Home   About Us   eMedicine Search   Drug Development   Feedback   Google Scholar Search   Intranet 
Literature Database   News   Photo Gallery   Publications   Site Map   Site Search   Useful Links 
 

Dopamine References: 2003

(917 References)

(2003). "[Parkinson disease: effective treatment of sleep disturbances]." Fortschr Neurol Psychiatr 71(1): 2 p following 54.

(2003). "Aripiprazole (Abilify) for schizophrenia." Med Lett Drugs Ther 45(1150): 15-6.

Acar, N., J. M. Chardigny, et al. (2003). "Modification of the dopaminergic neurotransmitters in striatum, frontal cortex and hippocampus of rats fed for 21 months with trans isomers of alpha-linolenic acid." Neurosci Res 45(4): 375-82.

            Deficiency in n-3 fatty acids is known to disturb the release of dopaminergic neurotransmitters in rat brain. Since isomerization reduces the bioavailability of dietary fatty acids, the effect of the conversion of alpha-linolenic acid into trans alpha-linolenic acid on the dopaminergic neurotransmission was studied. Rats were fed for 21 months with a control diet, a diet unbalanced in cis alpha-linolenic acid and containing trans alpha-linolenic acid or the same diet in which the imbalance was corrected by increasing the levels of cis alpha-linolenic acid. After 6 and 21 months of diet, the fatty acid composition and the amounts of endogenous dopaminergic neurotransmitters was assessed in the striatum, the frontal cortex and the hippocampus. The isomerization of a part of dietary alpha-linolenic acid induced some modifications of the levels of endogenous dopaminergic neurotransmitters in all brain areas but was related to a very low incorporation of trans polyunsaturated fatty acids. Increasing the dietary levels of cis alpha-linolenic acid succeeded in correcting the endogenous neurotransmitter concentrations only in the frontal cortex but not in the striatum and the hippocampus. Thus, the levels of dopamine were lowered by 95% in the hippocampus. These results suggest that in addition to the imbalance generated by their presence, trans fatty acids may directly act on the concentration of dopaminergic neurotransmitters.

Acerbo, M. J., B. Hellmann, et al. (2003). "Catecholaminergic and dopamine-containing neurons in the spinal cord of pigeons: an immunohistochemical study." J Chem Neuroanat 25(1): 19-27.

            Within the different species belonging to the vertebrate radiation, catecholaminergic elements of the spinal cord present a partly conservative, partly variable pattern. Unfortunately, the overall picture is far from clear since the situation for birds is largely obscure. Therefore, we examined the distribution of dopamine (DA)- and tyrosine hydroxylase (TH)-positive cells and fibers in the spinal cord of the adult pigeon by immunohistochemistry. TH-immunoreactive cells were located within two restricted areas. One group of cells with multipolar shape was located in laminae VI and VII, close to the white-gray border. These cells were more frequently found at rostral and caudal levels while being scarce at cervical-thoracic levels. The second group of cells was located in lamina VIII surrounding the central canal. These cells were bipolar in shape and were found ventrally and laterally to the central canal, with most of them contacting the lumen of the canal through a separate process. The TH-immunoreactive fibers were distributed in both the gray and the white matter. In the gray matter, they were mainly distributed around the central canal (lamina VIII), in the ventral horn close to the border of laminae VII-IX and in the lateral part of the dorsal horn in laminae II-VI. In the white matter the fibers were present in the lateral columns running longitudinal to the main axis. DA-immunoreactive cells were also located within two restricted areas, closely matching the distribution of TH-immunopositive ones. Additionally, the DA-immunoreactive cells had the same shape as the TH-immunoreactive cells, as bipolar neurons contacted the central canal and multipolar ones were located in the laminae VI and VII. Also the distribution of DA- and TH-immunoreactive fibers roughly matched. Both, DA-immunoreactive cells and fibers were scarcer than TH-immunoreactive ones. This finding suggests that the catecholaminergic system in the spinal cord consists of DA-immunoreactive cells as well as other catecholaminergic cells.

Adachi, K., M. Hasegawa, et al. (2003). "The superior colliculus contains a discrete region involved in the control of jaw movements: role of GABA(A) receptors." Eur J Pharmacol 464(2-3): 147-154.

            The role of GABA(A) receptors in the superior colliculus in the production of rat repetitive jaw movements was examined, as this nucleus receives tonic GABAergic inhibitory inputs from the dorsolateral part of the substantia nigra pars reticulata and the entopeduncular nucleus. Both regions are also connected with the ventrolateral striatum where stimulation of either dopamine or acetylcholine receptors has been found to elicit distinct types of jaw movements in rats. The GABA(A) receptor antagonist bicuculline (50 and 150 ng/0.2 &mgr;l per side) dose-dependently produced repetitive jaw movements only when injected bilaterally into a circumscribed region (A 3.0) of the lateral deeper layers of the superior colliculus; this region is known to receive input predominantly from the dorsolateral part of the substantia nigra pars reticulata. The effects of bicuculline were GABA(A) receptor specific because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz azepine-7,8-diol (SKF 82958; 5 &mgr;g) and quinpirole (10 &mgr;g), agonist at dopamine D1 and D2 receptors, respectively, or carbachol (2.5 &mgr;g), an acetylcholine receptor agonist, into the ventrolateral striatum. Nevertheless, injection of muscimol into the lateral deeper layers of the superior colliculus (A 3.0) inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation. Conversely, the jaw movements evoked by acetylcholine receptor stimulation were enhanced by injection of muscimol into the superior colliculus. In conclusion, GABA(A) receptor blockade in a circumscribed region (A 3.0) of the lateral deeper layers of the superior colliculus elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region modulate the dopamine D1/D2 receptor-mediated and acetylcholine receptor-mediated jaw movements in an opposite manner.

Adachi, Y. U., Y. Aramaki, et al. (2003). "Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release in the rat striatum." Neurochem Int 43(2): 113-119.

            The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200&mgr;gkg(-1) haloperidol (D(2) receptor antagonist), 10mgkg(-1) sulpiride (D(2) and D(3) antagonist), or 10mgkg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia.Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.

Adachi, H., Y. Sato, et al. (2003). "Direct evidence of facilitative actions of dopamine in the medial preoptic area on reflexive and noncontact erections in male rats." J Urol 169(1): 386-9.

            PURPOSE: We examined the effects of alterations of the extracellular dopamine level in the medial preoptic area on 2 erectile contexts, namely reflexive and noncontact erections, in male rats. MATERIALS AND METHODS: The extracellular dopamine level was measured in the medial preoptic area after administering the dopamine reuptake inhibitor bupropion hydrochloride (Sigma Chemical Co., St. Louis, Missouri) into the same area through a micro-dialysis tube. We measured the frequency and latency of reflexive erections, and the frequency of noncontact erection during infusion of bupropion. RESULTS: Administration of 10 mM. bupropion was associated with significant elevation in the extracellular dopamine level in the medial preoptic area. Bupropion (1 mM.) and Ringer's solution did not induce significant alterations in dopamine in the medial preoptic area. The number of reflexive erections significantly increased and erection latency decreased during infusion of 10 mM. bupropion into the medial preoptic area. The number of noncontact erections was also increased by administering 10 mM. of drug. CONCLUSIONS: The altered dopamine level in the medial preoptic area affected 2 distinct penile erectile contexts, suggesting that the dopamine levels in the medial preoptic area may be involved in the regulation of erection. These results may have important implications for the central regulation of penile erection.

Adamou, M. and A. S. Hale (2003). "Erotomania induced by venlafaxine: a case study." Acta Psychiatr Scand 107(4): 314-7.

            Adamou M, Hale AS. Erotomania induced by venlafaxine: a case study. Acta Psychiatr Scand 2003: 107: 314-317. Copyright Blackwell Munksgaard 2003. OBJECTIVE: To describe a never previously reported case of erotomania induced by venlafaxine and highlight the effect of antidepressants on the dopaminergic system. METHOD: A case of erotomania is described. RESULT: Erotomania occurring in two separate occasions developed after treatment with high doses of venlafaxine. The episode remitted only after lowering the dose of the venlafaxine. CONCLUSION: Erotomania may occur with agents such as antidepressants. The dopamine neurotransmission of mood can provide further evidence for the development of newer classes of antidepressants.

Adams, D. H., G. R. Hanson, et al. (2003). "Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA in rat striatal patch and matrix." J Neurochem 84(1): 87-93.

            We and others previously reported that equimolar doses of methamphetamine and cocaine differentially increase preprodynorphin mRNA in striatum: methamphetamine causes a patchy increase, whereas cocaine produces a more homogenous one. The current study directly examined whether this effect reflects differential induction in the patch-matrix division of striatum, as identified by micro opioid receptor immunohistochemistry. In addition, we determined whether doses of cocaine (30 mg/kg) and methamphetamine (2 mg/kg) that produced equivalent increases in extracellular dopamine differentially affected preprodynorphin mRNA expression in striatum of male, Sprague-Dawley rats. In both experiments, methamphetamine and cocaine differentially affected preprodynorphin mRNA in striatum after 3 h. The high, equimolar dose of methamphetamine selectively increased preprodynorphin mRNA in the patch division of rostral striatum, whereas cocaine increased preprodynorphin mRNA throughout patch and matrix divisions of striatum. In contrast, a dose of methamphetamine (2.0 mg/kg) that caused an increase in extracellular dopamine similar to that produced by 30 mg/kg cocaine did not significantly affect preprodynorphin mRNA in any region of striatum. These data provide further evidence that cocaine and amphetamines exert distinct effects on the patch-matrix division of striatum and suggest further that the post-synaptic consequences of elevated extracellular dopamine produced by methamphetamine and cocaine are distinct.

Adir, Y. and J. I. Sznajder (2003). "Regulation of lung edema clearance by dopamine." Isr Med Assoc J 5(1): 47-50.

            In the kidney, dopamine inhibits Na,K-ATPase, which results in natriuresis because less Na+ is reabsorbed by the proximal and distal tubules. In contrast, dopamine stimulates Na,K-ATPase activity in the alveolar epithelium, leading to increased alveolar fluid reabsorption. Importantly, dopamine increases alveolar fluid reabsorption not only in normal alveolar epithelium but also in models of lung injury. Dopamine short-term regulation of alveolar epithelial Na,K-ATPase occurs via D1 receptor activation, protein kinase C and protein phosphatase 2A pathways, leading to increased Na,K-ATPase activity by recruiting sodium pumps from the intracellular compartment to the basolateral membranes. Conversely, D2 receptor activation by long-term dopamine regulates (approximately 24 hours) alveolar epithelial Na,K-ATPase via the MAPK pathway, [figure: see text] which results in de novo synthesis of Na,K-ATPase proteins. Conceivably, by increasing Na,K-ATPase activity and promoting alveolar fluid reabsorption, dopamine can be of clinical relevance for the treatment of patients with acute hypoxemic respiratory failure due to pulmonary edema.

Agartz, I., S. Shoaf, et al. (2003). "CSF monoamine metabolites and MRI brain volumes in alcohol dependence." Psychiatry Res 122(1): 21-35.

            Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepinephrenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures.

Agid, Y., I. Arnulf, et al. (2003). "Parkinson's disease is a neuropsychiatric disorder." Adv Neurol 91: 365-70.

Agmo, A. (2003). "Lack of opioid or dopaminergic effects on unconditioned sexual incentive motivation in male rats." Behav Neurosci 117(1): 55-68.

            The effects of dopaminergic and opioidergic drugs on sexual incentive motivation were evaluated in sexually inexperienced male rats subjected to a choice procedure. Various parameters of ambulatory activity were recorded as well. Two drugs stimulating dopaminergic neurotransmission, amphetamine and apomorphine, failed to affect sexual incentive motivation, although ambulatory activity was enhanced by amphetamine. The dopamine antagonist cis(Z)-flupenthixol reduced sexual incentive motivation, but only at a dose that severely disrupted motor function. Morphine had marginal effects on sexual motivation but reduced ambulatory activity. These effects were not reduced by a peripheral opioid antagonist, methylnaloxone. Loperamide, a peripheral opioid agonist, reduced sexual motivation through an opioid-independent action. Naloxone was ineffective. Neither dopamine nor opioids seem to be important for sexual incentive motivation.

Ahlskog, J. E. (2003). "Slowing Parkinson's disease progression: recent dopamine agonist trials." Neurology 60(3): 381-9.

            In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.

Ahn, S. and A. G. Phillips (2003). "Independent modulation of basal and feeding-evoked dopamine efflux in the nucleus accumbens and medial prefrontal cortex by the central and basolateral amygdalar nuclei in the rat." Neuroscience 116(1): 295-305.

            Interactions of the central and basolateral nuclei of the amygdala with the mesocorticolimbic dopamine system are implicated in the acquisition and performance of conditioned responses for food reward. This study investigated whether dopamine transmission in the nucleus accumbens and the medial prefrontal cortex of the rat is influenced by the amygdala and if so, to assess the significance of the interaction in free feeding of a palatable food. To this end, we examined the effects of reverse-dialysis of the sodium channel blocker lidocaine into either the central or basolateral on dopamine efflux in the nucleus accumbens and the medial prefrontal cortex as determined by microdialysis and high-pressure liquid chromatography with electrochemical detection. The present results revealed for the first time that inactivation of the central decreased basal levels of dopamine efflux in the nucleus accumbens, but not in the medial prefrontal cortex. Furthermore, administration of lidocaine into the central significantly attenuated feeding-evoked increases in dopamine efflux in both terminal regions. These neurochemical effects were accompanied by feeding-related behaviours akin to the Kluver-Bucy syndrome. In contrast, inactivation of the basolateral affected neither food intake nor dopamine efflux in the nucleus accumbens, but triggered dramatic long-lasting oscillations in dopamine efflux in the medial prefrontal cortex, irrespective of whether food was presented or not. Overall, these findings indicate that the central and basolateral independently modulate dopamine transmission in both terminal regions of the mesocorticolimbic dopamine system. The central, in particular, and its influence on the dopamine system, may be involved in the regulation of food intake.

Akil, M., B. S. Kolachana, et al. (2003). "Catechol-o-methyltransferase genotype and dopamine regulation in the human brain." J Neurosci 23(6): 2008-13.

            A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.

Akpinar, S. (2003). "The primary restless legs syndrome pathogenesis depends on the dysfunction of EEG alpha activity." Med Hypotheses 60(2): 190-8.

            A dopaminergic drug - lisuride exhibited increase in alpha, decrease in beta and slow activities on brain function measured by computerized EEG. It was postulated that reverse EEG changes might play role in the pathogenesis of RLS. During transition from wakefulness to sleep stage 1 changes in alpha activity initiate long-lasting alpha arousal responses and they continue increasingly at sleep stage 2. This dysfunction is probably due to a genetic vulnerability of EEG alpha rhythm and disinhibits the diencephalospinal dopamine system, mostly during sleep but also during wakefulness. The disinhibition produces background for activation of PLMs, disturbing sensations in brainstem and urge to move, motor restlessness at cerebral cortex, generally for legs. All lead to severe insomnia. In RLS patients, forced deviations from alpha to theta or beta activity are unsuitable and resting EEGs reflect a dopamine receptor-specific 'individual sensitivity.' This vulnerability is alleviated after lisuride with suitable CEEG changes.

Albin, R. L. and K. A. Frey (2003). "Initial agonist treatment of Parkinson disease: a critique." Neurology 60(3): 390-4.

            The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.

Alcayaga, J., M. Retamal, et al. (2003). "Dopamine inhibits ATP-induced responses in the cat petrosal ganglion in vitro." Brain Res 966(2): 283-7.

            The petrosal ganglion (PG) provides sensory innervation to the carotid sinus and carotid body through the carotid (sinus) nerve (CN). Application of either acetylcholine (ACh) or adenosine 5'-triphosphate (ATP) to the PG superfused in vitro activates CN fibers. Dopamine (DA) modulates the effects of ACh. We have previously shown that DA when applied to the PG modulates the effects of ACh on carotid sinus nerve fibers. We currently report the effects of DA on the ATP-induced responses in the isolated PG in vitro. While DA had no effect on the basal activity recorded from the CN, it reduced ATP-induced responses in a dose-dependent manner, when preceding ATP applications by 30 s. Our results suggest that DA-a transmitter present in a group of PG neurons and in carotid body cells-may act as an inhibitory modulator of ATP-evoked responses in PG neurons.

Allen, B. S., J. S. Veluz, et al. (2003). "Deep hypothermic circulatory arrest and global reperfusion injury: Avoidance by making a pump prime reperfusate-A new concept." J Thorac Cardiovasc Surg 125(3 Pt 1): 625-32.

            OBJECTIVE: We sought to determine whether damage after deep hypothermic circulatory arrest can be diminished by changing pump prime components when reinstituting cardiopulmonary bypass. METHODS: Fifteen piglets (2-3 months old) were cooled to 19 degrees C by using the alpha-stat pH strategy. Five were cooled and rewarmed without ischemia (control animals), and the other 10 piglets underwent 90 minutes of deep hypothermic circulatory arrest. Of these, 5 were rewarmed and reperfused without altering the cardiopulmonary bypass circuit blood prime. In the other 5 animals, the bypass blood prime was modified (leukocyte depleted, hypocalcemic, hypermagnesemic, pH-stat, normoxic, mannitol, and an Na(+)/H(+) exchange inhibitor) during circulatory arrest before starting warm reperfusion. Oxidant injury was assessed on the basis of conjugated dienes, vascular changes on the basis of endothelin levels, myocardial function on the basis of cardiac output and dopamine need, lung injury on the basis of pulmonary vascular resistance and oxygenation, and cellular damage on the basis of release of creatine kinase and aspartate aminotransferase. Neurologic assessment (score 0, normal; score 500, brain death) was done 6 hours after discontinuing cardiopulmonary bypass. RESULTS: Compared with animals undergoing cardiopulmonary bypass without ischemia (control animals), deep hypothermic circulatory arrest without modification of the reperfusate produced an oxidant injury (conjugated dienes increased 0.78 vs 1.71 absorbance (Abs) 240 nmol/L per 0.5 mL, P <.001 vs control animals), depressed cardiac output (6.0 vs 4.0 L/min, P <.05 vs control subjects), prolonged dopamine need (P <.001 vs control subjects), elevated pulmonary vascular resistance (74% vs 197%, P <.05 vs control subjects), reduced oxygenation (P <.01 vs control subjects), increased neurologic injury (56 vs 244, P <.001 vs control subjects), and increased release of creatine kinase (2695 vs 6974 U/L, P <.05 vs control subjects), aspartate aminotransferase (144 vs 229 U/L), and endothelin (1.02 vs 2.56 pg/mL, P <.001 vs control subjects). Conversely, the oxidant injury was markedly limited (conjugated dienes of 0.85 +/- 0.09 Abs 240 nmol/L per 0.5 mL, P <.001 vs unmodified pump prime) with modification of cardiopulmonary bypass prime, resulting in increased cardiac output (5.1 +/- 0.8 L/min), minimal dopamine need (P <.001 vs unmodified pump prime), no increase in pulmonary vascular resistance (44% +/- 31%, P <.01 vs unmodified pump prime) or endothelin levels (0.64 +/- 0.15 pg/mL, P <.001 vs unmodified pump prime), complete recovery of oxygenation (P <.01 vs unmodified pump prime), reduced neurologic damage (144 +/- 33, P <.05 vs unmodified pump prime), and lower release of aspartate aminotransferase (124 +/- 23 U/L, P <.05 vs unmodified pump prime) and creatine kinase (3366 +/- 918, P <.05 vs unmodified pump prime). CONCLUSIONS: A global reperfusion injury after deep hypothermic circulatory arrest was identified and changed. The injury is mediated by oxygen-derived free radicals, resulting in organ and endothelial dysfunction. Modification of global organ and endothelial damage is achieved by modifying the blood prime in the cardiopulmonary bypass circuit to deliver a controlled global reperfusate when reinstituting bypass.

Allen, J. F. (2003). "Superoxide as an obligatory, catalytic intermediate in photosynthetic reduction of oxygen by adrenaline and dopamine." Antioxid Redox Signal 5(1): 7-14.

            The superoxide anion radical is known to be the first product of photosynthetic reduction of oxygen mediated by a variety of electron carriers. The effectiveness of many of these electron carriers as herbicides, and the toxicity of the superoxide they produce, have been suggested to rule out oxygen reduction as a physiological component of normal photosynthesis. Here results with isolated spinach chloroplasts are presented that demonstrate that the related catecholamines adrenaline and dopamine mediate photosynthetic reduction of oxygen. Complete inhibition by added superoxide dismutase of light-dependent oxygen uptake by isolated chloroplasts and of the electron transport it supports indicates that superoxide is an obligatory catalytic intermediate, not a product, in adrenaline- and dopamine-mediated oxygen reduction. These compounds might function as chemical analogues of a proposed natural mediator, or oxygen-reducing factor, that allows oxygen reduction to participate in energy transduction in photosynthesis. The identity of the putative natural mediator and the role of oxygen reduction in photosynthesis are discussed. The fully oxidized form of adrenaline, adrenochrome, also acts as a mediator of photosynthetic oxygen uptake, but only by reducing oxygen to superoxide.

Allen, D. D., P. R. Lockman, et al. (2003). "Active transport of high-affinity choline and nicotine analogs into the central nervous system by the blood-brain barrier choline transporter." J Pharmacol Exp Ther 304(3): 1268-74.

            Cigarette smoking is strongly implicated in the development of cardiovascular disorders. Recently identified nicotinium analogs may have therapeutic benefit as smoking cessation therapies but may have restricted entry into the central nervous system by the blood-brain barrier (BBB) due to their physicochemical properties. Using the in situ perfusion technique, lobeline, choline, and nicotinium analogs were evaluated for binding to the BBB choline transporter. Calculated apparent K(i) values for the choline transporter were 1.7 microM N-n-octyl choline, 2.2 microM N-n-hexyl choline, 27 microM N-n-decylnicotinium iodide, 31.9 microM N-n-octylpyridinium iodide, 49 microM N-n-octylnicotinium iodide (NONI), 393 microM lobeline, and >/=1000 microM N-methylnicotinium iodide. Nicotine and N-methylpyridinium iodide, however, do not apparently interact with the BBB choline transporter. Given NONI's apparent K(i) value determined in this study and its ability to inhibit nicotine-evoked dopamine release from superfused rat brain slices, potential brain entry of NONI via the BBB choline transporter was evaluated. [(3)H]NONI exhibited a BBB transfer coefficient value of approximately 1.6 x 10(-3) ml/s/g and a K(m) of approximately 250 microM. Unlabeled choline addition to the perfusion fluid reduced [(3)H]NONI brain uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI facilitates brain entry via the BBB choline transporter. Thus, NONI may have utility as a smoking cessation agent, given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally, and to be distributed to brain via the BBB choline transporter.

Alleweireldt, A. T., K. F. Kirschner, et al. (2003). "D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats." Psychopharmacology (Berl).

            RATIONALE. Dopamine D1-receptor antagonists and agonists both attenuate cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) elicited by a cocaine prime or cocaine-paired stimuli. It remains unclear whether these effects are D1-receptor mediated. OBJECTIVES. The present study tested whether a D1 antagonist (SCH-23390) would reverse the attenuating effects of a D1 agonist (SKF-81297) on cocaine-seeking behavior and whether behavioral disruption is involved in these effects. METHODS. Rats trained to press a lever for cocaine reinforcement with light and tone cues paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e., neither cocaine nor the cocaine-paired stimulus complex was available). After responding diminished, the effects of the D1 antagonist on the dose-response functions of the D1 agonist for reinstatement of cocaine-seeking behavior by response-contingent cue presentations or cocaine priming were examined. A separate experiment assessed the effects of the agonist on the dose-response function of the antagonist for cue reinstatement. Stereotyped behavior and activity were also measured during each test session. RESULTS. The attenuating effects of SKF-81297 on cocaine-seeking behavior during cocaine-primed reinstatement were reversed by co-administration of SCH-23390. However, no evidence for reversal of the attenuation during cue reinstatement was found even though agonist-induced stereotypy and antagonist-induced hypoactivity were reversed by co-administration of the two drugs during the same test session. CONCLUSIONS. The findings suggest that the attenuating effects of D1-receptor drugs on cocaine-seeking behavior during cocaine reinstatement are mediated by dopamine D1 receptors; however, it remains unclear whether the effects of these drugs on cocaine-seeking behavior during cue reinstatement are D1-receptor mediated. Nevertheless, it is evident that the attenuation of cocaine-seeking behavior by these drugs is not simply due to behavioral disruption.

Alvaro, J. D., J. R. Taylor, et al. (2003). "Molecular and behavioral interactions between central melanocortins and cocaine." J Pharmacol Exp Ther 304(1): 391-9.

            Behavioral and molecular studies have established a link between drugs of abuse and the central melanocortin system, particularly the melanocortin 4 receptor (MC4-R). The present study expands this line of investigation to characterization of the neurochemical and behavioral interactions between MC4-R and the psychomotor stimulant, cocaine. The results demonstrate that repeated, but not acute, cocaine administration up-regulates MC4-R mRNA expression in the striatum and hippocampus, but not cerebral cortex. Pharmacological studies indicate that the up-regulation of MC4-R expression occurs via dopamine D1 and D2 receptor-dependent mechanisms. The D1/D2 antagonist haloperidol and the D2-selective antagonist eticlopride mimic the effect of cocaine on MC4-R expression. In addition, coadministration of a D1-selective antagonist, SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine], completely blocks the up-regulation of MC4 mRNA by cocaine, demonstrating that D1 receptor activation is necessary for this response. Moreover, the results demonstrate that cocaine treatment increases behavioral responses (grooming and locomotor activity) to infusions of a melanocortin agonist, indicating that up-regulation of MC4-R expression results in functional consequences. These data further support a role for the melanocortin-MC4-R neuropeptide system in the biochemical and behavioral effects of cocaine.

Anchordoquy, H. C., C. McGeary, et al. (2003). "Genotyping of three candidate genes after whole-genome preamplification of DNA collected from buccal cells." Behav Genet 33(1): 73-8.

            The amount of genomic DNA obtained from buccal cell methods may be suboptimal for large-scale genetics projects, because the quantity of DNA may be insufficient for the number of analyses proposed. Primer extension preamplification (PEP) methods that can amplify the entire genome 100-fold or more, offer a potential solution to this problem. We compared PEP buccal DNA with genomic buccal DNA from 315 individuals from 97 families of the Colorado Longitudinal Twin Study for three loci: the dopamine transporter, dopamine D4 receptor, and serotonin transporter. A total of 1890 genomic and 1890 PEP alleles were assessed, and 1670 comparisons (88%) agreed after a single determination. Fifty-three individuals had one or more failed initial polymerase chain reactions (PCR), with 81 failed PCRs in total, accounting for 162 missing allele calls. The failed PCRs were repeated once, and 146 of the missing allele calls were recovered. Comparisons between genomic and PEP DNA allele calls showed 37 individuals had one or more discrepancies, for a total of 52 inconsistencies. Of these, the initial PEP result was found to be correct in 18 cases, the initial genomic result was found to be correct in 25 cases, and 9 could not be resolved. Overall, rates of true calls, missing data, and genotyping errors for genomic and PEP DNA samples were nearly identical: of the 1890 genotypes assessed, true calls were found in 1845 genomic and 1840 PEP samples, missing genotypes in 18 genomic and 16 PEP samples, and incorrect assignments in 18 genomic and 25 PEP samples. These results suggest that routine whole-genome preamplification of genomic DNA is an appropriate method for providing DNA to genotype these loci.

Andersen, M. L., M. Bignotto, et al. (2003). "Cocaine-induced genital reflexes during paradoxical sleep deprivation and recovery." Physiol Behav 78(2): 255-9.

            Paradoxical sleep deprivation (PSD) for 96 h together with cocaine administration elicits genital reflexes (penile erection [PE] and ejaculation [EJ]) in rats. Our objective was to examine genital reflexes after periods of 24, 48, 72, 96, 120, and 144 h of PSD and during a 4-day recovery period in acute cocaine-administered rats. After 24 h of PSD followed by cocaine administration, animals started to display PE and EJ, peaking in the 96th h of PSD, whereas PE and EJ were absent in control animals. The effects of more than 96 h of PSD decrease genital reflexes as observed after 120 and 144 h. Genital reflexes were present in the recovery periods but diminished gradually during the period evaluated. Even short periods of PSD probably cause supersensitivity of dopamine (DA) receptors and exacerbate the effects of cocaine on dopaminergic pathways to induce frequent PE and EJ.

Andersson, M., J. E. Westin, et al. (2003). "Time course of striatal DeltaFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment." Eur J Neurosci 17(3): 661-6.

            DeltaFosB-like proteins are particularly stable transcription factors that accumulate in the brain in response to chronic perturbations. In this study we have compared the time-course of striatal FosB/DeltaFosB-like immunoreactivity and prodynorphin mRNA expression after discontinuation of chronic cocaine treatment to intact rats and chronic L-DOPA treatment to unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. The animals were killed between 3 h and 16 days after the last drug injection. In both treatment paradigms, the drug-induced FosB/DeltaFosB immunoreactivity remained significantly elevated in the caudate putamen even at the longest withdrawal period examined. The concomitant upregulation of prodynorphin mRNA, a target of DeltaFosB, paralleled the time-course of DeltaFosB-like immunoreactivity in the 6-OHDA-lesion/L-DOPA model, but was more transient in animals treated with cocaine. These results suggest that DeltaFosB-like proteins have exceptional in vivo stability. In the dopamine-denervated striatum, these proteins may exert sustained effects on the expression of their target genes long after discontinuation of L-DOPA pharmacotherapy.

Andrews, Z. B. and D. R. Grattan (2003). "Opioid receptor subtypes involved in the regulation of prolactin secretion during pregnancy and lactation." J Neuroendocrinol 15(3): 227-36.

            Afferent endogenous opioid neuronal systems facilitate prolactin secretion in a number of physiological conditions including pregnancy and lactation, by decreasing tuberoinfundibular dopamine (TIDA) inhibitory tone. The aim of this study was to investigate the opioid receptor subtypes involved in regulating TIDA neuronal activity and therefore facilitating prolactin secretion during early pregnancy, late pregnancy and lactation in rats. Selective opioid receptor antagonists nor-binaltorphimine (kappa-receptor antagonist, 15 micro g/5 micro l), beta funaltrexamine (mu-receptor antagonist, 5 microg/5 microl) and naltrindole (delta-receptor antagonist, 5 microg/5 microl) or saline were administered intracerebroventricularly (i.c.v.) on day 8 of pregnancy during a nocturnal prolactin surge, on day 21 of pregnancy during the ante partum prolactin surge or on day 7 of lactation before the onset of a suckling stimulus. Serial blood samples were collected at regular time intervals, via chronic indwelling jugular cannulae, before and after drug administration and plasma prolactin was determined by radioimmunoassay. TIDA neuronal activity was measured using the 3,4-dihydroxyphenylacetic acid (DOPAC) : dopamine ratio in the median eminence 2 h 30 min after i.c.v. drug injection. In each experimental condition, plasma prolactin was significantly inhibited by both kappa- and mu-receptor antagonists, whereas the delta-receptor antagonist had no effect compared to saline-injected controls. Similarly, nor-binaltorphimine and beta funaltrexamine significantly increased the median eminence DOPAC : dopamine ratio during early and late pregnancy, and lactation whereas naltrindole had no effect compared to saline-injected controls. These data suggest that TIDA neuronal activity, and subsequent prolactin secretion, is regulated by endogenous opioid peptides acting at both kappa- and mu-opioid receptors during prolactin surges of early pregnancy, late pregnancy and lactation.

Anlauf, M., M. K. Schafer, et al. (2003). "Chemical coding of the human gastrointestinal nervous system: Cholinergic, VIPergic, and catecholaminergic phenotypes." J Comp Neurol 459(1): 90-111.

            The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal (GI) tract. For this purpose, antibodies against the vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), serotonin (5-HT), vasoactive intestinal peptide (VIP), and protein gene product 9.5 (PGP 9.5) were used. For in situ hybridization (35)S-labeled VMAT1, VMAT2, and VAChT riboprobes were used. In all regions of the human GI tract, 50-70% of the neurons were cholinergic, as judged by staining for VAChT. The human gut unlike the rodent gut exhibits a cholinergic innervation, which is characterized by an extensive overlap with VIPergic innervation. Neurons containing VMAT2 constituted 14-20% of all intrinsic neurons in the upper GI tract, and there was an equal number of TH-positive neurons. In contrast, DBH was absent from intrinsic neurons. Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes. In conclusion, the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species, but also significant differences. VIP is a cholinergic cotransmitter in the intrinsic innervation of the human gut. The substantial overlap between VMAT2 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life. The absence of DBH from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype. J. Comp. Neurol. 459:90-111, 2003.

Arai, S., K. Morita, et al. (2003). "Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics." Brain Res 964(1): 83-90.

            The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

Arbelle, S., J. Benjamin, et al. (2003). "Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism." Am J Psychiatry 160(4): 671-6.

            OBJECTIVE: Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). METHOD: The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. RESULTS: Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. CONCLUSIONS: This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.

Archer, T. and A. Fredriksson (2003). "An antihypokinesic action of alpha(2)-adrenoceptors upon MPTP-induced behaviour deficits in mice." J Neural Transm 110(2): 183-200.

            The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.

Ashby, F. G., S. Noble, et al. (2003). "Category learning deficits in Parkinson's disease." Neuropsychology 17(1): 115-24.

            Sixteen patients with Parkinson's disease (PD), 15 older controls (OCs), and 109 younger controls (YCs) were compared in 2 category-learning tasks. Participants attempted to assign colored geometric figures to 1 of 2 categories. In rule-based tasks, category membership was defined by an explicit rule that was easy to verbalize, whereas in information-integration tasks, there was no salient verbal rule and accuracy was maximized only if information from 3 stimulus components was integrated at some predecisional stage. The YCs performed the best on both tasks. The PD patients were highly impaired compared with the OCs, in the rule-based categorization task but were not different from the OCs in the information-integration task. These results support the hypothesis that learning in these 2 tasks is mediated by functionally separate systems.

Asif, A., R. A. Preston, et al. (2003). "Radiocontrast-induced Nephropathy." Am J Ther 10(2): 137-47.

            Radiocontrast administration remains the third leading cause of hospital-acquired acute renal failure. Clinically, radiocontrast-induced nephropathy (RIN) is defined as a sudden decline in renal function after radiocontrast administration. Typically, the serum creatinine level begins to increase at 24 to 72 hours after the administration of contrast, peaks at 3 to 5 days, and requires another 3 to 5 days to return to baseline. RIN increases the incidence of life-threatening complications such as sepsis, bleeding, and respiratory failure and increases the cost of medical care by extending the hospital stay. The increased mortality associated with acute renal failure encountered in this scenario calls for a heightened awareness of the diagnosis and prevention of RIN. Whereas individuals with healthy renal function are not generally considered to be at particular risk for RIN, patients with preexisting renal insufficiency and diabetes mellitus are much more likely to experience acute renal failure after contrast administration. In the past, a variety of therapeutic interventions have been used to prevent or attenuate RIN, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, hemodialysis, and dopamine. More recently, studies demonstrate a positive impact of fenoldopam (dopamine-1 receptor, dopamine-1 agonist) and the antioxidant N-acetylcysteine in ameliorating RIN. This article discusses the pathophysiology, risk factors, and prevention of RIN.

Attanasio, R., M. Barausse, et al. (2003). "Raloxifene lowers IGF-I levels in acromegalic women." Eur J Endocrinol 148(4): 443-448.

            BACKGROUND: IGF-I suppression in acromegaly obtained by tamoxifen, a selective estrogen receptor modulator (SERM), prompted us to evaluate the effects of the administration of a newer SERM, raloxifene (RAL), devoid of estrogenic activity at uterine level, on GH/IGF-I levels in patients with this disease. PATIENTS: Thirteen post-menopausal acromegalic women (aged 55-84 Years) with active acromegaly entered a prospective open pilot study of RAL treatment at 60 mg/day. Nine of the patients, who were resistant to somatostatin analog and dopamine agonist treatment, were not undertaking therapy; the other four, who were partially sensitive to medical treatment, maintained treatment at the maximally effective dosages throughout the study. RESULTS: IGF-I levels fell significantly from 444 (median, interquartile 393-590) &mgr;g/l to 300 (216-608) &mgr;g/l (P=0.0192) after 1 Month of RAL administration and this fall remained stable up to the final evaluation at 5+/-1 Months from the start of RAL treatment (260 (187-410) &mgr;g/l). An IGF-I decrease greater than 30% of basal values was observed in 10 patients (mainly in patients with IGF-I levels lower than 600 &mgr;g/l) and normal values were reached in seven (54%). GH levels did not change (basal 6 (4.1-8) &mgr;g/l, final 5.5 (3.2-7.4) &mgr;g/l). The clinical picture improved in patients sensitive to RAL. RAL withdrawal was followed by the return of IGF-I levels to pretreatment values within 8 weeks in all patients. CONCLUSIONS: RAL decreases IGF-I levels in most acromegalic women with mild or intermediate disease (i.e. with values lower than 600 &mgr;g/l) and normalizes it in many. A prospective randomized study in patients resistant or partially sensitive to other medical treatments is warranted.

Auricchio, A., P. D. Acton, et al. (2003). "In vivo quantitative noninvasive imaging of gene transfer by single-photon emission computerized tomography." Hum Gene Ther 14(3): 255-61.

            Systems aimed at detecting gene expression noninvasively in vivo are desirable for evaluating the outcome of gene transfer in clinical trials. Several approaches have been exploited using magnetic resonance imaging and spectroscopy ((31)P MRS), positron emission tomography (PET), single-photon emission tomography (SPECT), and detection of bioluminescent signals. An ideal system is based on transfer of a marker gene, the activity of which can be detected against a background from the target tissue without interfering with normal physiology or eliciting an immune response. The majority of approaches described to date use genes encoding a nonmammalian protein that can elicit immune responses or a transmembrane receptor as a marker gene whose ectopic expression may cause aberrant signaling in the target cell through binding to endogenous ligands. The dopamine transporter (DAT) is normally expressed at high levels, mainly in the dopaminergic neurons of the central nervous system. We previously synthesized a radioactive ligand, [(99m)Tc]TRODAT-1, that binds with high affinity to the dopamine transporter, allowing for SPECT imaging of the striatum in normal control subjects and individuals affected with Parkinson's disease. Here we describe a strategy to monitor gene transfer based on adeno-associated viral vector (AAV)-mediated transduction of DAT in murine muscle followed by [(99m)Tc]TRODAT-1 imaging by SPECT of cells expressing the transgene. We show that quantitative, noninvasive imaging of gene transfer is successfully achieved in vivo, using a single-photon computed tomography camera. This system employs a reporter gene encoding a mammalian protein that is absent in most tissues, has no enzymatic activity, and does not activate intracellular pathways. This should be useful to monitor gene transfer in the settings of gene therapy.

Avshalumov, M. V., B. T. Chen, et al. (2003). "Glutamate-Dependent Inhibition of Dopamine Release in Striatum Is Mediated by a New Diffusible Messenger, H2O2." J Neurosci 23(7): 2744-50.

            How glutamate regulates dopamine (DA) release in striatum has been a controversial issue. Here, we resolve this by showing that glutamate, acting at AMPA receptors, inhibits DA release by a nonclassic mechanism mediated by hydrogen peroxide (H(2)O(2)). Moreover, we show that GABA(A)-receptor activation opposes this process, thereby enhancing DA release. The influence of glutamate and GABA on DA release was assessed in striatal slices using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Modulation by both transmitters was prevented by H(2)O(2)-metabolizing enzymes. In addition, the influence of GABA(A)-receptor activation was lost when AMPA receptors were blocked with GYKI-52466. Together, these data show that modulation of DA release by glutamate and GABA depends on H(2)O(2) generated downstream from AMPA receptors. This is the first evidence that endogenous glutamate can lead to the generation of reactive oxygen species under physiological conditions. We also show that inhibition of DA release by H(2)O(2) is mediated by sulfonylurea-sensitive K(+) channels: tolbutamide blocked DA modulation by glutamate and by GABA. The absence of ionotropic glutamate or GABA receptors on DA terminals indicates that modulatory H(2)O(2) is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H(2)O(2) that must diffuse from postsynaptic sites to inhibit presynaptic DA release via K(+)-channel opening. These findings have significant implications not only for normal striatal function but also for understanding disease states that involve DA and oxidative stress, including disorders as diverse as Parkinson's disease and schizophrenia.

Azorin, J. M. (2003). "[Criteria defining antimanic drugs (psychopharmacological specificity and/or nonspecificity?)]." Encephale 29(Pt 1): 59-67.

            The question as to whether specific antimanic drugs differ in their action profile from nonspecific drugs is addressed in regard to symptomatic, nosographic, regulatory and physiopathological issues. Results from clinical studies have shown that mood stabilizers and typical neuroleptics differ as regards improvement of manic symptoms: the former appear to act more evenly on all symptoms of mania, showing a more total normalization of affect, ideation and behaviour whereas the latter tend to sedate patients or to cause a psychomotor retardation, leaving the core manic symptoms unaffected. This has been many times underlined, in particular for lithium, notwithstanding the fact that rating scales employed in clinical trials have often been charged to fall far short of being sensitive enough to pick up the qualitative changes in manic psychopathology. Antimanic drugs may also be more or less specific in their capacities to treat all facets of the manic episode (psychotic, depressive, irritable) whatever the bipolar subtype (bipolar I, II, rapid and non-rapid cycling, secondary bipolar disorder) or the disease stage (early and late episodes). In this respect divalproate seems to have a broader spectrum of efficacy than other available agents. Newer antipsychotics such as olanzapine are promising too. From a regulatory point of view, the current European requirements for a specific antimanic drug are more stringent than the US requirements of the Food and Drug Administration (FDA). Efficacy must be demonstrated in short-term studies showing an effect in acute mania; moreover it has to be shown that efficacy is to be maintained during the episode. So far, three armed randomized controlled trials are required, in which the test product is compared both with placebo and with a standard treatment. A possible design is a comparison of test product, placebo and active control for 3 weeks followed by a two-arm phase for the remaining 9 weeks, comparing only test product and active control. In addition, a specific antimanic has to demonstrate that it does not cause switching to depression. As regards physiopathology, integrative models of bipolar disorder, ie kindling and behavioural sensitization, offer an exciting perspective on the specificity issue; agents active in these models initialize a cascade of intracellular signaling that leads to changes in the expression of immediate early genes as well as late effector genes in corticolimbic structures: the former may contribute to acute symptomatology whereas the latter give rise to neuroanatomical reorganization which could underlie more stable changes in mood and cognition. Due to their action on intracellular messaging systems, dopamine D(1) receptors, serotonin 5HT(1a) or 5HT(2a) receptors, especially in orbitofrontal circuit, antimanic agents may exhibit a more specific activity than other drugs. This specificity could concern a whole spectrum of bipolarity which might be characterized by impulsivity.

Bai, O., J. Chlan-Fourney, et al. (2003). "Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs." J Neurosci Res 71(1): 127-31.

            Typical and atypical antipsychotic drugs, though both effective, act on different neurotransmitter receptors and are dissimilar in some clinical effects and side effects. The typical antipsychotic drug haloperidol has been shown to cause a decrease in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in neuronal cell survival, differentiation, and neuronal connectivity. However, it is still unknown whether atypical antipsychotic drugs similarly regulate BDNF expression. We examined the effects of chronic (28 days) administration of typical and atypical antipsychotic drugs on BDNF mRNA expression in the rat hippocampus using in situ hybridization. Quantitative analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down-regulated BDNF mRNA expression in both CA1 (P < 0.05) and dentate gyrus (P < 0.01) regions compared with vehicle control. In contrast, the atypical antipsychotic agents clozapine (10 mg/kg) and olanzapine (2.7 mg/kg) up-regulated BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat hippocampus compared with their respective controls (P < 0.01). These findings demonstrate that the typical and atypical antipsychotic drugs differentially regulate BDNF mRNA expression in rat hippocampus.

Bairam, A. and F. Marchal (2003). "Carotid sinus nerve chemosensory response to dopamine and acetylcholine in catecholamine depleted cats." Respir Physiolo Neurobiol 134(1): 1-12.

            The aim of this study was to determine the role of endogenous dopamine (DA) and the combined effect of DA and acetylcholine (ACh) on the carotid sinus nerve chemosensory discharge (CSND). CSND was measured in vivo in 6 control cats and 6 cats pre-treated with reserpine and alpha-methyl-paratyrosine [catecholamine depleted group: CAD] during infusions of DA and DA+ACh. In normoxia, CSND was similar between CAD's and controls. DA induced CSND depression was transient in controls but sustained in CAD's. Addition of ACh increased CSND in both groups. In hypoxia (8% O(2) in N(2)), the dynamic CSND response was slowed by DA in CAD's but not controls. Addition of ACh increased this response in both groups. Neither DA nor DA+ACh altered the steady state hypoxic CSND in either group. It is concluded that endogenous DA is important in expressing the dynamic characteristics of both the response to exogenous DA and the response to hypoxia under constant DA infusion. The study also confirms the opposing effects of exogenous DA and ACh on the normoxic CSND.

Balla, A., H. Sershen, et al. (2003). "Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release." Neuropsychopharmacology 28(1): 34-44.

            Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.

Balle, T., J. Perregaard, et al. (2003). "Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective alpha1 adrenoceptor antagonists." Bioorg Med Chem 11(6): 1065-78.

            A new class of selective alpha(1) adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The most potent and selective compound 1-(2-(4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl)eth yl)-2-imidazolidinone (11) binds with 0.50 nM affinity for alpha(1) adrenergic receptors and with more than 44 times lower affinity for dopamine D(2),D(3), D(4) and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptors. The molecular features providing high affinity for adrenergic alpha(1) receptors and high selectivity towards dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors are discussed.

Balle, T., J. Perregaard, et al. (2003). "Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists." J Med Chem 46(2): 265-83.

            A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1- piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.

Balon, N., J. J. Risso, et al. (2003). "Striatal dopamine release and biphasic pattern of locomotor and motor activity under gas narcosis." Life Sci 72(24): 2731-40.

            Inert gas narcosis is a neurological syndrome appearing when humans or animals are exposed to hyperbaric inert gases (nitrogen, argon) composed by motor and cognitive impairments. Inert gas narcosis induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity. We have investigated, in freely moving rats exposed to different narcotic conditions, the relationship between the locomotor and motor activity and the striatal dopamine release, using respectively a computerized device that enables a quantitative analysis of this behavioural disturbance and voltammetry. The use of 3 MPa of nitrogen, 2 MPa of argon and 0.1 MPa of nitrous oxide, revealed after a transient phase of hyperactivity, a lower level of the locomotor and motor activity, in relation with the decrease of the striatal dopamine release. It is concluded that the striatal dopamine decrease could be related to the decrease of the locomotor and motor hyperactivity, but that other(s) neurotransmitter(s) could be primarily involved in the behavioural motor disturbances induced by narcotics. This biphasic effect could be of major importance for future pharmacological investigations, and motor categorization, on the basic mechanisms of inert gas at pressure.

Bao, S., V. T. Chan, et al. (2003). "Suppression of cortical representation through backward conditioning." Proc Natl Acad Sci U S A 100(3): 1405-8.

            Temporal stimulus reinforcement sequences have been shown to determine the directions of synaptic plasticity and behavioral learning. Here, we examined whether they also control the direction of cortical reorganization. Pairing ventral tegmental area stimulation with a sound in a backward conditioning paradigm specifically reduced representations of the paired sound in the primary auditory cortex (AI). This temporal sequence-dependent bidirectional cortical plasticity modulated by dopamine release hypothetically serves to prevent the over-representation of frequently occurring stimuli resulting from their random pairing with unrelated rewards.

Barber, M., B. S. Kasturi, et al. (2003). "Diabetes-induced neuroendocrine changes in rats: role of brain monoamines, insulin and leptin." Brain Res 964(1): 128-35.

            Diabetes is characterized by hyperphagia, polydypsia and activation of the HPA axis. However, the mechanisms by which diabetes produces these effects are not clear. This study was conducted to examine the effects of diabetes on the neuroendocrine system and to see if treatment with insulin and/or leptin is capable of reversing these effects. Streptozotocin-induced diabetic adult male rats were subjected to the following treatments: vehicle, insulin (2 U/day, s.c.), leptin (100 microg/kg BW) or leptin+insulin every day for 2 weeks. Food intake, water intake, and body weight were monitored daily. We measured changes in monoamine concentrations in discrete nuclei of the hypothalamus at the end of treatment. Diabetes produced a marked increase in food intake and water intake and this effect was completely reversed by insulin treatment and partially reversed by leptin treatment (P<0.05). Diabetes caused an increase in norepinephrine (NE) concentrations in the paraventricular nucleus with a concurrent increase in serum corticosterone. Treatment with insulin and leptin completely reversed these effects. Induction of diabetes also increased the concentrations of NE, dopamine and serotonin in the arcuate nucleus and NE concentrations in the lateral hypothalamus, ventromedial hypothalamus (VMH) and suprachiasmatic nucleus (P<0.05). Although insulin treatment was capable of reversing all these changes, leptin treatment was unable to decrease diabetes-induced increase in NE concentrations in the VMH. These data provide evidence that hypothalamic monoamines could mediate the neuroendocrine effects of diabetes and that insulin and leptin act as important signals in this process.

Bares, M., P. Kanovsky, et al. (2003). "Excessive daytime sleepiness and 'sleep attacks' induced by entacapone." Fundam Clin Pharmacol 17(1): 113-6.

            Three patients with advanced Parkinson's disease, all of whom developed excessive daytime sleepiness and 'sleep attacks' after the administration of entacapone, are described. This is another demonstration that inappropriate daytime sleep episodes are not exclusive to dopamine agonists.

Barrier, L., G. Page, et al. (2003). "Sulfatide and GM1 ganglioside modulate the high-affinity dopamine uptake in rat striatal synaptosomes: evidence for the involvement of their ionic charges." Neurochem Int 42(4): 305-13.

            The present study was undertaken to examine the effects of the anionic glycolipids GM1 ganglioside and sulfatide on the high-affinity dopamine (DA) uptake in rat striatal synaptosomes.After 1h of incubation, GM1 stably bound to synaptosomes and modified the activity of the neuronal dopamine transporter (DAT). With 1.2 and 12 microM GM1, V(max) decreased by 13 and 23%, respectively, reflecting a slight reduction of the number of functional uptake sites and K(m) was lowered by 21 and 33%, thus showing an increase of the affinity. Treatment of synaptosomes with 1.2 microM of sulfatide, which possesses an anionic sulfated group, led to a similar decrease of V(max) (19%) than GM1, but to a significantly higher reduction of K(m) (35%). In fact, sulfatide associated to synaptosomes in a 3.5-fold higher extent than GM1. Conversely, when GM1 and sulfatide were replaced by GM1 alcohol and galactosylceramide, respectively, no modification of the DA uptake occurred, although these neutral glycolipids incorporated into the synaptosomes to the same extent as the related anionic compounds.Altogether, these results demonstrate the key role of negative charges linked to the oligosaccharide chains of glycolipids in the modulation of DA transport across the synaptosomal membrane.

Barrier, L., S. Barc, et al. (2003). "Evidence that acidosis alters the high-affinity dopamine uptake in rat striatal slices and synaptosomes by different mechanisms partially related to oxidative damage." Neurochem Int 42(1): 27-34.

            Several experimental studies have shown that acidosis impairs neurotransmitter uptake processes. The purpose of this study was to determine the mechanism underlying acidosis-induced alterations of the high-affinity dopamine (DA) uptake in rat striatal synaptosomes and slices. Acidosis (pH 5.5) performed either by lactic acid or phosphoric acid induced a decrease in the high-affinity DA uptake in the two striatal models, slices being lesser affected than synaptosomes. Addition of the acid prior to uptake measurement led to a strong reduction of the DA uptake velocity. This early inhibitory effect was completely reversed when acid was removed from the medium by washings. Conversely, when slices and synaptosomes were pre-incubated for different times with each acid, DA uptake remained inhibited in spite of washings. This later inhibition was accompanied by the production of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and was partially prevented by the antioxidant Trolox. Taken together, these results suggest that acidosis, in a degree encountered during ischemia, alters the high-affinity DA uptake by at least two ways: an early and direct effect of H(+) ions on the DA transporters, and subsequently an inhibition partially mediated by free radical damage.

Bartholomeusz, C. F., G. Box, et al. (2003). "The modulatory effects of dopamine D1 and D2 receptor function on object working memory in humans." J Psychopharmacol 17(1): 9-15.

            The role of dopamine D1 and D2 receptors in modulating object working memory in humans is poorly understood. The current study was designed to investigate the effects of D1 and D2 receptor modulation on object working memory. Twelve healthy subjects underwent testing under three conditions (0.05 mg pergolide (D1/D2 receptor agonist), 2.5 mg bromocriptine (D2 receptor agonist) and placebo] in a double-blind, placebo-controlled repeated measures design. Subjects performed the object working memory N-back task pre-drug and 1.5 h and 3 h post-drug administration. Neither pergolide nor bromocriptine had an effect on object working memory performance. These findings suggest that object working memory may not be modulated by D1 and D2 receptors in humans.

Barzilai, A., D. Daily, et al. (2003). "The molecular mechanisms of dopamine toxicity." Adv Neurol 91: 73-82.

Bastia, E. and M. A. Schwarzschild (2003). "DARPP chocolate: a caffeinated morsel of striatal signaling." Sci STKE 2003(165): PE2.

            The psychomotor stimulant effects of caffeine, the most widely consumed psychoactive substance, are mediated through its antagonism of extracellular adenosine receptors in the basal ganglia. In the absence of caffeine, adenosine stimulates inhibitory striatopallidal neurons that suppress motor activity by binding to A2A receptors, thereby activating a cyclic adenosine 3',5'-monophosphate (cAMP) and protein kinase A signaling pathway. Bastia and Schwarzschild discuss recent research implicating DARRP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kilodaltons) as an attractive mediator of the sustained psychomotor stimulant effect seen with low doses of caffeine. They highlight the role of postsynaptic A2A receptor blockade, but leave open the possibility that antagonism of presynaptic or postsynaptic A1 receptors also contributes to DARPP-32-dependent psychomotor stimulation by caffeine.

Baufreton, J., M. Garret, et al. (2003). "D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance." J Neurosci 23(3): 816-25.

            Dopamine is a crucial factor in basal ganglia functioning. In current models of basal ganglia, dopamine is postulated to act on striatal neurons. However, it may also act on the subthalamic nucleus (STN), a key nucleus in the basal ganglia circuit. The data presented here were obtained in brain slices using whole-cell patch clamp. They reveal that D5 dopamine receptors strengthen electrical activity in the subset of subthalamic neurons endowed with burst-firing capacity, resulting in longer discharges of spontaneous or evoked bursts. To distinguish between D1 and D5 subtypes, the action of agonists in the D1/D5 receptor family was first investigated on rat subthalamic neurons. Single-cell reverse transcription-PCR profiling showed that burst-competent neurons only expressed D5 receptors. Accordingly, receptors localized in postsynaptic membranes within the STN were labeled by a D5-specific antibody. Second, agonists in the D1/D5 family were tested in mouse brain slices. It was found that these agonists were active in D1 receptor knock-out mice in a similar way to wild-type mice or rats. This proved that D5 rather than D1 receptors were involved. Pharmacological tools (dihydropyridines, omega-conotoxins, and calciseptine) were used to identify the target of D5 receptors as an L-type channel. This was reached via G-protein and protein kinase A. The action of dopamine on D5 receptors therefore shapes neuronal activity. It contributes to normal information processing in basal ganglia outside striatum. This finding may be useful in drug therapy for various disorders involving changes in STN activity, such as Parkinson's disease and related disorders.

Bauter, M. R., B. J. Brockel, et al. (2003). "Glutamate and dopamine in nucleus accumbens core and shell: sequence learning versus performance." Neurotoxicology 24(2): 227-43.

            This study sought to determine whether neurochemical changes associated with chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the learning impairments also associated with this Pb regimen, and whether core or shell subregions of nucleus accumbens would be more important to such effects. If so, then mimicking these neurochemical changes in normal (control) rats should reproduce these Pb-induced learning impairments. For this purpose, the effects of DA (20-80 microg), the non-competitive NMDA antagonist MK-801 (1.0-2.5 microg) or DA+MK-801 (40+1.0, 80+2.5 microg) were infused in core or shell of nucleus accumbens in normal rats and effects on a multiple schedule of repeated learning (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb exposure, selectively reducing RL accuracy with no corresponding changes in P accuracy, an effect derived from an increased frequency of perseverative errors. DA produced non-specific changes, reducing accuracy levels in RL and P components. Accuracy and rate effects of DA could be reversed by concurrent administration of the higher MK-801 dose. In shell, MK-801, primarily the lower dose, reduced accuracy in both the RL and P components, while DA did not produce any systematic effects. Collectively, these results point to a greater importance of core as compared to shell in the mediation of learning of spatial sequences, and suggest that inhibition of glutamatergic NMDA function may play a critical role in the selective learning impairments associated with chronic low level Pb exposure.

Beard, J., K. M. Erikson, et al. (2003). "Neonatal iron deficiency results in irreversible changes in dopamine function in rats." J Nutr 133(4): 1174-9.

            Iron deficiency in human infants and in young animal models produces changes in neural functioning that may be related to monoamine metabolism. This study employed both behavioral and biochemical approaches in a design using cross-fostering to examine alterations in dopamine (DA) function when iron deficiency occurs during the neonatal period. We measured brain Fe, dopamine transporters (DAT) and dopamine receptor density in rats made iron deficient, or not, from postnatal day (PND) 4 to PND 14 or 21. Some pups were then weaned to an iron-deficient diet and others to the control diet to examine the reversibility of these effects. Behaviors related to dopamine function were measured. Dopamine D(2) receptor (D(2)R), D(1)R and iron concentrations were approximately 70, 80 and 30% of control values, respectively, in the nucleus accumbens and striatum in iron-deficient rats at PND 14. The DAT density was also reduced to 50% of control density in the nucleus accumbens but was unchanged in the striatum. By PND 21, there was also a significant 50% lowering of DAT, D(1)R and D(2)R densities in the prefrontal cortex (PFC). Iron repletion at PND 21-49 normalized D(1)R, D(2)R, and DAT levels in the nucleus accumbens, PFC and ventral midbrain but not in the striatum. In summary, neonatal iron deficiency is associated with changes in DA biology that vary with duration of iron deficiency, and are not completely normalized despite replenishment of iron status. Changes in DA-related behaviors that were persistent after postweaning iron repletion suggest the existence of a critical neonatal developmental period that is expressed by alterations in DA functioning.

Behrens, S. and K. Sommerville (2003). "Non-oral drug delivery in Parkinson's disease: a summary from the symposium at the 7th International Congress of Parkinson's Disease and Movement Disorders." Expert Opin Pharmacother 4(4): 595-9.

            This symposium reviewed the issues of non-oral therapy in the late stage Parkinson's disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy.

Bello, N. T., K. L. Sweigart, et al. (2003). "Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter." Am J Physiol Regul Integr Comp Physiol 284(5): R1260-8.

            Recent studies suggest that the mesoaccumbens dopamine system undergoes neurochemical alterations as a result of restricted feeding conditions with access to sugars. This effect appears to be similar to the neuroadaptation resulting from drugs of abuse and may underlay some pathological feeding behaviors. To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats. The restricted feeding regimen consisted of daily limited access to either a normally preferred sucrose solution (0.3 M) or a less preferred chow in a scheduled (i.e., contingent) fashion for 7 days. Restricted-fed rats with the contingent sucrose access lost less body weight, ate more total food, and drank more fluid than free-fed, contingent food, or noncontingent controls. In addition, these animals had selectively higher DAT binding in the nucleus accumbens and ventral tegmental area. This increase in protein binding also was accompanied by an increase in DAT mRNA levels in the ventral tegmental area. In contrast to the restricted-fed groups, no differential effect in DAT regulation was observed across free-fed groups. The observed alteration in behavior and DAT regulation suggest that neuroadaptation in the mesoaccumbens dopamine system develops in response to repeated feeding on palatable foods under dietary constraints. This supports the notion that similar cellular changes may be involved in restrictive eating disorders and bingeing.

Ben, J. (2003). "Prolactin Regulation by Heparin-Binding Growth Factors Expressed in Mouse Pituitary Cell Lines." Endocrine 20(1-2): 35-44.

            Prolactin (PRL) secretion is regulated by both inhibitory and stimulatory factors. Dopamine is the primary inhibitor, but multiple factors stimulate PRL gene expression and release. These can be divided into two categories: those that rapidly stimulate PRL release and those that induce the PRL gene followed by increased release. The pituitary intermediate lobe (IL) contains a PRL-releasing factor (PRF) that rapidly stimulates PRL release. From a mouse IL tumor, we established a nonmelanotroph cell line, mIL5, which secretes a factor that stimulated PRL gene expression and release in vitro. This PRF activity did not rapidly stimulate PRL release and bound to heparin. Our objective was to examine the regulation of PRL by heparin-binding proteins and characterize the PRF activity produced by mIL5 cells. PRL gene expression and release was determined using GH3 cells, stably transfected with a PRL promoter/luciferase reporter (GH(3)/luc). After screening mIL5 cells by reverse transcriptase polymerase chain reaction, we found that they expressed two heparin-binding growth factors basic fibroblast growth factor (FGF-2) and heparin-binding epidermal growth factor (HB-EGF) which were considered strong candidates for PRL transcriptional regulatory activity. To determine whether the activity produced by mIL5 cells is attributed to FGF-2 or HB-EGF, three approaches were used: heparin-affinity chromatography, Western blotting, and immunoneutralization. The PRF activity in conditioned media eluted from heparin with 1 M NaCl whereas both FGF- 2 and HB-EGF eluted with >1 M NaCl. Neither growth factor was detectable in mIL5 cells by Western blotting. Antibodies directed against FGF-2 and HB-EGF, alone or together, did not abolish this activity from mIL5 cells. In conclusion, FGF-2 and HB-EGF are potent stimulators of PRL gene expression and release but do not account for most of the endogenous PRL gene activity in mIL5 cells. The distinct heparin-binding factor that stimulates PRL gene transcription remains to be identified.

Ben-Shlomo, A., I. Miklovsky, et al. (2003). "Leukemia inhibitory factor regulates prolactin secretion in prolactinoma and lactotroph cells." J Clin Endocrinol Metab 88(2): 858-63.

            Leukemia inhibitory factor (LIF) stimulates the hypothalamic-pituitary-adrenal axis, and transgenic mice overexpressing pituitary LIF develop Cushing-like syndrome accompanied by reduced prolactin (PRL) expression. Effects of LIF were, therefore, tested on PRL expression in human prolactinomas and normal and tumorous rat lactotrophs. Normal human pituitary tissue expressed LIF, as well as the LIF receptor (LIFR) signaling subunits, gp130 and LIFR. Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA. All of four prolactinomas had no detectable LIF immunoreactivity, in contrast to all other pituitary tumor types that expressed LIF. LIF (5 nM) treatment reduced PRL secretion in primary human prolactinoma cultures by up to 42% (P < 0.0005), an effect that was surprisingly blocked by sulpiride, a D2-like dopamine receptor antagonist. LIF (5 nM) also suppressed PRL levels in primary rat pituitary cultures by 70% (P < 0.005), and in rat MMQ pituitary tumor cells, and this effect was also reversed by sulpiride (200 micro M). D2R agonist suppression of PRL was not additive with LIF. GH levels in these cells were unchanged by LIF, consistent with a selective effect on PRL. Transfection of human long-form D2R into an LIF-resistant MMQ cell clone restored LIF responsiveness. These results show that even though human prolactinomas express gp130 and LIFR, and respond to exogenous LIF, albeit less than normal lactotrophs, they are largely devoid of LIF. These observations indicate a role for LIF in loss of autocrine PRL suppression contributing to unrestrained prolactinomas PRL secretion. Moreover, PRL suppression by LIF may be mediated by gp130 and D2R interaction.

Benavides, S., K. Nicol, et al. (2003). "Yersinia septic shock following an autologous transfusion in a pediatric patient." Transfus Apheresis Sci 28(1): 19-23.

            Although the literature on infections transmitted via transfused blood focuses on viruses, Yersinia enterocolitica can also cause severe infections in patients receiving transfusions. A 13-year-old patient developed severe sepsis after an autologous blood transfusion contaminated with Y. enterocolitica. The patient was an otherwise healthy female undergoing posterior spinal fusion for congenital scoliosis. Prior to surgery, the patient donated blood for perioperative and postoperative use. A few days before the donation, she had complained of abdominal pain and was experiencing mild diarrhea. The patient received four units of packed red blood cells (PRBCs) during the surgery. Intraoperatively, the patient developed fever up to 103.6 degrees F, became hypotensive requiring epinephrine and dopamine, and developed metabolic acidosis with serum bicarbonate concentration dropping to 16 mmol/l. The surgery team believed the patient was experiencing malignant hyperthermia and attempted to cool patient during the procedure. Postoperatively, the patient was transferred to the pediatric intensive care unit and treated for severe shock of unknown etiology. The patient further developed disseminated intravascular coagulation. The patient received supportive care and was started on ampicillin/sulbactam on postoperative day (POD) one which was changed to clindamycin, ciprofloxacin and tobramycin on POD two when blood cultures grew gram-negative bacilli. On POD three, cultures were identified as Y. enterocolitica and antibiotics were changed to tobramycin and cefotaxime based on susceptibility data. Sequelae of the shock included adult respiratory distress syndrome requiring intubation and a tracheostomy and multiple intracranial hemorrhagic infarcts with subsequent seizure disorder. Due to severe lower extremity ischemia, she required a bilateral below the knee amputation. The cultures of the snippets from the bags of blood transfused to the patient also grew Y. enterocolitica. This case illustrates the importance of considering transfusion related bacterial infections in patients receiving PRBCs. All patients in shock following any type of transfusion may require aggressive antibiotic therapy, until the diagnosis and etiology are known.

Benians, A., J. L. Leaney, et al. (2003). "The dynamics of formation and action of the ternary complex revealed in living cells using a G-protein-gated K+ channel as a biosensor." J Biol Chem 278(12): 10851-8.

            Traditionally the consequences of activation of G-protein-coupled receptors (GPCRs) by an agonist are studied using biochemical assays. In this study we use live cells and take advantage of a G-protein-gated inwardly rectifying potassium channel (Kir3.1+3.2A) that is activated by the direct binding of Gbetagamma subunit to the channel complex to report, in real-time, using the patch clamp technique the activity of the "ternary complex" of agonist/receptor/G-protein. This analysis is further facilitated by the use of pertussis toxin-resistant fluorescent and non-fluorescent Galpha(i/o) subunits and a series of HEK293 cell lines stably expressing both channel and receptors (including the adenosine A(1) receptor, the adrenergic alpha(2A) receptor, the dopamine D(2S) receptor, the M4 muscarinic receptor, and the dimeric GABA-B(1b/2) receptor). We systematically analyzed the contribution of the various inputs to the observed kinetic response of channel activation. Our studies indicate that the combination of agonist, GPCR, and G-protein isoform uniquely specify the behavior of these channels and thus support the importance of the whole ternary complex at a kinetic level.

Bennett, S. A. and D. C. Roberts (2003). "Analysis of protein expression in brain tissue by ELISA." Methods Mol Med 79: 283-95.

Benoit, S. C., J. A. McQuade, et al. (2003). "Altered feeding responses in mice with targeted disruption of the dopamine-3 receptor gene." Behav Neurosci 117(1): 46-54.

            Dopamine signaling has been implicated in the control of food intake and body weight. In particular, dopamine is important in the control of meal size and number and is thought to mediate the response to metabolic deprivation states. In the present experiments, the authors assessed the role of the dopamine-3 receptor (D3R) in the feeding responses to 2-deoxy-D-glucose, mercaptoacetate, and peripheral insulin. All 3 compounds increased food intake in wild-type mice, but the hyperphagic responses were blunted in D3R-/- mice. In other experiments, D3R-/- mice were hyperresponsive to the administration of amylin and leptin relative to wild-type mice. These results support the hypothesis that D3Rs chronically inhibit the effects of adiposity hormones, thereby contributing to a net anabolic state.

Berding, G., T. Brucke, et al. (2003). "[[(123)I]beta-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson's disease and multiple system atrophy]." Nuklearmedizin 42(1): 31-8.

            AIMS: Definition of the regional pattern of dopamine transporter (DAT) dysfunction in advanced Parkinson's disease (PD) and evaluation of a potential correlation between DAT binding and symptoms; elucidation of the role of DAT imaging in the differential diagnosis of PD and multiple system atrophy (MSA); assessment and comparison of serotonin transporter (SERT) binding in PD and MSA. METHODS: [(123)I]ss-CIT SPECT was performed in 14 patients with advanced PD, 10 with moderate MSA and 20 healthy persons. Specific to nonspecific tracer binding ratios (V(3)") were calculated via ROI analysis of uptake images at 4 h (SERT binding) and 24 h (DAT binding) p. i. RESULTS: In PD bilateral reduction of striatal DAT binding (63-70%) was seen. The caudate ipsilateral to the clinically predominantly affected side showed relatively the least impairment. Significant correlations (r = -0.54 to -0.64) between DAT binding and Hoehn and Yahr stage, UPDRS-scores and duration of disease were found. In MSA DAT binding was less reduced (40-48%) targeting the putamen contralateral to the side of clinical predominance. Significantly lower SERT binding was observed in PD midbrain and MSA hypothalamus compared to controls - and in MSA relative to PD mesial frontal cortex. CONCLUSIONS: In advanced PD striatal DAT binding is markedly reduced with the least reduction in caudate ipsilateral to the clinically predominantly affected side. In moderate MSA with asymmetrical symptoms DAT dysfunction is predominant in the contralateral putamen, a pattern seen in early PD. The reduction of SERT in the midbrain area of PD patients suggests additional tegmental degeneration while in MSA the serotonergic system seems to be more generally affected.

Berenguer, P., C. Soulage, et al. (2003). "Behavioral and neurochemical effects induced by subchronic exposure to 40 ppm toluene in rats." Pharmacol Biochem Behav 74(4): 997-1003.

            Chronic toluene inhalation at concentrations above occupational exposure limits (e.g., 100 ppm; NIOSH) has been repeatedly shown to induce neurotoxic effects. In contrast, although few clinical and experimental data are available on the effects of toluene exposure at concentrations below occupational exposure standards, some of these data may support adverse effects of long-term exposure to low toluene concentrations. To test this hypothesis, we investigated the neurobehavioral and neurochemical effects of 40 ppm inhaled toluene in a rat model of 16-week subchronic exposure, examining locomotor and rearing activities; adaptation/sensitization to narcosis produced by acute exposure to toluene at high concentration; and tyrosine hydroxylase and tryptophan hydroxylase activities, and dopamine (DA) and serotonin (5-HT) turnovers in the caudate-putamen, nucleus accumbens, hippocampus, prefrontal cortex, and cerebellum. Our results mainly show that subchronic exposure to 40 ppm toluene significantly resulted in a sensitization to toluene-induced narcosis, a decrease in rearing activity, and alterations in DA and 5-HT transmissions. This demonstrates that subchronic toluene exposure at a low concentration may lead to adverse changes in neurobehavioral and neurochemical functioning, and further questions in a public health perspective the actual neurotoxic potential of toluene and other organic compounds, because deficits in functioning are generally viewed as precursors of more serious adverse effects.