Anichtchik, O. V., N. Peitsaro, et al. (2001). "Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease." Neurobiol Dis 8(4): 707-16.
Parkinson's disease (PD) is a brain degenerative disorder with unknown etiology, and specific degeneration of mesencephalic dopaminergic cells is a morphological manifestation of the disease. The central histaminergic system appears to be activated in PD, since the histaminergic innervation is increased in the substantia nigra. The aim of the present study was to investigate the expression and function of histamine H(3) receptors in PD, using receptor mRNA in situ hybridization with oligonucleotide probes, receptor binding assay with a specific radioactive agonist, and GTP-gamma-[(35)S]-binding assay as a tool to study the activation of the receptor G-protein. H(3) receptor binding sites were detected using N-alpha-methylhistamine autoradiography in the basal ganglia and cortex, being most abundant in the substantia nigra and striatum. In PD substantia nigra we detected an increase of the receptor binding density. In situ hybridization study of the receptor mRNA revealed prominent sites of H(3) receptor synthesis in the putamen, cortex, and globus pallidus, whereas very low mRNA expression was seen in the substantia nigra. In the PD pallidum externum, H(3) receptor mRNA expression was elevated as compared with the normal brains. GTP-gamma-[(35)S]-binding assay did not reveal any significant difference between PD and normal brains, although the density values in PD substantia nigra tended to be lower than in the normal brain, and density values in PD striatum were higher. The dopaminergic neurons did not express significant amount of H(3) receptor mRNA, suggesting that the effects of H(3) receptor-mediated modulation of dopamine release are indirect. Our data indicates modulation of the histamine H(3) receptor in PD at the level of the mRNA expression in the striatum and receptor density in the substantia nigra. The receptor activity seems to be unchanged or decreased, as revealed by GTP-gamma-[(35)S]-binding assay. Modulation of the histamine H(3) receptor may influence the activity of other neurotransmitter systems, e.g., the GABAergic one, in the substantia nigra.

Chen, J. F., K. Xu, et al. (2001). "Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease." J Neurosci 21(10): RC143.
Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5 -c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.

Cowan, W. M. and E. R. Kandel (2001). "Prospects for neurology and psychiatry." Jama 285(5): 594-600.
Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.

Dracheva, S. and V. Haroutunian (2001). "Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice." Brain Res 905(1-2): 142-51.
Mice that incorporate the dopamine D1 receptor transgene controlled by the D1 receptor promoter exhibit a marked increase of D1 binding in several extra-striatal brain regions and show a paradoxical hypokinetic response to D1 agonist [Exp. Neurol. 157 (1999) 169]. The agonist-induced locomotor behavior of D1 receptor transgenic mice is similar to baseline locomotor activity manifested by D2 receptor deficient mice [J. Neurosci. 18 (1998) 3470]. The similarity between these two behavioral phenotypes raised the possibility that stimulation of the over-expressed D1 receptors in the transgenic mice could cause a suppression of D2 receptor responses that manifest in hypokinesia. Alternatively, the similar phenotypes could result from altered D1/D2 receptor balance in both animal models. Two different approaches were undertaken to test these alternative hypotheses. (1) The effects of pharmacological blockade of D2 receptors on D1 agonist-stimulated hypokinesia of the D1 over-expressing animals were investigated. (2) The behavioral phenotype of hybrid D1 receptor over-expressing/D2 receptor deficient mice generated by crossbreeding the D2 knockout mice and the D1 transgenic animals was studied. The results of these studies suggested that the hypomotor response of the D1 transgenic mice was not a result of an interaction of the over-expressed D1 receptors with the native D2 receptors and that over-expressed D1 receptors likely mediate hypokinesia in the D1 transgenic animals. Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors.

Frechilla, D., A. Cobreros, et al. (2001). "Serotonin 5-HT(1A) receptor expression is selectively enhanced in the striosomal compartment of chronic parkinsonian monkeys." Synapse 39(4): 288-96.
Cynomolgus monkeys (Macaca fascicularis) were chronically treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until stable parkinsonism was reached. Two months later, monkeys were sacrificed and monoamine content was measured in different brain regions of the lesioned monkeys and of age-matched controls. 5-HT(1A) serotonin receptor density was measured in coronal sections labeled with [(3)H]8-OH-DPAT. As expected, dopamine was virtually nonexistent in the caudate nucleus and putamen of MPTP-treated monkeys. Serotonin levels were significantly reduced in different brain regions, particularly in the raphe nuclei. 5-HT(1A) receptor density of control animals was high in the hippocampus, notably in the CA1 field and also in the raphe nuclei, and much lower in the striatum, where 5-HT(1A) receptors showed a patchy distribution which corresponded to striosomes with poor calbindin immunostaining. 5-HT(1A) receptor density was reduced in hippocampal fields and in the raphe nuclei of parkinsonian monkeys. Conversely, in the severely lesioned striatal nuclei 5-HT(1A) receptor density was increased at caudal levels of the striatum, particularly in the putamen. The results tend to support the possibility of an increased synthesis of 5-HT(1A) receptors in brain regions with higher neuronal cell death. Upregulation of this 5-HT receptor subtype in the limbic compartment of the striatum may represent a compensatory event for the serotonergic dysfunction and associated mental disorders in neurodegenerative diseases such as Parkinson disease. Copyright 2001 Wiley-Liss, Inc.

Goetz, C. G., P. F. Burke, et al. (2001). "Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study." Arch Neurol 58(2): 209-13.
BACKGROUND: Visual hallucinations in Parkinson disease (PD) occur in approximately one third of patients treated long-term with dopaminergic medications. In Alzheimer disease, hallucinations and psychosis have been linked to increased representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without hallucinations did not show differences in D2 and D3 polymorphisms, although careful case-control matching was not performed. Another study linked the apolipoprotein E4 (APOE4) allele to hallucinations in PD. OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease. METHODS: We conducted a case-control study of 44 patients with PD and chronic hallucinations and 44 patients with PD who had never hallucinated. Cases and controls were matched for current age and medications. DNA was isolated from blood samples and assayed for DRD1, DRD2, DRD3, DRD4, and APOE polymorphisms. Receptor polymorphisms were genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies were compared using Wilcoxon signed rank tests within pairs. RESULTS: Neither D1 receptor genotypes (P =.37) nor allele frequencies (P =.38) differed, and there was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there was a higher frequency of allele 2 (P =.047), but there was no significant difference between frequencies of homozygotes vs heterozygotes (P =.39) as reported in Alzheimer disease. D4 receptor distribution of long and short alleles did not differ between the 2 patient groups, and there were too few C alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99). CONCLUSIONS: With careful case-control matching, visual hallucinations in PD are not associated with the pattern seen for patients with Alzheimer disease and visual hallucinations. Furthermore, there was no association between hallucinations and APOE. Similar methods using larger sample sizes might be adapted to test whether specific dopaminergic receptor genetic variants are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.

Guillin, O., J. Diaz, et al. (2001). "BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization." Nature 411(6833): 86-9.
Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

Guzman, M., C. Sanchez, et al. (2001). "Control of the cell survival/death decision by cannabinoids." J Mol Med 78(11): 613-25.
Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.

Hurley, M. J., D. C. Mash, et al. (2001). "Dopamine D(1) receptor expression in human basal ganglia and changes in Parkinson's disease." Brain Res Mol Brain Res 87(2): 271-9.
The expression of the human dopamine D(1) receptor was examined by reverse transcription polymerase chain reaction (RT-PCR) and radioligand binding using [(3)H]-SCH23390 in post-mortem brain tissue that was obtained from normal subjects and patients dying with Parkinson's disease who were receiving treatment with dopaminergic drugs. D(1) receptor mRNA and specific [(3)H]-SCH23390 binding sites were found in both striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus and substantia nigra) brain regions. In parkinsonian brain, D(1) receptor mRNA was increased in the nucleus accumbens, while a decrease was detected in the substantia nigra pars compacta. No change in D(1) mRNA levels was found in the other brain areas examined. An increase in the density of specific [(3)H]-SCH23390 binding sites was found in the anterior putamen and a decrease in the external segment of the globus pallidus, no changes were detected elsewhere. This study demonstrates that regulation of D(1) receptor expression in the brain of patients dying with Parkinson's disease that were treated with L-DOPA is confined to small alterations in restricted brain regions.

Ilani, T., D. Ben-Shachar, et al. (2001). "A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes." Proc Natl Acad Sci U S A 98(2): 625-8.
Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker may enable a simpler, more rapid, and more accurate diagnosis and monitoring. In recent years, human peripheral blood lymphocytes have been found to express several dopamine receptors (D(3), D(4), and D(5)) by using molecular biology techniques and binding assays. It has been suggested that these dopamine receptors found on lymphocytes may reflect receptors found in the brain. Here we demonstrate a correlation between the D(3) dopamine receptor on lymphocytes and schizophrenia and show a significant elevation of at least 2-fold in the mRNA level of the D(3), but not of the D(4), dopamine receptor in schizophrenic patients. This increase is not affected by different antipsychotic drug treatments (typical or atypical). Moreover, nonmedicated patients exhibit the same pattern, indicating that this change is not a result of medical treatment. We propose the D(3) receptor mRNA on blood lymphocytes as a marker for identification and followup of schizophrenia.

Johnson, S. (2001). "Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease?" Med Hypotheses 56(5): 641-5.
Zinc has several crucial functions in brain development and maintenance: it binds to p53, preventing it from binding to supercoiled DNA and ensuring that p53 cause the expression of several paramount genes, such as the one that encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP), which directs embryonic development of the brain cortex, adrenal glands, etc.; it is required for the production of CuZnSOD and Zn-thionein, which are essential to prevent oxidative damage; it is required for many proteins, some of them with Zn fingers, many of them essential enzymes for growth and homeostasis. For example, the synthesis of serotonin involves Zn enzymes and since serotonin is necessary for melatonin synthesis, a Zn deficiency may result in low levels of both hormones. Unfortunately, Zn levels tend to be low when there is excess Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of Cu and Cd, and smoking and eating food contaminated with Cd result in high levels of the latter. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD).Increased Cu levels may also be found in people with Wilson's disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. Therefore, the developing fetus of a pregnant women who is low in Zn and high in Cu may experience major difficulties in the early development of the brain, which may later manifest themselves as schizophrenia, autism or epilepsy. Similarly, a person who gradually accumulates Cu, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson's disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases. Copyright 2001 Harcourt Publishers Ltd.

Labarca, C., J. Schwarz, et al. (2001). "Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety." Proc Natl Acad Sci U S A 98(5): 2786-91.
Knock-in mice were generated that harbored a leucine-to-serine mutation in the alpha4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.

McGuire, S. O., Z. D. Ling, et al. (2001). "Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons." Exp Neurol 169(2): 219-30.
Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNFalpha-induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNFalpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNFalpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNFalpha-treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNFalpha-induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNFalpha receptor 1 (p55, R1) and TNFalpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNFalpha treatment. These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD. Copyright 2001 Academic Press.

Paterson, I. C., J. B. Matthews, et al. (2001). "Decreased expression of TGF-beta cell surface receptors during progression of human oral squamous cell carcinoma." J Pathol 193(4): 458-67.
This study examined the immunocytochemical expression of the transforming growth factor-beta (TGF-beta) isoforms TGF-beta1, TGF-beta2, and TGF-beta3, together with the TGF-beta cell surface receptors TbetaR-I and TbetaR-II, in patient-matched tissue pairs of normal human oral epithelium, primary squamous cell carcinomas, and metastatic lymph node tumour deposits. There were no significant differences in the intensity of TGF-beta isoform specific staining between the normal oral epithelium, the primary tumours, and the lymph node metastases. By contrast, there was significantly less TbetaR-II in the metastases than in the primary tumour and between the primary tumour and the normal oral epithelium. Similar trends were evident with TbetaR-I, but not at a statistically significant level. This study also examined the structure of TbetaR-I and TbetaR-II in normal human oral keratinocytes in vitro and in 14 human oral carcinoma cell lines with known responses to TGF-beta1. No structural abnormalities of TbetaR-II were present in the normal keratinocytes or in 13 of 14 malignant cell lines; in one line, there were both normal and mutant forms of TbetaR-II, the latter being in the form of a frameshift mutation with the insertion of a single adenine base (bases 709-718, codons 125-128), predicting a truncated receptor having no kinase domain. No defects were present in TbetaR-I. The structures of TbetaR-I and TbetaR-II did not correlate with growth inhibition by TGF-beta1. The data suggest that decreased expression of TGF-beta receptors, rather than structural defects of these genes, may be important in oral epithelial tumour progression. In order to examine the functional significance of a specific decrease in TbetaR-II expression, a dominant-negative TbetaR-II construct (dnTbetaR-II) was transfected into a human oral carcinoma cell line with a normal TGF-beta receptor profile and known to be markedly inhibited by TGF-beta1. In those clones that overexpressed the dnTbetaR-II, growth inhibition and Smad binding activity were decreased, whilst the regulation of Fra-1 and collagenase-1 remained unchanged following treatment with TGF-beta1. The results demonstrate that a decrease in TbetaR-II relative to TbetaR-I leads to selective gene regulation with loss of growth inhibition but continued transcription of AP-1-dependent genes that are involved in the regulation of the extracellular matrix. Copyright 2001 John Wiley & Sons, Ltd.

Pirker, W., J. Tedroff, et al. (2001). "Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions." Exp Neurol 169(1): 122-34.
The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway. Copyright 2001 Academic Press.

Sherer, T. B., R. Betarbet, et al. (2001). "Pathogenesis of Parkinson's disease." Curr Opin Investig Drugs 2(5): 657-62.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway and the appearance of cytoplasmic proteinaceous aggregates known as Lewy bodies. Studies of familial PD have uncovered rare causative mutations in genes, including alpha-synuclein. Mutations or oxidative modification of alpha-synuclein causes it to aggregate; alpha-synuclein is a major component of the Lewy body in both familial and sporadic PD. Biochemical analysis has implicated mitochondrial dysfunction in PD. Epidemiological studies indicate a role of exposure to pesticides, some of which are mitochondrial toxins. Mitochondrial dysfunction, resulting from genetic defects, environmental toxins, or a combination of the two, may cause alpha-synuclein aggregation and produce selective neurodegeneration through mechanisms involving oxidative stress and excitotoxicity. Efforts to better define PD pathogenesis should reveal novel therapeutic targets.

Silverdale, M. A., S. McGuire, et al. (2001). "Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson's disease." Exp Neurol 169(2): 400-6.
High levels of both endocannabinoids and endocannabinoid receptors are present in the basal ganglia. Attention has recently focused on the role of endocannabinoids in the control of movement and in movement disorders of basal ganglia origin such as Parkinson's disease. We investigated CB1 cannabinoid receptor mRNA expression in the reserpine-treated rat model of Parkinson's disease using in situ hybridization. Reserpine treatment caused a topographically organized reduction in CB1 receptor mRNA expression in the striatum (ranging from 11.6% medially to 53.6% laterally and dorsally). No change in CB1 receptor mRNA expression was observed in the cerebral cortex or septum. This reduction in CB1 receptor mRNA expression may be secondary to increased endocannabinoid stimulation of the receptor as increased basal ganglia endocannabinoid levels have been shown to occur in this model of Parkinson's disease. The data support the idea that cannabinoid receptor antagonists may provide a useful treatment for the symptoms of Parkinson's disease. Copyright 2001 Academic Press.

Tang, K., M. J. Low, et al. (2001). "Dopamine-dependent synaptic plasticity in striatum during in vivo development." Proc Natl Acad Sci U S A 98(3): 1255-60.
The neurotransmitters dopamine (DA) and glutamate in the striatum play key roles in movement and cognition, and they are implicated in disorders of the basal ganglia such as Parkinson's disease. Excitatory synapses in striatum undergo a form of developmental plasticity characterized by a decrease in glutamate release probability. Here we demonstrate that this form of synaptic plasticity is DA and DA D2 receptor dependent. Analysis of spontaneous synaptic responses indicates that a presynaptic mechanism involving inhibition of neurotransmitter release underlies the developmental plasticity. We suggest that a major role of DA in the striatum is to initiate mechanisms that regulate the efficacy of excitatory striatal synapses, producing a decrease in glutamate release.

Wang, J., Z. L. Liu, et al. (2001). "Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease." Neurosci Lett 308(1): 21-4.
Motor fluctuations are the most common complication of levodopa therapy for Parkinson's disease (PD). Genetic factors could play a role in determining the occurrence of motor fluctuations. To investigate whether dopamine receptor D5 (DRD5) T978C polymorphism is associated with the risk of developing motor fluctuations in PD, we studied this polymorphism in a case-control study of 120 subjects with sporadic PD and 110 control subjects. We found that the overall allelic and genotypic frequencies did not differ significantly between patients with PD and control subjects (all P>0.7), and between motor fluctuators (n=50) and non-motor fluctuators (n=50) (all P>0.8). It suggests that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations in PD. Therefore, other polymorphisms that alter the expression of the dopamine receptors should be further studied.

Wang, J., Z. L. Liu, et al. (2001). "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD." Neurology 56(12): 1757-9.
The authors investigated the association between dopamine receptor D2, D3 gene polymorphisms, and the risk of developing motor fluctuations in PD. DRD3 BalI and MspI polymorphisms were not associated with risk of developing motor fluctuations. However, the genotypic distribution of DRD2 TaqIA polymorphism was significantly different in motor fluctuators and nonmotor fluctuators. These findings suggest that DRD2 TaqIA polymorphism may be associated with an increased risk for developing motor fluctuations in PD.

Wang, L., S. Andersson, et al. (2001). "Morphological abnormalities in the brains of estrogen receptor beta knockout mice." Proc Natl Acad Sci U S A 98(5): 2792-6.
Estrogen receptor beta (ERbeta) is expressed at high levels in both neurons and glial cells of the central nervous system. The development of ERbeta knockout (BERKO) mice has provided a model to study the function of this nuclear receptor in the brain. We have found that the brains of BERKO mice show several morphological abnormalities. There is a regional neuronal hypocellularity in the brain, with a severe neuronal deficit in the somatosensory cortex, especially layers II, III, IV, and V, and a remarkable proliferation of astroglial cells in the limbic system but not in the cortex. These abnormalities are evident as early as 2 mo of age in BERKO mice. As BERKO mice age, the neuronal deficit becomes more pronounced, and, by 2 yr of age, there is degeneration of neuronal cell bodies throughout the brain. This is particularly evident in the substantia nigra. We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain.

Yu, T. S., S. D. Wang, et al. (2001). "Changes in the gene expression of GABA(A) receptor alpha1 and alpha2 subunits and metabotropic glutamate receptor 5 in the basal ganglia of the rats with unilateral 6-hydroxydopamine lesion and embryonic mesencephalic grafts." Exp Neurol 168(2): 231-41.
By using an animal model of parkinsonism, we examined the expression of GABA(A) receptor (R) and metabotropic glutamate receptor (mGluR) 5 in the basal ganglia after transplantation with dopamine-rich tissue. The adult rats were unilaterally lesioned by the injection of 6-hydroxydopamine to their left medial forebrain bundles. At 5-10 weeks following the dopaminergic denervation, the levels of GABA(A)R in the left caudate-putamen and globus pallidus were about 20 and 16% lower than that of the right intact (control) sides, as shown by [3H]flunitrazepam binding autoradiography on the brain sections. However, the receptor density increased to around 132 and 130% of control levels in the entopeduncular nucleus and substantia nigra pars reticulata of the lesioned sides. Furthermore, in situ hybridization analysis exhibited parallel trends of changes in the levels of the GABA(A)R alpha1 and alpha2 subunit and mGluR5 mRNAs in the neurons of the brain regions with that of the proteins detected by the binding assay. A number of the rats 5 weeks postlesion were transplanted with the ventral mesencephalon of the embryonic rat into their left striata. Five weeks later, the changes in the [3H]flunitrazepam binding seemed to be recovered by approximately 50-63% on the grafted sides of the areas. Moreover, the transplantation appeared to produce a nearly complete reversal of the lesion-induced alterations in the levels of the mRNAs. Thus, the data indicate the mechanism of gene regulation for the modified expression of the receptors and could implicate the participation of the receptors in the pathogenesis of Parkinson's disease.