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Understanding the actions of the neurotransmitter dopamine in the brain is important in view of its roles in neuropsychiatric illnesses. Dopamine D1 receptors, which stimulate both adenylyl cyclase and phospholipase C, and D2 receptors, which inhibit them, can nevertheless act synergistically to produce many electrophysiological and behavioral responses. Because this functional synergism can occur at the level of single neurons, another, as yet unidentified, signalling pathway activated by dopamine has been hypothesized. We report here that in Chinese hamster ovary (CHO) cells transfected with the D2 receptor complementary DNA, D2 agonists potently enhanced arachidonic acid release, provided that such release has been initiated by stimulating constitutive purinergic receptors or by increasing intracellular Ca2+. In CHO cells expressed D1 receptors, D1 agonists exert no such effect. When D1 and D2 receptors are coexpressed, however, activation of both subtypes results in a marked synergistic potentiation of arachidonic acid release. The numerous actions of arachidonic acid and its metabolites in neuronal signal transduction suggest that facilitation of its release may be implicated in dopaminergic responses, such as feedback inhibition mediated by D2 autoreceptors, and may constitute a molecular basis for D1/D2 receptor synergism.

A study was conducted to characterize the tissue carboxypeptidase inhibitor (TCI) from the rat brain. Purified tissues of carboxypeptidase A (CPA) that were cloned with the corresponding cDNA were expressed in Escherichia coli. Molecular analyses identified a protein of 30 kDa and a full-length cDNA encoding a 223-amino acid protein containing three phosphorylation sites. The results showed that expression of TCI in the tissues inhibits CPA activity.

Analysis of the effect of interruption of dopaminergic transmission or sustained blockade of dopamine receptors by neuroleptics on the dopamine D3 receptor reveals that an anterograde factor from mesolimbic dopaminergic neurons is associated with the transcription of the D3 receptor gene. This anterograde factor is distinct from dopamine and peptide cotransmitters.

The existence of the dopamine D3 receptor has been calculated, and its distribution and characteristics in the brain were determined by identifying 7-(H)hydroxy-N,N-di-n-propyl-2-aminotetralin ((H)7-OH-DPAT) as a selective probe for this receptor. (H)7-OH-DPAT binds to D3 receptors with subnanomolar affinity in transfected Chinese hamster ovary cells. A unique pattern of neurotransmission in a confined subpopulation of dopamine neurons probably includes D3 receptors.

More than 20 radioactive ligands have been used to label dopamine receptors, and these ligands have already provided much information about the pharmacology, biochemistry, and localization of the receptors, as [...]

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/ MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout ( KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. [ABSTRACT FROM AUTHOR]

Various studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and establish that patients suffering from schizophrenia and attention deficit hyperactivity disorder (ADHD) have a high tobacco consumption, potentially for the purpose of self-medication. Owing to its neuroprotective and procognitive effects, transdermal nicotine was proposed to be an effective treatment of some neurodegenerative and psychiatric diseases. Mice deficient in the dopamine transporter (DAT KO) exhibit a phenotype reminiscent of schizophrenia and ADHD, including hyperdopaminergia, hyperactivity, paradoxical calming by methylphenidate and cognitive deficits, some of which being improved by antipsychotic agents. We recently demonstrated that nicotinic receptor content and function were profoundly modified in DAT KO mice. In this study, we assessed the effects of a chronic nicotine treatment in the drinking water on the nicotine-induced locomotion, anxiety status and learning performance. Chronically nicotine-treated DAT KO mice were always hypersensitive to the hypolocomotor effect of nicotine without tolerance and did not exhibit the anxiogenic effect of nicotine treatment observed in WT mice. Very interestingly, both acute and chronic nicotine treatments greatly improved their deficits in the cued and spatial learning, without eliciting tolerance. We speculate that the procognitive effects of nicotine in DAT KO mice are related to the upregulation of α7 nicotinic receptors in the hippocampus, amygdala, and prelimbic cortex, all areas involved in cognition. Data from our studies on DAT KO mice shed light on the nicotine self-medication in psychiatric patients and suggest that nicotinic agonists could favorably lead to additional therapy of psychiatric diseases.Neuropsychopharmacology (2007) 32, 2465–2478; doi:10.1038/sj.npp.1301385; published online 21 March 2007 [ABSTRACT FROM AUTHOR]

(-)DO 710, a substituted benzamide derivative which discriminates dopamine D-2 and D-4 binding sites (Sokoloff et al. 1984), and antagonises in a differential manner several apomorphine-induced behavioral responses (Schwartz et al. 1984) was tritiated and used namely to differentially label the D-4 site. In striatum the H-(-)DO 710 saturation curve was best explained by the presence of two classes of sites with a 7-fold difference in affinity ( K values of 3.0 nM and 0.42 nM) and B values of 316 and 106 fmol · mg protein, respectively which correspond to the D-2 and D-4 sites (Sokoloff et al. 1984). In spite of its limited selectivity, H-(-)DO 710 in low concentration (0.2 nM) could be used to preferentially label striatal D-4 site as shown by the inhibition potencies of discriminant benzamide derivatives (DBD), significantly higher than at pituitary D-2 site (receptor) whereas classical neuroleptics including metoclopramide were equally potent at both sites. The affinity of a variety of agonists for striatal sites labeled with 0.2 nM H-(-)DO 710 generally differed from their affinity for the two states of the pituitary D-2 receptor (with high and low affinity for agonists, respectively); compounds like lisuride, N-propylnorapomorphine or pergolide had very high affinity for the striatal H-(-)DO 710 site. In pituitary from oestradiol-treated rats, where only D-2 site occurs, only the low-affinity site for H-(-)DO 710 ( K=2.8 nM) was found. In contrast, in the olfactory bulb there was a large proportion of the high-affinity site for H-(-)DO 710 since binding occurred with a mean K value of 0.72 nM. The effects of a guanylnucleotide [0.1 mM Gpp(NH)p] differed in the three tissues. In pituitary Gpp(NH)p elicited marked effects: i) a 63% increase of specific binding of 0.2 nM H-(-)DO 710; ii) a 9-fold increase in the IC value of dopamine; iii) a large increase in the pseudo-Hill coefficient of dopamine, so that the latter did not anymore differ from unity. In constrast, Gpp(NH)p produced only marginal changes in olfactory bulb in both the binding of 0.2 nM H-(-)DO 710 and its inhibition by dopamine. In striatum, an intermediate and more complex situation was found: Gpp(NH)p i) slightly decreased the mean K value of -H-(-)DO 710 from 1.8 to 1.2 nM; ii) increased by 30% the binding of 0.2 nM H-(-)DO 710; iii) decreased by 6-fold the mean affinity of dopamine. In striatum and olfactory bulb, the pseudo-Hill coefficient of dopamine was not modified by Gpp(NH)p. In addition, at a high H-(-)DO 710 concentration (5 nM), where part of the binding presumably occurred at H-(-)DO 710 low-affinity site, partial effects of Gpp(NH)p were observed. It is concluded that sites labeled with high affinity by the DBD H-(-)DO 710 in striatum and olfactory bulb are little or not affected by guanylnucleotides and presumably differ from either of the two agonist affinity states of the pituitary D-2 receptor. [ABSTRACT FROM AUTHOR]

H-Domperidone (H-DOMP) binding sites were compared in rat striatum and pituitary, regarding the effects of the non-hydrolysable GTP analog, Gpp(NH)p and inhibition by various dopamine (DA) antagonists. Gpp(NH)p (0.1 mM) elicited in both tissues a rightward shift in DA concentration-inhibition curves, but the changes in either IC values or pseudo-Hill coefficients were larger in pituitary than in striatum. Computer analysis of the data showed that, in the presence of Gpp(NH)p, the curve obtained in striatum is best explained by the presence of two classes of binding site, a high-affinity site ( K=95 nM, 27% of total binding) and a low-affinity site ( K=5, 100 nM, 73% of total binding), whereas in pituitary only a low-affinity site ( K=5,070 nM) could be detected. In striatum, several discriminant benzamide derivatives (DBD), (−)-sulpiride and recently developped compounds, allowed to distinguish two components among H-DOMP binding sites: a high-affinity site representing one-third of total binding and a low-affinity component displaying a 8-17 fold lower affinity. Classical neuroleptics like haloperidol, chlorpromazine and metoclopramide inhibited striatal H-DOMP binding in a monophasic manner. In pituitary a single component could be detected for all tested antagonists including the DBD and K values for the latters were identical to those found for the low-affinity component in striatum. Gpp(NH)p (0.1 mM) had no effect on the biphasic inhibition of striatal binding by the most discriminant compound RIV 2093, suggesting that the presence of two components for this DBD is not related to the two conformational states of the D-2 receptor. Also the discriminant property of RIV 2093 is not related to its binding to a sodium-dependent site, since the sodium effects (leftward shift of the inhibition curve) are very similar for RIV 2093 and the non discriminant substituted benzamide metoclopramide. It is concluded that, in addition to a fully GTP-sensitive site, analogous to the D-2 receptor detected in pituitary, striatum also contains a distinct class of binding site, not or less affected by GTP, for which DBD display a high affinity. [ABSTRACT FROM AUTHOR]

A novel dopamine D receptor gene that may be involved in psychiatric diseases has recently been characterized. It has been assigned to chromosome 3 by hybridization with a D receptor probe to human sorted chromosomes, and localized to band 3q 13.3 by in situ hybridization. [ABSTRACT FROM AUTHOR]