, and 1520 amino acids of wild-type (19 CAG) or mutant htt (44, 66, and 82 CAG) driven by either the phosphoglycerate kinase 1 (PGK) or the cytomegalovirus (CMV) promoters were injected in rat striatum. A progressive pathology characterized by sequential appearance of ubiquitinated htt aggregates, loss of dopamine- and cAMP-regulated phosphoprotein of 32 kDa staining, and cell death was observed over 6 months with mutant htt. Earlier onset and more severe pathology occurred with shorter fragments, longer CAG repeats, and higher expression levels. Interestingly, the aggregates were predominantly located in the nucleus of PGK-htt171-injected rats, whereas they were present in both the nucleus and processes of CMV-htt171-injected animals expressing lower transgene levels. Finally, a selective sparing of interneurons was observed in animals injected with vectors expressing mutant htt. These data demonstrate that lentiviral-mediated expression of mutant htt provides a robust in vivo genetic model for selective neural degeneration that will facilitate future studies on the pathogenesis of cell death and experimental therapeutics for HD.

Ding, Y. C., H. C. Chi, et al. (2002). "Evidence of positive selection acting at the human dopamine receptor D4 gene locus." Proc Natl Acad Sci U S A 99(1): 309-14.
Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold "younger" than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.

Drouin, C., L. Darracq, et al. (2002). "Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates." J Neurosci 22(7): 2873-84.
Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

Dunah, A. W., H. Jeong, et al. (2002). "Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease." Science.
Huntington's Disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Co-expression of Sp1 and TAFII130 in cultured striatal cells from wild type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before development of disease symptoms.

Dybing, E. and T. Sanner (2002). "[Nicotine dependence--medico-biological aspects]." Tidsskr Nor Laegeforen 122(3): 302-5.
The nicotine in tobacco products is strongly addictive. This was generally recognised no earlier than in the late 1970s, though it was well known within the international tobacco industry in the early 1960s. Nicotine acts as an addictive substance by binding to acetylcholine receptors and causing the release of dopamine in the brain, though other signalling substances are also important for the action of nicotine in the central nervous system. Withdrawal syndrome is the typical evidence of physical addiction to nicotine. Nicotine addiction can develop rapidly. There are, however, individual differences; genetic predisposition may have a bearing on these differences.

Eaton, M. J., J. P. Herman, et al. (2002). "Immortalized chromaffin cells disimmortalized with Cre/lox site-directed recombination for use in cell therapy for pain after partial nerve injury." Exp Neurol 175(1): 49-60.
To prepare immortalized adrenal chromaffin cells for eventual clinical use, the immortalizing oncogene must be removed. We have utilized a Cre-mediated excision of a loxP-flanked Tag sequence to test whether immortalized chromaffin cells could be disimmortalized by this method. Cultures of embryonic rat adrenal cells were immortalized with the tsA-TN retroviral vector encoding the loxP-flanked temperature-sensitive allele of SV40 large T antigen (tsA-TN) and a positive/negative neo/HSV-TK sequence for selection with either G418 or gancyclovir, respectively. These cells were then infected with the 1710-CrePR1 bicistronic retroviral vector coding for a form of Cre modulatable by the synthetic steroid RU486. These immortalized loxTsTag/CrePR1/RAD cells expressed immunoreactivities (ir) for all the catecholamine enzymes: tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine-N-methyltransferase (PNMT). After initial incubation at 37 degrees C with RU486 for 3 days, followed by the addition of gancyclovir for 7 days, Tag-ir was not detectable in most of the surviving chromaffin cells, compared to 100% expression in immortalized loxTsTag/CreR1/RAD cells not treated with RU486 and gancyclovir. The expression of TH, DbetaH, and PNMT was increased after disimmortalization and the ability of disimmortalized cells to synthesize norepinephrine was also significantly increased compared to immortalized cells. When both types of chromaffin cells were transplanted in a model of neuropathic pain and partial nerve injury, both cell grafts were equally able to reverse the behavioral hypersensitivity induced by the injury. The use of Cre/lox site-directed disimmortalization of chromaffin cells that are able to deliver neuroactive molecules offers a novel approach to cell therapy.

Esposito, G., A. Rapacciuolo, et al. (2002). "Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress." Circulation 105(1): 85-92.
BACKGROUND: A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis. METHODS AND RESULTS: To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress (sigma(es)) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of sigma(es) in pressure-overloaded wild-type mice (287+/-39 versus sham, 254+/-34 g/cm2), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize sigma(es) (415+/-81 g/cm2, P<0.05). Remarkably, despite inadequate normalization of sigma(es), cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure. CONCLUSIONS: These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.

Farbu, E. and L. A. Bindoff (2002). "[Dopa-responsive dystonia--a hereditary dystonia easy to treat]." Tidsskr Nor Laegeforen 122(4): 379-81.
BACKGROUND: Dopa-responsive dystonia is a genetically determined disorder with early onset. The dystonia usually manifests as a disturbance of gait with fatigue and may be confused with spasticity. The diagnosis is based on clinical recognition and response to l-dopa, which is usually complete and long lasting. The most common genetic defect involves the gene for GTP cyclohydroxylase I. MATERIAL AND METHODS: We describe a Norwegian family in which three generations are affected. RESULTS: All those affected had gait disturbance from childhood; the disturbance became worse during the day and after exercise. Clinical examination revealed reduced fine motor skills and brisk tendon reflexes. Dystonic posturing of one or both legs could be seen during walking. All patients were treated with l-dopa with excellent effect. INTERPRETATION: Though uncommon, this disorder is an important differential diagnosis in children with gait disturbance, particularly in those suspected as having spastic paraparesis.

Felder, R. A., H. Sanada, et al. (2002). "G protein-coupled receptor kinase 4 gene variants in human essential hypertension." Proc Natl Acad Sci U S A 99(6): 3872-7.
Essential hypertension has a heritability as high as 30-50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D(1)-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D(1) dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4gamma, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D(1) receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4gammaA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D(1)-like agonist stimulation. These findings provide a mechanism for the D(1) receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.

Fernandez Noda, E. I., H. Rivera Luna, et al. (2002). "New concept regarding chest pain due to hypoxia of the internal mammary arteries in more than 1,600 operated patients with cerebral thoracic neurovascular syndrome (CTNVS)." Panminerva Med 44(1): 47-59.
In this article we describe the role of compression of the vertebral, subclavian, internal mammary, internal carotid arteries, brachial plexus and coiling and kinking of the vertebral and basilar arteries, the faulty irrigation of blood supply and oxygen of the cerebellum and basal ganglia and other areas of the brain followed by metabolic processes. Among the effects are: a decrease in the secretion of dopamine at the level of the putamen, which produces the symptoms of symptomatic Parkinson's disease, chorea due to chronic transitory faulty blood supply and oxygen to the caudate nucleus, ballism by hypoxia at the level of sub-thalamic and thalamus nuclei and athetosis in the lenticular nucleus. This compression is caused by hypertrophy of the anterior scalenus muscles and the cervical ribs at the level of the vertebrae C6-C7; by the sternocleidomastoid at the level of the cervical atlas, by the pectoralis minor muscles and coiling and kinking of the vertebral, basilar and the internal carotid arteries. The decreased blood supply to the cerebellum and basal ganglia is the cause of the cerebral thoracic neuro vascular syndrome (CTNVS) and its neurological complications, among which are ipsilateral paralysis, symptomatic Parkinson's disease, functional Alzheimer's disease multiple sclerosis and others. We are presently engaged in genetic studies to widen our understanding of these illness.

Frim, D. M. and H. N. Le (2002). "Gene therapy for Parkinson's disease." Expert Opin Biol Ther 2(2): 151-61.
Significant progress has been made in the field of gene therapy for Parkinson's disease (PD). Successful vehicles for gene transfer into the central nervous system have been developed and clinical efficacy and safety have both been shown in various animal models of PD. Further optimisation of dosing, timing and location of gene therapy delivery as well as the ability to regulate and prolong gene expression will be important for the commencement of human trials. Current gene therapy models for PD have focused on two treatment strategies. One is the replacement of biosynthetic enzymes for dopamine synthesis and the second strategy is the addition of neurotrophic factors for protection and restoration of dopaminergic neurones. Concepts of neuroprotection and restoration of the nigrostriatal pathway will become important themes for future genetic treatment strategies for PD and may include, in addition to neurotrophic factors, genes to prevent apoptosis or detoxify free radical species. This review will highlight the recent literature on gene therapy for PD and summarise general approaches to gene therapy.

Gordon, N. (2002). "Stuttering: incidence and causes." Dev Med Child Neurol 44(4): 278-81.

Grattan-Smith, P. J., R. A. Wevers, et al. (2002). "Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy." Mov Disord 17(2): 354-9.
Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with tyrosine hydroxylase (TOH) deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH deficiency can be seen as a model of pure catecholamine deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine deficiency in infancy can be broadly subdivided. Signs of dopamine deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.

Greenwood, T. A., M. Alexander, et al. (2002). "Segmental linkage disequilibrium within the dopamine transporter gene." Mol Psychiatry 7(2): 165-73.
The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3' repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5' (distal promoter through intron 6) and 3' (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Hening, W. A. (2002). "Restless legs syndrome: a sensorimotor disorder of sleep/wake motor regulation." Curr Neurol Neurosci Rep 2(2): 186-96.
Restless legs syndrome (RLS) remains an underappreciated sensorimotor disorder of sleep/wake regulation. It is one of the few sensorimotor disorders that is provoked by rest and that also follows a clear circadian pattern. Recent epidemiologic studies have verified that the condition is common in populations derived from the north and west of Europe, and have begun to uncover some of the genetic substrate of the disorder. New instruments have been developed to facilitate diagnosis and assessment of severity. The pathogenesis of the condition remains uncertain, but recent discoveries implicate areas of the nervous system from the spinal cord up to the basal ganglia. A current hypothesis undergoing vigorous exploration is that the condition results from a deficiency of dopaminergic function based on abnormalities of iron transport and storage. Therapeutically, studies have shown the dopamine agonists to be the most reliable treatment for severe cases, whereas other recent studies have successfully utilized a number of other medications, including levodopa, opioids, and anticonvulsants. New standards provide guidelines for management of RLS and make specific pharmacotherapeutic recommendations.

Himei, A., J. Koh, et al. (2002). "The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms." Psychiatry Clin Neurosci 56(1): 97-102.
The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia.

Hironaka, N., T. Yagi, et al. (2002). "Light-potentiation of acoustic startle response (ASR) and monoamine efflux related to fearfulness in Fyn-deficient mice." Brain Res Mol Brain Res 98(1-2): 102-10.
Fyn tyrosine kinase deficient mice are known to show increased fearfulness. We investigated the fear response of these mice using the light-potentiation of the acoustic startle response (ASR) and examined its neurochemical correlates using in vivo microdialysis. Female homozygous Fyn-deficient mice showed an enhancement of the startle amplitude under a bright light while heterozygotes and wild-types did not show such a change. Along with these behavioral findings, the homozygous Fyn-deficient mice showed an increase in extracellular serotonin (5-HT) and dopamine (DA) in the prefrontal cortex and 5-HT in the hippocampus when they were exposed to bright light, while heterozygous and wild-type mice did not show such changes. These results suggest that the increased fearfulness of Fyn-deficient mice is related to enhanced serotonergic and dopaminergic activity in the prefrontal cortex and limbic system.

Huang, Y., X. Liu, et al. (2002). "[Transmission disequilibrium test of DRD4 exon III 48bp variant number tandem repeat polymorphism and tic disorder]." Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19(2): 100-3.
OBJECTIVE: To investigate whether DRD4 exon III48 bp variant number tandem repeat(VNTR) polymorphism is associated with tic disorder. METHODS: One hundred and twenty-two nucleus families were collected using Structured clinical interview for genetic study of Tourette syndrome and related disorders for family-based association analysis of tic disorder and DRD4 exon III 48bp VNTR polymorphism. One hundred and twenty-two trios were divided into two groups: tic disorder group (82 trios of Tourette syndrome or chronic tic disorder, TS&CT) and tic disorder accompanied with attention deficit and hyperactivity disorder (ADHD) group (40 trios of Tourette syndrome or chronic tic disorder accompanied with ADHD, TS&ADHD). Transmission disequilibrium test (TDT), in addition to polymerase chain reaction and VNTR technique were conducted in 122 trios. RESULTS: There exist 5 alleles at this polymorphic locus in this sample including DRD4 exon III 48bp 2-6 repeats. No transmission disequilibrium was found between DRD4 exon III 48 bp VNTR and tic disorder (chi square=7.44, P 0.12); however, when the sample was divided into two groups, transmission disequilibrium was noticed between the cases of TS&ADHD and this locus by overall allele-wise analysis (chi square=11.74, P 0.02), and there exists transmission disequilibrium exclusively between 5 or 6 repeats of 48bp VNTR(longer alleles) by allele-wise analysis (chi square=10.57, P 0.032, chi square=6.13, P 0.01). No transmission disequilibrium was seen between TS&CT and DRD4 exon III 48bp VNTR(chi square=3.38, P 0.50). CONCLUSION: The results of this study have revealed an association between the longer alleles of DRD4 exon III 48bp VNTR polymorphism and tic disorder accompanied with ADHD, thus suggesting a possible genetic risk factor of tic disorder accompanied with ADHD in Chinese.

Hutchison, K. E., H. LaChance, et al. (2002). "The DRD4 VNTR polymorphism influences reactivity to smoking cues." J Abnorm Psychol 111(1): 134-43.
Recent research has indicated that craving for tobacco can be reliably elicited by exposure to smoking cues, suggesting that cue-elicited craving for tobacco may be a useful phenotype for research on genetic factors related to nicotine dependence. Given the potential role of dopamine in cue-elicited craving, the authors examined whether the DRD4 VNTR polymorphism is associated with cue-elicited craving for tobacco. Participants who were homozygous or heterozygous for the 7 repeat (or longer) allele were classified as DRD4 L, and all other participants were classified as DRD4 S. Participants were exposed to smoking cues before smoking either high-nicotine cigarettes or control cigarettes. Analyses suggested that participants in the L group demonstrated significantly greater craving, more arousal, less positive affect, and more attention to the smoking cues than did the participants in the S group.

Jose, P. A., G. M. Eisner, et al. (2002). "Dopamine Receptor-coupling Defect in Hypertension." Curr Hypertens Rep 4(3): 237-44.
Dopamine synthesized in non-neural tissues, eg, renal proximal tubule, functions in an autocrine or paracrine manner. The effects of dopamine are transduced by two classes of receptors (D(1)- and D(2)-like) that belong to the superfamily of G protein-coupled receptors. In genetic hypertension, the D(1) receptor, a member of the D(1)-like receptor family, is uncoupled from its G protein complex, resulting in a decreased ability to regulate renal sodium transport. The impaired D(1) receptor/G protein coupling in renal proximal tubules in genetic hypertension is secondary to abnormal phosphorylation and desensitization of the D(1) receptor caused by activating single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK type 4.

Joseph, J. D., Y. M. Wang, et al. (2002). "Dopamine autoreceptor regulation of release and uptake in mouse brain slices in the absence of D(3) receptors." Neuroscience 112(1): 39-49.
The effects of the dopamine D(3) receptor, a putative autoreceptor, have been investigated by comparing behavioral and neurochemical properties of wild-type mice and mice with a genetic deletion of the D(3) receptor. The D(3) knock-out mice were modestly hyper-responsive to a novel environment relative to wild-type mice, and, consistent with this, quantitative in vivo microdialysis revealed elevated striatal dopamine extracellular levels. The dynamic actions of autoreceptors on electrically evoked dopamine release were examined in striatal brain slices from these animals and monitored with fast scan cyclic voltammetry at carbon-fiber microelectrodes. Quinpirole, a dopamine receptor agonist with potency at both D(2) and D(3) receptors, inhibited evoked dopamine in a dose-dependent manner with a slightly higher dose required in the knock-out animals (EC(50) of 60+/-10 nM in wild-type animals and 130+/-40 in D(3) knock-out animals; both curves had a Hill slope near 2). Dopamine synthesis inhibition with alpha-methyl-p-tyrosine caused released dopamine levels to decrease in each genotype. However, regulation of secretion by autoreceptors was still operant. Dose-response curves to quinpirole were unchanged in D(3) knock-out tissue, but secretion-regulated release exhibited a Hill slope decreased to 1 in the wild-type animals. In both genotypes, similar quinpirole-evoked increases in uptake rate were evident following synthesis inhibition.These data are consistent with the D(3) receptor having a small but significant role as a dopamine autoreceptor that partially regulates secretion, but not synthesis, in the caudate-putamen.

Junn, E. and M. M. Mouradian (2002). "Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine." Neurosci Lett 320(3): 146-50.
alpha-Synuclein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Two point mutations in alpha-synuclein (A53T and A30P) are identified in few families with dominantly inherited PD. Yet the mechanism by which this protein is involved in nigral cell death remains poorly understood. Mounting evidence suggests the importance of oxidative stress in the pathogenesis of PD. Here we investigated the effects of wild-type and two mutant forms of alpha-synuclein on intracellular reactive oxygen species (ROS) levels using clonal SH-SY5Y cells engineered to over-express these proteins. All three cell lines, and particularly mutant alpha-synuclein-expressing cells, had increased ROS levels relative to control LacZ-engineered cells. In addition, cell viability was significantly curtailed following the exposure of all three alpha-synuclein-engineered cells to dopamine, but more so with mutant alpha-synuclein. These results suggest that over-expression of alpha-synuclein, and especially its mutant forms, exaggerates the vulnerability of neurons to dopamine-induced cell death through excess intracellular ROS generation. Thus, these findings provide a link between mutations or over-expression of alpha-synuclein and apoptosis of dopaminergic neurons by lowering the threshold of these cells to oxidative damage.

Kanner, A. M. and A. Balabanov (2002). "Depression and epilepsy: how closely related are they?" Neurology 58(8 Suppl 5): S27-39.
Article abstract Depressive disorders (DDs) are the most common type of psychiatric co-morbidity in patients with epilepsy. They are more likely to occur in patients with partial seizure disorders of temporal and frontal lobe origin and are more frequent among patients with poorly controlled seizures. Despite their relatively high prevalence, DDs remain unrecognized and untreated in a large proportion of patients. This article highlights the evidence of a close association between DDs and epilepsy, beginning with the bi-directional relationship between the two disorders. Not only are patients with epilepsy more likely to experience a DD, but a history of DD preceding the onset of the seizure disorder is more likely to be identified in patients with epilepsy than in a control group. In support of these observations, we review data from animal models of epilepsy showing that decreased activity of serotonin, norepinephrine, dopamine, and GABA facilitate the kindling process of seizure foci, worsen seizure frequency and severity, and are reversed or blocked by antidepressant drugs. Decreased activity of these neurotransmitters is a pivotal pathogenic mechanism of DDs and forms the basis of their pharmacotherapy. Thus, DDs and epilepsy may share common pathogenic mechanisms that facilitate the occurrence of one in the presence of the other. Contrary to long-held beliefs by patients and clinicians alike, in the sense that DDs are a "normal reaction" to the obstacles posed by epilepsy, we review evidence that points to their biologic or endogenous nature. We find a genetic predisposition to DDs, as evidenced by the frequent family history of mood disorders in these patients. Neuroimaging and neuropsychological data support a frontal lobe dysfunction in DDs, and a recent study documents concomitant dysfunction of mesial temporal structures. Depressive disorders have various clinical presentations, some typical of the different types of mood disorders in non-epileptic patients, others constituting rather frequent atypical presentations that can easily go unrecognized. A review of the pharmacologic treatment of DDs in epilepsy highlights the lack of scientific data and points to the empirical form in which these patients have been treated up to the present time. Contrary to clinicians' fears, most antidepressant drugs are safe in patients with epilepsy.

Kim, C. H., D. Y. Hwang, et al. (2002). "A proximal promoter domain containing a homeodomain-binding core motif interacts with multiple transcription factors, including HoxA5 and Phox2 proteins, and critically regulates cell type-specific transcription of the human norepinephrine transporter gene." J Neurosci 22(7): 2579-89.
Expression of the norepinephrine transporter (NET), which mediates the reuptake of norepinephrine into presynaptic nerve terminals, is restricted to noradrenergic (NA) neurons. We have demonstrated previously that the 9.0 kb upstream sequences and the first intron residing in the 5' untranslated area are critical for high-level and NA cell-specific transcription. Here, using transient transfection assays, we show that 4.0 kb of the 5' upstream sequences contains sufficient genetic information to drive reporter gene expression in an NA cell type-specific manner. Three functional domains appear to be potentially important for the regulation of human NET (hNET) gene transcription: an upstream enhancer region at -4.0 to -3.1 kb, a proximal domain at -133 to -75 bp, and a middle silencer region between these two domains. DNase I footprinting analysis of the proximal promoter region shows that a subdomain at -128 to -80 bp is protected in a cell-specific manner. We provide evidence that multiple protein factors interact with the proximal promoter domain to critically regulate the transcriptional activity of the hNET gene. In the middle of this proximal subdomain resides a homeodomain (HD)-binding core motif, which interacts with HD factors, including Phox2a and HoxA5, in an NA-specific manner. Cotransfection analyses suggest that HoxA5 and Phox2a may transactivate the hNET gene promoter. Together with previous studies indicating direct activation of dopamine beta-hydroxylase transcription by Phox2a/2b, the present results support a model whereby Phox2 proteins may coordinately regulate the phenotypic specification of NA neurons by activating both NA biosynthetic and reuptake genes.

Kirik, D., C. Rosenblad, et al. (2002). "Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system." J Neurosci 22(7): 2780-91.
Recombinant adeno-associated viral vectors display efficient tropism for transduction of the dopamine neurons of the substantia nigra. Taking advantage of this unique property of recombinant adeno-associated viral vectors, we expressed wild-type and A53T mutated human alpha-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including alpha-synuclein-positive cytoplasmic inclusions and swollen, dystrophic neurites similar to those seen in brains from patients with Parkinson's disease, developed progressively over time. These pathological alterations occurred preferentially in the nigral dopamine neurons and were not observed in other nondopaminergic neurons transduced by the same vectors. The degenerative changes were accompanied by a loss of 30-80% of the nigral dopamine neurons, a 40-50% reduction of striatal dopamine, and tyrosine hydroxylase levels that was fully developed by 8 weeks. Significant motor impairment developed in those animals in which dopamine neuron cell loss exceeded a critical threshold of 50-60%. At 6 months, signs of cell body and axonal pathology had subsided, suggesting that the surviving neurons had recovered from the initial insult, despite the fact that alpha-synuclein expression was maintained at a high level. These results show that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant alpha-synuclein, pointing to a key role for alpha-synuclein in the pathogenesis of Parkinson's disease. Targeted overexpression of alpha-synuclein in the nigrostriatal system may provide a new animal model of Parkinson's disease that reproduces some of the cardinal pathological, neurochemical, and behavioral features of the human disease.

Kitamura, Y., J. Kakimura, et al. (2002). "Antiparkinsonian drugs and their neuroprotective effects." Biol Pharm Bull 25(3): 284-90.
In Parkinson's disease, while dopamine (DA) replacement therapy, such as with L-DOPA (levodopa), improves the symptoms, it does not inhibit the degeneration of DA neurons in the substantia nigra. Numerous studies have suggested that both endogenous and environmental neurotoxins and oxidative stress may participate in this disease, but the detailed mechanisms are still unclear. Recent genetic studies in familial Parkinson's disease and parkinsonism have shown several gene mutations. This new information regarding its pathogenesis offers novel prospects for effective strategies involving the neuroprotection of vulnerable DA neurons. This review summarizes current findings regarding the pathogenesis and antiparkinsonian drugs, and discusses their possibilities of targets to develop novel neuroprotective drugs.

Koller, W. C. (2002). "Treatment of early Parkinson's disease." Neurology 58(4 Suppl 1): S79-86.
The early treatment of Parkinson's disease (PD) consists of nonpharmacologic treatment, consideration of neuroprotective therapy, and initial symptomatic treatment. Education for the patient and family, access to support groups, regular exercise, and good nutrition are essential to the overall management of PD. Disease-modifying therapies, such as agents that provide neurorescue or neuroprotection, will provide a major advance in the treatment of PD. Intervention at the genetic/environmental level or that affects the cascade of pathophysiologic events, protein aggregation, or apoptosis could result in neuroprotection. Many agents are now being investigated for neuroprotective potential. A major paradigm shift has recently occurred because of the recent basic and clinical data indicating that dopamine agonists, rather than levodopa, should be the initial symptomatic therapy in PD. However, levodopa may be started first in some patients because of patient age, cognitive status, or cost of drugs.

Leckman, J. F. and A. E. Herman (2002). "Maternal behavior and developmental psychopathology." Biol Psychiatry 51(1): 27-43.
This paper reviews recent developments in the phenomenology, neurobiology, and genetics of maternal behavior in animal model systems from an evolutionary perspective on psychopathology. Following a review of the phenomenology and neurobiology of maternal behavior, recent studies addressing the role of genetic factors in the maternal behavior of rodents were identified in a search of literature in peer-reviewed journals. Gene knockout studies were evaluated with regard to mouse strain background, method of behavioral phenotyping, and quantification of the behavioral deficits. Gene knockout data were then analyzed using a cluster analysis technique. At least nine genes have been identified that are necessary for the expression of one or more aspects of maternal behavior. These genes encode for three transcription factors: three enzymes, including dopamine beta hydroxylase and neuronal nitric oxide synthase; two receptors, including the prolactin and the estrogen alpha receptor; and one neuropeptide, oxytocin. Cluster analysis suggested possible relationships between specific genes. Gene knockout technology has provided new insights into the molecular basis of maternal behavior that are congruent with the existing neurobiological literature. Future studies of genetic and environmental influences on maternal behavior have the potential to inform models of disease pathogenesis.

Li, T., X. Liu, et al. (2002). "Allelic association analysis of the dopamine D2, D3, 5-HT(2A), and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects." Am J Med Genet 114(3): 329-35.
Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism.

Lucas, L. A. and B. A. McMillen (2002). "Differences in brain area concentrations of dopamine and serotonin in Myers' High Ethanol Preferring (mHEP) and outbred rats." J Neural Transm 109(3): 279-92.
Both male and female mHEP rats consume excessive amounts of ethanol and thus offer a rational model for examining biochemical and behavioral differences with non-drinking rat lines. Differences in basal concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) correlate with the consumption of ethanol in some ethanol-preferring rat lines. The concentrations of 5-HT and DA were examined by HPLC in five brain areas (prefrontal cortex, hippocampus, nucleus accumbens, striatum and hypothalamus) of ethanol-naive rats and after the oral administration of 0.25 or 1.0 g ethanol/kg in the male and female mHEP rat, the male Wistar rat, and the female Sprague-Dawley rat. The mHEP and control rats that received ethanol were screened for drinking in a 10-day "step-up" 3% to 30% ethanol solutions beginning at postnatal days 40 and 80, and then tested at 150 days of age. The levels of DOPAC in females were lower in the hippocampus of both naive mHEP and ethanol-treated Sprague-Dawley rats. In striatum, the concentrations of 5-HT and DA were elevated in both mHEP and ethanol-treated Sprague-Dawley female rats. The concentrations of 5-HT and its metabolite, 5-HIAA, were lower in the nucleus accumbens of the ethanol-naive female mHEP rat relative to the female outbred control. In the male rats, the levels of DA, HVA and DOPAC, as well as 5-HT and 5-HIAA were reduced in the hypothalamus of both ethanol-naive mHEP rats and Wistar rats receiving ethanol by gavage. These data demonstrate differences in neurotransmitter activity between the selectively bred mHEP rat and the outbred rat strains. There are few common features found in both the male and the female mHEP rat when compared to their respective controls. Differences in neurotransmitter function in these brain areas may account for some of the behavioral differences previously demonstrated between the two sexes of the mHEP rat.

Malhotra, A. K., L. J. Kestler, et al. (2002). "A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition." Am J Psychiatry 159(4): 652-4.
OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.

Massat, I., D. Souery, et al. (2002). "Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European multicenter association study of affective disorders." Am J Med Genet 114(2): 177-85.
Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.

Mill, J. S., A. Caspi, et al. (2002). "The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study." Mol Psychiatry 7(4): 383-91.
Attention-deficit hyperactivity disorder (ADHD) affects 2-6% of school-age children and is a precursor of behavioural problems in adolescence and adulthood. Underlying the categorical definition of ADHD are the quantitative traits of activity, impulsivity, and inattention which vary continuously in the population. Both ADHD and quantitative measures of hyperactivity are heritable, and influenced by multiple genes of small effect. Several studies have reported an association between clinically defined ADHD and the seven-repeat allele of a 48-bp tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene (DRD4). We tested this association in a large, unselected birth cohort (n = 1037) using multiple measures of the hyperactivity phenotype taken at multiple assessment ages across 20 years. This longitudinal approach allowed us to ascertain whether or not DRD4 has a general effect on the diagnosed (n = 49) or continuously distributed hyperactivity phenotype, and related personality traits. We found no evidence to support this association.

Momose, Y., M. Murata, et al. (2002). "Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms." Ann Neurol 51(1): 133-6.
We studied 20 single nucleotide polymorphisms in 18 candidate genes for association with Parkinson's disease. We found that homozygosity for the V66M polymorphism of the brain-derived neurotrophic factor (BDNF) gene occurs more frequently in patients with Parkinson's disease than in unaffected controls (chi(2) = 5.46) and confirmed an association with the S18Y polymorphism of the UCH-L1 gene. Our results provide genetic evidence supporting a role for BDNF in the pathogenesis of Parkinson's disease.

Morimoto, K., R. Miyatake, et al. (2002). "Delusional disorder. Molecular genetic evidence for dopamine psychosis." Neuropsychopharmacology 26(6): 794-801.
Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls. RESULTS: (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a "dopamine psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required.

Muglia, P., U. Jain, et al. (2002). "A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder." Behav Brain Res 130(1-2): 91-5.
Convincing data support the hypothesis that genetic factors are involved in the etiology of attention-deficit hyperactivity disorder (ADHD). Various lines of evidence have shown that the dopamine system plays a crucial role in the pathophysiology of ADHD. The dopamine D3 receptor gene (DRD3) represents a promising candidate to examine in ADHD. Animal studies have shown that DRD3 mRNA is highly expressed in the ventral striatum suggesting an involvement of this receptor in the control of motor behaviour. Manipulation of DRD3 in rodents has led to a mouse model with nonfunctional D3 receptors that displays hyperactive behaviour in various environmental conditions. Furthermore, administration of 7-OH-DPAT, a dopaminergic agonist that binds preferentially to D3 receptors exerts an inhibitory effect on locomotor activity while D3 antagonists induce hyperactivity. Among various polymorphisms described for DRD3, the BalI polymorphism is most interesting because it codes for an aminoacid substitution in the N-terminus of the receptor. The receptor products of the two alleles (Ser/Gly) exhibit differential affinity for dopamine. To determine if DRD3 Ser9/Gly is involved in the susceptibility to ADHD we genotyped 39 adults with ADHD and their respective parents (trios). Adult ADHD represents a promising phenotype for studying the genetic component of the disorder. In fact, a recent family study has shown that relatives of adult ADHD patients have a higher rate of ADHD compared to relatives of children with ADHD suggesting a stronger genetic component for the adult version. The results of genotyping in the 39 trios analyzed with the transmission disequilibrium test showed no excess of transmission for DRD3 MscI/BalI alleles (chi(2) = 0.360; df = 1; P = 0.54). This result, although from a relatively small sample, indicates that it is unlikely that DRD3 is playing a major role in the etiology of ADHD in our sample.

Muramatsu, S., K. Fujimoto, et al. (2002). "Behavioral recovery in a primate model of Parkinson's disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes." Hum Gene Ther 13(3): 345-54.
One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associated virus (AAV) vectors, we previously demonstrated that expression of these three enzymes in the striatum resulted in long-term behavioral recovery in rat models of PD. We here extend the preclinical exploration to primate models of PD. Mixtures of three separate AAV vectors expressing TH, AADC, and GCH, respectively, were stereotaxically injected into the unilateral putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. Coexpression of the enzymes in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-TH/-AADC/-GCH-injected side. Behavioral recovery persisted during the observation period (four monkeys: 48 days, 65 days, 50 days, and >10 months, each). TH-immunoreactive (TH-IR), AADC-IR, and GCH-IR cells were present in a large region of the putamen. Microdialysis demonstrated that concentrations of DA in the AAV-TH/-AADC/-GCH-injected putamen were increased compared with the control side. Our results show that AAV vectors efficiently introduce DA-synthesizing enzyme genes into the striatum of primates with restoration of motor functions. This triple transduction method may offer a potential therapeutic strategy for PD.

Nass, R., D. H. Hall, et al. (2002). "Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans." Proc Natl Acad Sci U S A 99(5): 3264-9.
Parkinson's disease is a complex neurodegenerative disorder characterized by the death of brain dopamine neurons. In mammals, dopamine neuronal degeneration can be triggered through exposure to neurotoxins accumulated by the presynaptic dopamine transporter (DAT), including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium. We have established a system for the pharmacological and genetic evaluation of neurotoxin-induced dopamine neuronal death in Caenorhabditis elegans. Brief (1 h) exposure of green fluorescent protein-tagged, living worms to 6-OHDA causes selective degeneration of dopamine neurons. We demonstrate that agents that interfere with DAT function protect against 6-OHDA toxicity. 6-OHDA-triggered neural degeneration does not require the CED-3/CED-4 cell death pathway, but is abolished by the genetic disruption of the C. elegans DAT.

Nguimfackmbodie, P. C. (2002). "[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?]." Encephale 28(2): 147-53.
The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.

Paletzki, R. F. (2002). "Cloning and characterization of guanine deaminase from mouse and rat brain." Neuroscience 109(1): 15-26.
A search for genes differentially expressed in the rat striatum revealed a gene fragment with a ventral to dorsal striatal expression pattern. The sequence of the fragment was used to isolate mouse and rat clones that upon sequencing were identified as homologous to human guanine deaminase. Here we report the distribution of guanine deaminase in the rodent brain. In situ hybridization localization of the encoding mRNA showed a distribution primarily in forebrain areas including cortical pyramidal neurons, ventral striatal medium spiny neurons, hippocampal pyramidal neurons in CA3-CA1 and granule cells in the dentate gyrus, and neurons of the amygdala. Immunohistochemistry using antibodies raised against peptide fragments derived from the guanine deaminase protein sequence showed localization of guanine deaminase in areas predicted by the mRNA distribution. In addition to immunolabeling of neurons in the cerebral cortex, hippocampus, striatum and amygdala there was also labeling in the terminal fields of these neurons including the thalamus, globus pallidum and substantia nigra. A functional histochemical assay that demonstrates the site of guanine deamination shows guanine deaminase activity in a pattern that matched the immunohistochemical localization. The cellular distribution of guanine deaminase to distal areas of the cell including terminals and dendrites was additionally demonstrated by the expression of recombinant guanine deaminase in transformed cortical neurons in culture.In summary we have described the isolation and characterization of mouse and rat guanine deaminase. The expression of guanine deaminase is primarily restricted to forebrain neurons. A histochemical assay was used to localize guanine deaminase activity to the dendrites and axons of neurons expressing guanine deaminase.

Philippe, A., M. Guilloud-Bataille, et al. (2002). "Analysis of ten candidate genes in autism by association and linkage." Am J Med Genet 114(2): 125-8.
We studied the possible involvement of ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight families with two affected siblings and one family with two affected half-siblings, recruited by the Paris Autism Research International Sibpair Study (PARIS), were tested using the transmission disequilibrium test and two-point affected sib-pair linkage analysis. We found no evidence for association or linkage with intragenic or linked markers. Our family sample has good power for detecting a linkage disequilibrium of 0.80. Thus, these genes are unlikely to play a major role in the families studied, but further studies in a much larger sample would be needed to highlight weaker genetic effects.

Pittenger, C., Y. Y. Huang, et al. (2002). "Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory." Neuron 34(3): 447-62.
CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB.

Prasad, S., P. Semwal, et al. (2002). "Molecular genetics of schizophrenia: past, present and future." J Biosci 27 Suppl 1: 35-52.
Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance which is also governed by non-genetic factors. Candidate genes identified on the basis of biochemical and pharmacological evidence are being tested for linkage and association studies. Neurotransmitters, especially dopamine and serotonin have been widely implicated in its etiology. Genome scan of all human chromosomes with closely spaced polymorphic markers is being used for linkage studies. The completion and availability of the first draft of Human Genome Sequence has provided a treasure-trove that can be utilized to gain insight into the so far inaccessible regions of the human genome. Significant technological advances for identification of single nucleo-tide polymorphisms (SNPs) and use of microarrays have further strengthened research methodologies for genetic analysis of complex traits. In this review, we summarize the evolution of schizophrenia genetics from the past to the present, current trends and future direction of research.

Richfield, E. K., M. J. Thiruchelvam, et al. (2002). "Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice." Exp Neurol 175(1): 35-48.
Human alpha-synuclein (halpha-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed halpha-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of halpha-SYN in nigrostriatal terminals produced effects in both constructs resulting in increased density of the dopamine transporter and enhanced toxicity to the neurotoxin MPTP. Expression of hm2alpha-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwalpha-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2alpha-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.

Rouge-Pont, F., A. Usiello, et al. (2002). "Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors." J Neurosci 22(8): 3293-301.
An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the increase in extracellular DA induced by both drugs was strikingly higher in D2R-/- than in wild-type littermates. This indicates that D2Rs play a key role in the modulation of DA release in response to drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2 receptor in D2R-/- mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of D2R, despite unchanged DA uptake and basal DA efflux. Finally, we propose that the short isoform D2S receptor of the D2 receptors is the one controlling change in DA release induced by drugs of abuse. Indeed, the neurochemical effects of cocaine and morphine are unchanged in animals with a selective deletion of the long isoform D2L receptor. Thus, deregulated expression of D2R isoforms might be involved in the vulnerability of an individual to drug abuse.

Russell, V. A. (2002). "Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat." Behav Brain Res 130(1-2): 191-6.
Evidence supports dysfunction of dopaminergic and noradrenergic systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect functionally distinct cortical areas with separate striatal regions and remain segregated in parallel striato-pallidal-thalamic and striato-substantia nigra pars reticulata-thalamic pathways. Prefrontal cortex performance is maximal at moderate stimulation of postsynaptic dopaminergic and noradrenergic receptors, and is reduced by either higher or lower levels of receptor stimulation. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity, poor stability of performance, impaired ability to withhold responses and poorly sustained attention, when compared with their normotensive Wistar-Kyoto (WKY) control rats. Evidence suggests that terminals of mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of SHR release less dopamine in response to electrical stimulation and/or depolarization as a result of exposure to high extracellular K+ concentrations, than WKY. Vesicular storage of dopamine was suggested to be impaired in SHR, causing leakage of dopamine into the cytoplasm and increased d-amphetamine-induced transporter-mediated release. While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine release appears to be impaired in SHR, suggesting that noradrenergic function may be poorly regulated in the prefrontal cortex of the SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls.

Sawa, A. and S. H. Snyder (2002). "Schizophrenia: diverse approaches to a complex disease." Science 296(5568): 692-5.
Schizophrenia is a debilitating mental illness that affects 1% of the population. Despite intensive study, its molecular etiology remains enigmatic. Like many common diseases, schizophrenia is multifactorial in origin, with both genetic and environmental contributions likely playing an important role in the manifestation of symptoms. Recent advances based on pharmacological studies, brain imaging analyses, and genetic research are now converging on tantalizing leads that point to a central role for several neurotransmitters, including dopamine, glutamate, and serotonin, that may interface with neurodevelopmental defects reflecting disease-related genetic aberrations. Here, we provide a brief overview of the parallel approaches being used to identify the molecular causes of schizophrenia and discuss possible directions for future research.

Schapira, A. H. (2002). "Neuroprotection and dopamine agonists." Neurology 58(4 Suppl 1): S9-S18.
Several factors are known to be capable of inducing relatively selective dopaminergic cell death in the substantia nigra and inducing the clinical features that characterize Parkinson's disease (PD). Neuronal toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce parkinsonism in human and animal models, and rotenone, another specific mitochondrial complex I inhibitor, can induce similar effects in rodents to produce a model for PD. Studies in twins suggest a significant genetic component to young-onset PD, and several gene mutations have now been identified as causing familial autosomal dominant or autosomal recessive PD. Etiologic factors including free radical-mediated damage (including excitotoxicity), mitochondrial dysfunction, and inflammation-mediated cell damage can contribute to pathogenesis. In addition, the recent interest in protein misfolding, aggregation, and proteosomal activity has provided further insight into potential pathogenetic pathways in PD. Against this background there has been increasing interest in the development of drugs to modify these biochemical abnormalities and thus alter the course of PD, either by retarding the rate of cell death or by restoring function to neurons that are likely to be damaged but not dead. In this context, dopamine agonists have shown significant promise. Not only do these drugs provide symptomatic relief of PD but they also appear to be associated with a significant decrease in the rate of motor complications and to be capable of protecting against some of the adverse consequences of levodopa use. However, evidence is now emerging that dopamine agonists may have additional neuroprotective properties. As a group, they have antioxidant actions in vitro and in vivo. More specifically, the D(2)/D(3) dopamine agonist pramipexole may have neuroprotective activity that is, at least in part, unrelated to its dopamine agonist action. Protection in cell and animal models against a variety of toxins, including MPTP and 6-hydroxydopamine, confirms that this agonist has in vitro and in vivo neuroprotective action. Evidence is now emerging that some of this may be mediated by direct action on mitochondrial membrane potential and the inhibition of apoptosis. If the neuroprotective action of this drug is confirmed in patients with PD, this will have important implications for its early use in patients.

Shepherd, A. G., R. A. Lea, et al. (2002). "Dopamine receptor genes and migraine with and without aura: an association study." Headache 42(5): 346-51.
Objective.-To investigate the role of the dopamine receptor genes, DRD1, DRD3, and DRD5 in the pathogenesis of migraine. Background.-Migraine is a chronic debilitating disorder affecting approximately 12% of the white population. The disease shows strong familial aggregation and presumably has a genetic basis, but at present, the type and number of genes involved is unclear. The study of candidate genes can prove useful in the identification of genes involved in complex diseases such as migraine, especially if the contribution of the gene to phenotypic expression is minor. Genes coding for proteins involved in dopamine metabolism have been implicated in a number of neurologic conditions and may play a contributory role in migraine. Hence, genes that code for enzymes and receptors modulating dopaminergic activity are good candidates for investigation of the molecular genetic basis of migraine. Methods.-We tested 275 migraineurs and 275 age- and sex-matched individuals free of migraine. Genotypic results were determined by restriction endonuclease digestion of polymerase chain reaction products to detect DRD1 and DRD3 alleles and by Genescan analysis after polymerase chain reaction using fluorescently labelled oligonucleotide primers for the DRD5 marker. Results.-Results of chi-square statistical analyses indicated that the allele distribution for migraine cases compared to controls was not significantly different for any of the three tested gene markers (chi2 = 0.1, P =.74 for DRD1; chi2 = 1.8, P =.18 for DRD3; and chi2 = 20.3, P =.08 for DRD5). Conclusions.-These findings offer no evidence for allelic association between the tested dopamine receptor gene polymorphisms and the more prevalent forms of migraine and, therefore, do not support a role for these genes in the pathogenesis of the disorder.

Sohn, E. H., T. Wolden-Hanson, et al. (2002). "Testosterone (T)-induced changes in arcuate nucleus cocaine-amphetamine-regulated transcript and NPY mRNA are attenuated in old compared to young male brown Norway rats: contribution of T to age-related changes in cocaine-amphetamine-regulated transcript and NPY gene expression." Endocrinology 143(3): 954-63.
The age-related decrease in serum T levels is associated with impairments in food intake and weight regulation and alterations in brain peptides that regulate energy balance. To test the hypothesis that reduced T levels contribute to altered hypothalamic cocaine-amphetamine-regulated transcript (CART) and NPY gene expression, the mRNA content of these neuropeptides was measured by in situ hybridization in sham-operated (intact), castrated, and T-replaced castrated young and old male Brown Norway rats. T levels in T-replaced young and old rats were similar to those in intact young animals. Compared with castrated rats, arcuate nucleus CART mRNA was lower and NPY mRNA was higher in both young and old T-replaced castrated animals, suggesting reciprocal regulation of these peptides by T; these T-induced changes were localized primarily in the rostral arcuate and were markedly attenuated in old animals. Compared with intact animals, paraventricular nucleus CART mRNA was lower in castrated animals and similar in T-replaced young and old rats. We conclude that hypothalamic CART and NPY neurons remain responsive to T regulation in old rats, albeit less so than in young animals, suggesting that the age-related reduction of T contributes in part to altered brain neuropeptide gene expression favoring anorexia and wasting with aging.

Soma, M., K. Nakayama, et al. (2002). "Ser9Gly polymorphism in the dopamine D3 receptor gene is not associated with essential hypertension in the Japanese." Med Sci Monit 8(1): CR1-4.
BACKGROUND: The Dopamine D3 receptor (DRD3) gene is thought to be involved in essential hypertension (EH) because dopamine inhibits renin secretion via this receptor and because disruption of the DRD3 gene increases blood pressure in mice. EH is a complex, polygenetic disease. Association studies using the candidate gene approach may provide important clues regarding the etiology of hypertension and define a basis for further genetic investigation. Therefore we examined the association between the Ser9Gly polymorphism in the DRD3 gene and EH. MATERIAL/METHODS: One hundred eighty-one patients with EH and 181 age-matched subjects with normal blood pressure were enrolled. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was used to amplify the Ser9Gly polymorphic site in the DRD3 gene, and restriction fragment length polymorphism (RFLP) analysis of the PCR product was used to score the A and G alleles. Plasma renin activity and plasma aldosterone concentration were measured in untreated EH subjects. RESULTS: The genotype distribution was in Hardy-Weinberg equilibrium, and was not significantly different between the NT and EH groups. The frequencies of A and G alleles were 0.674 (244/362) and 0.326 (118/362) for the NT group and 0.688 (249/362) and 0.312 (113/362) for the EH group, respectively, and did not differ significantly between the two groups. The genotype did not influence the plasma renin activity and aldosterone concentration in untreated EH patients. CONCLUSIONS: The Ser9Gly polymorphism in the DRD3 gene are not associated with EH. However, our negative result does not exclude the possibility of another variant elsewhere in or near the DRD3 gene in EH.

Sonuga-Barke, E. J. (2002). "Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition." Behav Brain Res 130(1-2): 29-36.
Psychological accounts have characterised attention-deficit/hyperactivity disorder (AD/HD) as either a neuro-cognitive disorder of regulation or a motivational style. Poor inhibitory control is thought to underpin AD/HD children's dysregulation while delay aversion is a dominant characteristic of their motivational style. A recent 'head to head' study of these two accounts suggest that delay aversion and poor inhibitory control are independent co-existing characteristics of AD/HD (combined type). In the present paper we build on these findings to propose a dual pathway model of AD/HD that recognises two quite distinct sub-types of the disorder. In one AD/HD is the result of the dysregulation of action and thought resulting from poor inhibitory control associated with the meso-cortical branch of the dopamine system projecting in the cortical control centres (e.g. pre-frontal cortex). In the other AD/HD is a motivational style characterised by an altered delay of reward gradient linked to the meso-limbic dopamine branch associated with the reward circuits (e.g. nucleus accumbens). The two pathways are further distinguished at the levels of symptoms, cognitive and motivation profiles and genetic and non-genetic origins.

Tanigawara, Y., O. Iketani, et al. (2002). "[Variability in drug response caused by the genetic polymorphisms of receptors]." Nippon Rinsho 60(1): 51-7.
A greater deal of attention has been given to the genetic polymorphism of receptors and related variability in drug response. In recent years, studies on pharmacogenomics accomplished remarkable progress in this issue. These studies include, the relationships between beta 2-adrenegic receptor polymorphism and the pharmacological effect of blonchodilator, dopamine D2 or 5-HT2 receptor polymorphism and response to antipsychotic medication, vitamin D receptor variants and the active vitamin D therapy, PPAR gamma and the insulin resistance treatment and so on. However, some of them are still controversial, and it requires further investigation to apply these studies to the actual therapy.

Todd, R. D. and E. A. Lobos (2002). "Mutation screening of the dopamine D2 receptor gene in attention-deficit hyperactivity disorder subtypes: Preliminary report of a research strategy." Am J Med Genet 114(1): 34-41.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable syndrome with onset in childhood that is associated with clinical response to drugs, which increase the release of monoamines, especially dopamine. A variety of studies have reported on genetic associations of ADHD with polymorphisms for various component genes of the dopamine pathway. The promise of preliminary associations found with several genes is mitigated by the significant controversy that exists over what are the appropriate clinical characteristics of ADHD associated with its familial transmission. In the current report, we describe a strategy for mutation screening in common, complex disorders and its application to the systematic screening for coding region variation in the dopamine D2 receptor (DRD2) gene. We used groups of individuals who met diagnostic criteria for DSM-IV-defined ADHD subtypes, as well as recently defined latent class criteria for pure familial forms of ADHD. No coding region sequence variations were identified in the DRD2 gene that met our requirements for prevalence to be considered a candidate variant contributing to susceptibility for ADHD.

Tsai, S. J., Y. W. Yu, et al. (2002). "Dopamine D2 Receptor and N-Methyl-D-Aspartate Receptor 2B Subunit Genetic Variants and Intelligence." Neuropsychobiology 45(3): 128-30.
The dopaminergic and glutamate systems have been implicated in cognitive function. We tested the associations between the dopamine D2 receptor (DRD2) and N-methyl-D-aspartate receptor 2B subunit (GRIN2B) gene variants and intelligence quotient (IQ). Subjects with the DRD2 A1/A1 genotype had a significantly higher mean performance IQ than A2/A2 carriers, while no significant differences in IQ scores were determined for the three GRIN2B genotype groups. These results suggest that genetic variants of the DRD2 gene may play a role in cognitive function. Considering the major role played by the dopaminergic system in general cognitive function, genetic variants of the dopamine receptors and those involved in metabolism and modulation of reuptake should be tested to improve gene-based prediction of general cognitive function.

Uhl, G. R., F. S. Hall, et al. (2002). "Cocaine, reward, movement and monoamine transporters." Mol Psychiatry 7(1): 21-6.
Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities.

Umegaki, H., K. Ishiwata, et al. (2002). "In vivo assessment of adenoviral vector-mediated gene expression of dopamine D(2) receptors in the rat striatum by positron emission tomography." Synapse 43(3): 195-200.
For functional assessment of gene therapy in experimental animals, in vivo assessment of transferred genes will provide a major advance over an in vitro analysis which must be done post-hoc. In the current study we conducted positron emission tomography (PET) analysis in rats following injection of the adenoviral vector encoding the cDNA for the rat dopamine D(2) receptors (D(2)R) (AdCMV.DopD(2)R) into rat brain to provide a quantitative evaluation of D(2)R overexpression. Quantitative measurements as well as images by PET and ex vivo autoradiography demonstrated the significant increase of D(2)R binding of [(11)C]raclopride, a specific D(2)R radioligand, in the AdCMV.DopD(2)R-injected rat striatum 2 or 3 days after vector injection. Longitudinal in vivo assessment of the gene expression by PET demonstrated decreased binding of [(11)C]raclopride with time, which was in agreement with the observation in a cross-sectional autoradiographic study. The results of the current study demonstrate that PET can be used for longitudinal in vivo assessment of D(2)R expression mediated by adenoviral vector in rat brain.

Vanitallie, T. B. (2002). "Stress: A risk factor for serious illness." Metabolism 51(6 Pt 2): 40-5.
The body's principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome, as well as certain disorders of immune function. The brain's limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition. The ability of stress to cause illness in humans is most clearly exemplified by post-traumatic stress disorder (PTSD), which consists of a predictable constellation of distressing behavioral symptoms and physiological features. An appreciable proportion of the observed variance in vulnerability to PTSD is attributable to genetic factors. The relationship of this disorder to its precipitating cause-a recent, severely traumatic event-is unambiguous. The neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also have been shown to exhibit exaggerated catecholamine responses to trauma-related stimuli. On the other hand, severely maltreated prepubertal children with PTSD continue to excrete greater than normal urinary cortisol, catecholamines, and dopamine years after disclosure of the causative abuse.

Viggiano, D., G. Grammatikopoulos, et al. (2002). "A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD." Behav Brain Res 130(1-2): 181-9.
The hyperfunctioning dopamine hypothesis in the mesocorticolimbic (MCL) system has been addressed by a neurogenetic approach in model systems. Thus, a morphometric analysis was carried out on neurons of origin of Substantia Nigra (SN) and Ventral Tegmental Area (VTA) dopamine systems of the Naples High-Excitability (NHE), Low-Excitability (NLE) and control lines. Male adult rats were tested in a spatial novelty for indices of activity and non-selective attention. Mesencephalic coronal sections were processed for tyrosine hydroxylase (TH) immunohistochemistry and cytochromoxidase (C.O.) histochemistry. Image analysis in the rostro-caudal plane showed (i) a higher neuron size of TH+ elements in the VTA of NHE and NLE, across the entire structure in the NHE, and only in the middle portion in the NLE; (ii) a higher expression of TH in the neuropil of the VTA in NHE; (iii) a lower C.O. activity in both NLE and NHE; (iv) no differences in the SN. The larger neuron size in both NHE and NLE rats as compared with control rats, along with higher TH expression mainly in the NHE, in absence of any relevant alteration in the SN, reveals an unbalance between the two dopamine systems and a subsequent alteration in limbic (reward, motivation, sustained attention) functions. The decreased C.O. activity might be due to reduced feedback inhibition by striatal GABA neurons and interneurons leading to increased DA neuron firing. In conclusion, the increased behavioral activity and impaired attention observed in the NHE rats are associated to hyperfunctioning MCL system in this genetic model of Attention-Deficit Hyperactivity Disorder (ADHD).

Visser, J. E., D. W. Smith, et al. (2002). "Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease." Brain Res Dev Brain Res 133(2): 127-39.
Lesch-Nyhan disease, a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase, is associated with a prominent loss of striatal dopamine. The current studies address the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model of the disease, by assessing several markers of oxidative damage and free radical scavenging systems. Some of these measures provided evidence for an increase in oxidative stress in the mutant mice (aconitase activity, oxidized glutathione, and lipid peroxides), but others did not (superoxide dismutase, protein thiol content, carbonyl protein content, total glutathione, glutathione peroxidase, catalase, and thiobarbituric reducing substances). Immunolocalization of heme-oxygenase 1 provided no evidence for oxidative stress restricted to specific elements of the striatum or midbrain in the mutants. Striatal dopamine systems of the mutant mice were more vulnerable to a challenge with the neurotoxin 6-hydroxydopamine, but they were not protected by cross-breeding the mutants with transgenic mice over-expressing superoxide dismutase. Overall, these data provide evidence for increased oxidative stress, but the failure to protect the knockout mice by over-expressing SOD1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine.

Walters, M. R., M. Dutertre, et al. (2002). "SKF-82958 is a subtype-selective estrogen receptor-alpha (ERalpha ) agonist that induces functional interactions between ERalpha and AP-1." J Biol Chem 277(3): 1669-79.
The transcriptional activity of estrogen receptors (ERs) can be regulated by ligands as well as agents such as dopamine, which stimulate intracellular signaling pathways able to communicate with these receptors. We examined the ability of SKF-82958 (SKF), a previously characterized full dopamine D1 receptor agonist, to stimulate the transcriptional activity of ERalpha and ERbeta. Treatment of HeLa cells with SKF-82958 stimulated robust ERalpha-dependent transcription from an estrogen-response element-E1b-CAT reporter in the absence of estrogen, and this was accompanied by increased receptor phosphorylation. However, induction of ERbeta-directed gene expression under the same conditions was negligible. In our cell model, SKF treatment did not elevate cAMP levels nor enhance transcription from a cAMP-response element-linked reporter. Control studies revealed that SKF-82958, but not dopamine, competes with 17beta-estradiol for binding to ERalpha or ERbeta with comparable relative binding affinities. Therefore, SKF-82958 is an ERalpha-selective agonist. Transcriptional activation of ERalpha by SKF was more potent than expected from its relative binding activity, and further examination revealed that this synthetic compound induced expression of an AP-1 target gene in a tetradecanoylphorbol-13-acetate-response element (TRE)-dependent manner. A putative TRE site upstream of the estrogen-response element and the amino-terminal domain of the receptor contributed to, but were not required for, SKF-induced expression of an ERalpha-dependent reporter gene. Overexpression of the AP-1 protein c-Jun, but not c-Fos, strongly enhanced SKF-induced ERalpha target gene expression but only when the TRE was present. These studies provide information on the ability of a ligand that weakly stimulates ERalpha to yield strong stimulation of ERalpha-dependent gene expression through cross-talk with other intracellular signaling pathways producing a robust combinatorial response within the cell.

Wang, L., S. Muramatsu, et al. (2002). "Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease." Gene Ther 9(6): 381-9.
Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or beta-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.

Waterwort, D. M., A. S. Bassett, et al. (2002). "Recent advances in the genetics of schizophrenia." Cell Mol Life Sci 59(2): 331-48.
The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.

Weiss, F. and L. J. Porrino (2002). "Behavioral neurobiology of alcohol addiction: recent advances and challenges." J Neurosci 22(9): 3332-7.
Addictive behavior associated with alcoholism is characterized by compulsive preoccupation with obtaining alcohol, loss of control over consumption, and development of tolerance and dependence, as well as impaired social and occupational functioning. Like other addictive disorders, alcoholism is characterized by chronic vulnerability to relapse after cessation of drinking. To understand the factors that compel some individuals to drink excessively, alcohol research has focused on the identification of brain mechanisms that support the reinforcing actions of alcohol and the progression of changes in neural function induced by chronic ethanol consumption that lead to the development of dependence. More recently, increasing attention has been directed toward the understanding of neurobiological and environmental factors in susceptibility to relapse.

Wood, J. G., P. R. Joyce, et al. (2002). "A polymorphism in the dopamine beta-hydroxylase gene is associated with "paranoid ideation" in patients with major depression." Biol Psychiatry 51(5): 365-9.
BACKGROUND: Increased dopaminergic activity may play a primary role in psychotic depression. Dopamine beta-hydroxylase (DbetaH) catalyses the key step in biosynthesis of the neurotransmitter noradrenaline from dopamine, and low DbetaH activity is a possible risk factor for developing psychotic depression. An exon 2 polymorphism (DBH*444 g/a) of the DbetaH gene (DBH) is significantly associated with both serum and cerebrospinal fluid levels of DbetaH. METHODS: We determined the genotype of the DBH*444g/a polymorphism in a cohort of 164 patients with major depression and examined the association o