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International audience; Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

International audience; Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. We investigated the modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors.

International audience; We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.

International audience; We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.

International audience; The spontaneous and the electrically evoked release of [3H]GABA were studied in vitro on slices of rat medial prefrontal cortex. The slices were preincubated with [3H]GABA and then superfused with a Krebs' solution. The superfusion with a Ca(2+)-free medium progressively increased the spontaneous [3H]GABA release and strongly decreased the electrically evoked release of [3H]GABA (-65%). The effects of three dopaminergic D2 receptor agonists (RU24926, lisuride and LY171555) were studied on both the spontaneous and the electrically evoked [3H]GABA release. The spontaneous release of [3H]GABA was increased by exposure to each of these three D2 agonists. RU24926 produced a dose-dependent increase from 10(-9) to 3 x 10(-8) M and the maximal effect was totally abolished by the dopaminergic D2 receptor antagonist sulpiride (10(-5) M). With lisuride a progressive increase of [3H]GABA release was observed and a plateau value was reached with concentrations between 10(-7) and 10(-6) M. These effects were totally reversed by 10(-5) M sulpiride. The dose-response relation for LY171555 was bell-shaped, with a maximal effect being obtained with 10(-9) M) LY171555. This effect decreased with a higher concentration (10(-8) M) and finally was no longer observed for 10(-7) M LY171555. The maximal increase induced by LY171555 was totally abolished by 10(-5) M sulpiride. In contrast, the electrically evoked release of [3H]GABA was inhibited by these three D2 agonists. The IC50 value of the inhibition was 4.1 x 10(-8) M for RU24926 and 2 x 10(-7) M for lisuride. Sulpiride (10(-5) M) totally abolished the effect of 10(-7) M RU24926. In the concentration range of lisuride examined, a 50% reduction of the lisuride inhibition was obtained in the presence of sulpiride (10(-5) M). The dose-response curve obtained with LY171555 had a U-shape, with a maximal inhibition reached with 10(-8) M, whereas no effect was observed with 10(-6) M. The inhibition induced by 10(-8) M LY171555 was completely antagonized by 10(-5) M sulpiride. The D2 agonist-induced inhibition of the electrically evoked release of [3H]GABA was mimicked by dopamine endogenously released by 10(-5) M amphetamine. This effect was reversed by 10(-5) M sulpiride. Our data provide further evidence for a dopaminergic control of GABA interneurons in the prefrontal cortex. This regulation implies the activation of D2 dopaminergic receptors. The possible mechanisms underlying the opposite effects of D2 agonists on the spontaneous and the electrically evoked release of [3H]GABA are discussed.

International audience; BACKGROUND: Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS: We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS: The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION: This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

RATIONALE: The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate-dopamine receptor interactions. OBJECTIVES: The purpose of this study was to examine the effects of intra-accumbens co-administrations of glutamate and DA antagonists on the consolidation of spatial information. METHODS: On day 1, CD1 male mice were placed in an open field containing five different objects and immediately after three sessions of habituation the animals were injected intra-accumbens with either vehicle or low doses of the N-methyl-D: -aspartate (NMDA; AP-5 50 ng/side), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; DNQX 5 ng/side), the D1 (SCH23390 12.5 ng/side) and the D2 (sulpiride 25 ng/side) antagonists that were ineffective alone in disrupting object displacement. Separate groups were then focally injected with a combination of one of the glutamate antagonists with one of the dopamine antagonists. Twenty-four hours later, the ability of mice to discriminate object displacement was assessed. RESULTS: Controls and mice injected with ineffective doses of the NMDA, the AMPA, the D1 or the D2 antagonists were always able to react to the object displacement. On the contrary, the groups administered with the different combinations (AP-5 and SCH23390, AP-5 and sulpiride, DNQX and SCH23390, DNQX and sulpiride) of glutamate and dopamine antagonists did not discriminate the spatial change. CONCLUSIONS: These results demonstrate that glutamate-dopamine receptor interactions within the accumbens are essential for the consolidation process of spatial information.

International audience; The aim of the study was to examine the action of low-dose amisulpride (100 mg/d), an atypical antipsychotic from the benzamide class with a high affinity for the D2 and D3 dopamine receptors, given for 4 weeks in 19 schizophrenic patients with the deficit syndrome, in terms of clinical response, modifications in their cognitive performance and changes in brain perfusion values. A secondary objective was to distinguish between primary and secondary deficit, according to Carpenter's definition. Both efficacy and a relatively low rate of side effects of low-dose amisulpride in the deficit forms of schizophrenia were found as expected from earlier placebo-controlled studies. Our study found significant changes in the cerebral blood flow, before and after treatment, more marked in the frontal area and particularly in the dorso-lateral frontal area. A significant improvement of cognitive function was found after treatment, without a link to any particular changes in a loco-regional perfusion value. Finally, a distinction between primary and secondary deficit showed a higher percentage of clinical improvement in the patients with a secondary deficit. The psychometric and cerebral perfusion changes were no different in the two groups.

International audience; The effects of D1 and D2 dopaminergic agonists and antagonists on the electrically-evoked release of gamma-[3H] aminobutyric acid (3H-GABA) have been studied on rat prefrontal cortex slices. The major part of the electrically-evoked release of 3H-GABA appeared to be Ca++ dependent since a 62% decrease was observed when calcium was removed from the superfusion medium. Two specific D2 dopaminergic agonists, RU 24926 (10(-7) M) and lisuride (10(-6) M), respectively induced a 32% and a 50% inhibition of the electrically-evoked release of 3H-GABA. The selective D2 dopaminergic antagonists sulpiride (10(-5) M) totally abolished the effect of RU 24926 and partially abolished the effect of lisuride. The selective D1 agonist SKF 38393 (10(-5) M) did not affect 3H-GABA release. These results suggest that in the rat prefrontal cortex in vitro, the dopaminergic modulation of 3H-GABA release is mediated through D2 but not D1 receptors. The activation of D2 dopaminergic receptors induces an inhibition of the electrically-evoked release of 3H-GABA.

International audience; The role in spatial divided and sustained attention of D1 and D2-like dopamine (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was investigated in a five-choice serial reaction time task. Rats were trained to detect brief flashes of light (0.5-0.25 sec) presented randomly in a spatial array of five apertures. When performance stabilized, animals received bilateral microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats were divided into two groups, with low (75%) baseline levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no significant effect on any task variable. SCH 23390 (0.3 microg) selectively impaired the accuracy of attentional performance in rats in the high baseline condition. By contrast, SKF 38393 (0.06 microg) enhanced the accuracy of attentional performance in the low baseline condition, a lower dose (0.03 microg) also increasing the speed of making correct responses. Finally, the beneficial effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0 microg). The results provide apparently the first demonstration of enhanced cognitive function after local administration of a D1 receptor agonist to the mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in modulating attentional function.