Dopamine D2 Receptor Antagonist Sulpiride Research Articles

Role of ventral pallidal D2 dopamine receptors in the consolidation of spatial memory

The role of dopamine (DA) receptors in spatial memory consolidation has been demonstrated in numerous brain regions, among others in the nucleus accumbens which innervates the ventral pallidum (VP). The VP contains both D1 and D2 DA receptors. We have recently shown that the VP D1 DA receptor activation facilitates consolidation of spatial memory in Morris water maze test. In the present study, the role of VP D2 DA receptors was investigated in the same paradigm.In the first experiment, the D2 DA receptor agonist quinpirole was administered into the VP of male Wistar rats in three doses (0.1, 1.0 or 5.0μg, respectively in 0.4μl physiological saline). In the second experiment, the D2 DA receptor antagonist sulpiride was applied to elucidate whether it can antagonise the effects of quinpirole. The antagonist (4.0μg, dissolved in 0.4μl physiological saline) was microinjected into the VP either by itself or prior to 1.0μg agonist treatment. Control animals received saline in both experiments.The two higher doses (1.0 and 5.0μg) of the agonist accelerated memory consolidation relative to controls and increased the stability of the consolidated memory against extinction. Sulpiride pretreatment antagonised the effects of quinpirole. In addition, the antagonist microinjected into the VP immediately after the second conditioning trial impaired learning functions.The present data provide evidences for the important role of VP D2 DA receptors in the consolidation and stabilization of spatial memory.

Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca2+) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3–10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.

Genetic and Functional Analysis of Polymorphisms in the Human Dopamine Receptor and Transporter Genes in Small Cell Lung Cancer

The regulatory role of dopamine (DA) in endocrine, cardiovascular and renal functions has been extensively studied and used for clinical purposes. More recently DA has been indicated as a regulatory molecule for immune cells and malignant cell proliferation. We assessed the expression and the functional role DA, DA receptors, and transporters in primary small cell lung cancer (SCLC). By HPLC DA plasma levels were more elevated in SCLC patients in comparison with NSCLC patients and healthy controls. SCLC cell expressed DA D1- and D2-like receptors and membrane and vesicular transporters at protein and mRNA levels. We also investigated the effects of independent D1- or D2-like receptor stimulation on SCLC cell cultures. DA D1 receptor agonist SKF38393 induced the increase of cAMP levels and DARPP-32 protein expression without affecting SCLC growth rate. Cell treatment with the DA D1 receptor antagonist SCH23390 inhibited SKF38393 effects. In contrast, the DA D2 receptor agonist quinpirole (10 μM) counteracted, in a dose and time dependent way, SCLC cell proliferation, it did not affect cAMP levels and decreased phosphorylated AKT that was induced by DA D2 receptor antagonist sulpiride. However, in only one SCLC line, stimulation of DA D2 receptor failed to inhibit cell proliferation in vitro. This effect was associated to the existence of rs6275 and rs6277 polymorphisms in the D2 gene. These results gave more insight into DA control of lung cancer cell behavior and suggested the existence of different SCLC phenotypes.

Dopamine D2 receptors regulate unconditioned fear in deep layers of the superior colliculus and dorsal periaqueductal gray

RationaleElectrical and chemical stimulation of the dorsal periaqueductal gray (dPAG), deep layers of the superior colliculus (dlSC), and inferior colliculus (IC) causes freezing and escape behavior in rodents. Systemic injections of the selective dopamine D2 receptor antagonist sulpiride increased the number of switch-off responses (SORs) to light and auditory evoked potentials in response to loud sounds. Dopamine D2 receptor inhibition in the IC was shown to enhance unconditioned fear. Nevertheless, the role of dopamine receptors in the dlSC and dPAG in the mediation of unconditioned fear has not yet been demonstrated. ObjectivesThe purpose of the present study was to characterize the effects of sulpiride injections (4 and 8μg/0.2μl) in the dlSC and dPAG in rats that were subjected to unconditioned fear paradigms. MethodsSwitch-off responses to light and exploratory behavior in the elevated plus maze were used to evaluate unconditioned fear in rats. ResultsIntra-dlSC microinjections of sulpiride increased the number of SORs to light. Intra-dlSC and intra-dPAG injections of sulpiride reduced the number of entries into and time spent on the open arms and decreased end-arm exploration and head dipping in the elevated plus maze. ConclusionThese findings suggest that dopamine, through D2 receptors in the dlSC and dPAG, is involved in defense reactions that are organized in the midbrain tectum.

Abnormal modulation of reward versus punishment learning by a dopamine D2-receptor antagonist in pathological gamblers.

RationalePathological gambling has been associated with dopamine transmission abnormalities, in particular dopamine D2-receptor deficiency, and reversal learning deficits. Moreover, pervasive theoretical accounts suggest a key role for dopamine in reversal learning. However, there is no empirical evidence for a direct link between dopamine, reversal learning and pathological gambling.ObjectiveThe aim of the present study is to triangulate dopamine, reversal learning, and pathological gambling.MethodsHere, we assess the hypothesis that pathological gambling is accompanied by dopamine-related problems with learning from reward and punishment by investigating effects of the dopamine D2-receptor antagonist sulpiride (400 mg) on reward- and punishment-based reversal learning in 18 pathological gamblers and 22 healthy controls, using a placebo-controlled, double-blind, counter-balanced design.ResultsIn line with previous studies, blockade of D2 receptors with sulpiride impaired reward versus punishment reversal learning in controls. By contrast, sulpiride did not have any outcome-specific effects in gamblers.ConclusionThese data demonstrate that pathological gambling is associated with a dopamine-related anomaly in reversal learning from reward and punishment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3986-y) contains supplementary material, which is available to authorized users.

Temporal and spatial transcriptional fingerprints by antipsychotic or propsychotic drugs in mouse brain.

Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R) activation, their precise mechanisms of action remain elusive. Antipsychotics are well known to induce transcriptional changes of immediate early genes (IEGs), raising the possibility that gene expressions play an essential role to improve psychiatric symptoms. Here, we report that while different classes of antipsychotics have complex pharmacological profiles against D2R, they share common transcriptome fingerprint (TFP) profile of IEGs in the murine brain in vivo by quantitative real-time PCR (qPCR). Our data showed that various types of antipsychotics with a profound interaction of D2R including haloperidol (antagonist), olanzapine (antagonist), and aripiprazole (partial agonist) all share common spatial TFPs closely homologous to those of D2R antagonist sulpiride, and elicited greater transcriptional responses in the striatum than in the nucleus accumbens. Meanwhile, D2R agonist quinpirole and propsychotic NMDA antagonists such as MK-801 and phencyclidine (PCP) exhibited the contrasting TFP profiles. Clozapine and propsychotic drug methamphetamine (MAP) displayed peculiar TFPs that reflect their unique pharmacological property. Our results suggest that transcriptional responses are conserved across various types of antipsychotics clinically effective in positive symptoms of schizophrenia and also show that temporal and spatial TFPs may reflect the pharmacological features of the drugs. Thus, we propose that a TFP approach is beneficial to evaluate novel drug candidates for antipsychotic development.

The COMT Val158Met polymorphism regulates the effect of a dopamine antagonist on the feedback-related negativity.

Consistent with dopamine accounts of internal and external feedback processing, prior work showed that the dopamine D2 receptor antagonist sulpiride modulates the relationship between the dopaminergic COMT Val158Met polymorphism and the error-related negativity (ERN). Here, we tested in an independent sample whether this Gene × Substance interaction generalizes to the feedback-related negativity (FRN), which presumably shares underlying dopaminergic mechanisms with the ERN. N = 83 female participants genotyped for COMT Val158Met received 200 mg sulpiride versus placebo and performed a virtual ball-catching task. The FRN to positive versus negative feedback was modulated by a significant COMT × Substance interaction. Mirroring prior work on the ERN, the tendency of the FRN to be more pronounced for VAL+ versus MET/MET carriers after placebo was reversed by sulpiride. The findings thus provide new evidence for dopaminergic models of feedback processing.

The reinforcing effects of ethanol within the posterior ventral tegmental area depend on dopamine neurotransmission to forebrain cortico-limbic systems

Ethanol can be self-infused directly into the posterior ventral tegmental area (pVTA) and these effects involve activation of local dopamine neurons. However, the neuro-circuitry beyond the pVTA involved in these reinforcing effects has not been explored. Intra-pVTA microinjection of ethanol increases dopamine release in the nucleus accumbens (NAC), medial prefrontal cortex (mPFC) and ventral pallidum (VP). The present study tested the hypothesis that the reinforcing effects of ethanol within the pVTA involve the activation of dopamine projections from the pVTA to the NAC, VP and mPFC. Following the acquisition of self-infusions of 200 mg% ethanol into the pVTA, either the dopamine D2 receptor antagonist sulpiride (0, 10 or 100 μM) or the D1 receptor antagonist SCH-23390 (0, 10 or 100 μM) was microinjected into the ipsilateral NAC shell (NACsh), NAC core (NACcr), VP or mPFC immediately prior to the self-infusion sessions to assess the involvement of the different dopamine projections in the reinforcing effects of ethanol. Microinjection of each compound at higher concentration into the NACsh, VP or mPFC, but not the NACcr, significantly reduced the responses on the active lever (from 40-50 to approximately 20 responses). These results indicate that activation of dopamine receptors in the NACsh, VP or mPFC, but not the NACcr, is involved in mediating the reinforcing effects of ethanol in the pVTA, suggesting that the 'alcohol reward' neuro-circuitry consist of, at least in part, activation of the dopamine projections from the pVTA to the NACsh, VP and mPFC.

Effects of SCH-23390 and sulpiride on active avoidance in ovariectomized rats treated with a low dose of 17β-estradiol.

We studied the effects of dopamine D1/D2 receptor antagonists on the dynamics of acquisition and extinction of active avoidance responses and open field behavior in ovariectomized female rats. Dopamine D1 receptor antagonist SCH-23390 (0.1 mg/kg intraperitoneally) and dopamine D2 receptor antagonist sulpiride (10.0 mg/kg intraperitoneally) were administered chronically (14 days) either alone or in combination with a low dose of 17β-estradiol (0.5 μg per rat subcutaneously) to females after ovariectomy. It was found that SCH-23390 in combination with a low dose of 17β-estradiol completely restored impaired conditioning and retention of a conditioned avoidance response in ovariectomized animals. Simultaneous correction of behavioral patterns in the open field test was also observed in ovariectomized females receiving SCH-23390. Sulpiride injected alone or in combination with low dose of 17β-estradiol did not correct conditioning and reproduction of active avoidance response in females with estrogen deficiency and did not significantly affect animal behavior. The results indicate positive effect of dopamine D1 receptor blockade on active learning under conditions of estrogen deficiency.

Dopamine modulates frontomedial failure processing of agentic introverts versus extraverts in incentive contexts

The agency facet of extraversion (aE) describes individual differences in goal-directed behavior and has been linked to dopamine function in incentive contexts. Because dopamine presumably modulates the processing of negative feedback/failure, aE may relate to failure processing in incentive contexts. To test this hypothesis, N = 86 participants performed a virtual ball-catching task. An incentive context was created by displaying potential rewards and subtle manipulations of task performance, which either was (control group) or was not (incentive context group) made explicit. To probe the involvement of dopamine, participants received either placebo or the selective dopamine D2 receptor antagonist sulpiride (200mg). Failure processing was assessed through negative-feedback-evoked differences in the frontal midline theta electroencephalogram power (DFMT) and in the feedback-related negativity event-related potential component (FRN). Before incentives were introduced, DFMT (but not the FRN) was related to neuroticism/anxiety. Importantly, once incentives were displayed, aE was associated with DFMT, FRN, task performance, and changes in self-reported positive affect, which further depended on incentive context group and/or substance group: In the incentive context group but not in the control group, agentic extraverts showed relatively blunted DFMT after placebo. Sulpiride significantly enhanced DFMT, whereas it reduced FRN amplitudes and performance in agentic extra- versus introverts. These findings provide strong support for current dopamine models of aE and failure processing, and also highlight the importance of task context. Moreover, the dissociations of FRN and DFMT suggest the existence of two nonredundant electrophysiological indices of feedback processing, both relating to dopamine and aE.

Involvement of dopamine D2 receptor signal transduction in the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats

We have reported previously that the inhibition of both dopaminergic and psychotomimetic/hallucinogenic components plays a role in the discriminative stimulus effects of U-50,488H. However, the mechanisms that underlie the discriminative stimulus effects of U-50,488H, and especially the component that plays a significant role, have not yet been clarified. The present study was designed to further investigate the mechanism(s) of the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats that had been trained to discriminate between 3.0 mg/kg U-50,488H and saline. The dopamine D2 receptor antagonist sulpiride, but not the D1 receptor antagonist SCH23390, generalized to the discriminative stimulus effects of U-50,488H. The mood-stabilizing agents lithium chloride and valproic acid, which have attenuating effects on the Akt/GSK3 pathway, also partially generalized to the discriminative stimulus effects of U-50,488H. In contrast, the 5-HT-related compound racemic 3,4-methylenedioxymethamphetamine, the cannabinoid receptor agonist WIN55,212-2, and the μ-opioid receptor agonist morphine failed to generalize to the discriminative stimulus effects of U-50,488H. These results suggest that the inhibition of the dopaminergic activity mediated by the postsynaptic D2 receptor, followed by suppression of the Akt/GSK3 pathway may be critical for the induction of the discriminative stimulus effects induced by U-50,488H.

Rewarding Effects of N-Methyl-1-(4-Methoxyphenyl)-2-Aminopropane (PMMA) in Mice: Roleof Modifications of Dopamine System Mediated through its Monoamine Oxidase Inhibition

Background: N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA) is a structurally abbreviated congener of methamphetamine that is abused as a “designer drug”. The aim of the present study was to investigate the behavioral and neurochemical properties of PMMA in mice. Methods: Using conditioned place preference paradigm, the rewarding effect of PMMA were examined in the ICR mice. As neurochemical study, we examined the effect of PMMA on monoamine transmission and monoamine oxidase (MAO) activity in the mouse limbic forebrain tissue (containing the nucleus accumbens). Results: PMMA (1-30 mg/kg) produced a significant heperlocomotion and conditioned place preference. The hyper locomotion and rewarding effects of PMMA were completely suppressed by the dopamine D1 receptor antagonist SCH23390, but were not modified by the dopamine D2 receptor antagonist sulpiride or the 5-HT2 receptor antagonist ketanserin. PMMA also significantly increased the dopamine and 3-methoxytyramine (3MT) contents in the limbic forebrain. On the other hand, the levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and Homovanillic acid (HVA) were markedly reduced by PMMA in a dose-dependent manner. Monoamine oxidase (MAO) activities in the limbic forebrain were suppressed by PMMA treatment (0.04-4mM). Conclusion: The present findings demonstrated that the dopamine D1 receptors might be involved in the expression of PMMA-induced heperlocomotion and the rewarding effects of the drug. Furthermore, the MAO-inhibitory effects of PMMA may play an important role in the PMMA-induced elevation of dopamine transmission. These behavioral and neurochemical data indicate that PMMA has a psychic dependence liability.

Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype, or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: depending on the personality trait agentic extraversion (agentic facet, aE; i.e., assertiveness, dominance, ambition, positive emotionality) the selective dopamine D2 receptor antagonist sulpiride (200 mg) had opposite effects on resting posterior vs. anterior theta activity in the electroencephalogram (EEG). In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over 5 h in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50, 200, or 400 mg). The findings suggest a model postulating stronger pre- vs. postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- vs. postsynaptic dopamine D2 subreceptor sensitivities and densities.

Cocaine-induced reinstatement of a conditioned place preference in developing rats: involvement of the d2 receptor.

Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) dopamine (DA) D2 receptor antagonist infusions would block (or potentiate) cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28–39)) were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement was determined by intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 μM) during a cocaine-primed reinstatement test (10 mg/kg cocaine, i.p.). Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of conditioned place preference. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate responsivity to cocaine-induced reinstatement of a conditioned place preference during development.

Selective inhibition of monoamine oxidase A or B reduces striatal oxidative stress in rats with partial depletion of the nigro-striatal dopaminergic pathway

Partial lesion (50%) of the nigro-striatal dopaminergic pathway induces compensatory increase in dopamine release from the remaining neurons and increased extracellular oxidative stress (OS-ec) in the striatum. The present study was designed to explore the role of monoamine oxidase types A and B (MAO-A, MAO-B) in producing this increased oxidative stress. Lesion of the dopaminergic pathways in the CNS was produced in rats by intra-cerebroventricular injection of 6-hydroxydopamine (6-OHDA; 250 μg) and striatal microdialysis was carried out 5 weeks later. Striatal OSec was determined by measurement of oxidized derivatives of the marker molecule N-linoleyl-tyrosine. Striatal tissue MAO-A activity was unchanged by 6-OHDA lesion but MAO-B activity was increased by 16%, together with a 45% increase in glial cell content. The selective MAO-B inhibitor rasagiline (0.05 mg/kg s.c. daily for 14 days) did not affect microdialysate dopamine concentration [DAec] in sham-operated rats, but decreased OSec by 30%. In lesioned rats, rasagiline decreased [DAec] by 42% with a 49% reduction in OSec. The decrease in [DAec] was reversed by the dopamine D2 receptor antagonist sulpiride (10 mg/kg s.c.). The selective MAO-A inhibitor clorgyline (0.2 mg/kg s.c. daily for 14 days) increased striatal [DAec] by 72% in sham-operated rats with no change in OSec. In lesioned rats clorgyline increased [DAec] by 66% and decreased OSec by 44%. Rasagiline and clorgyline were effective to a similar extent in reduction of tissue levels of 7-ketocholesterol and the ratio GSSG/GSH, indicative of reduced intracellular oxidative stress level. This data implies that gliosis in our 6-OHDA animals together with inhibition of glial cell MAO-B by rasagiline causes an increase in local levels of dopamine at the presynaptic receptors, and a reduction in dopamine release (and in [DAec]) by presynaptic inhibition. Moreover, inhibition of MAO-A or MAO-B reduces the enhanced level of oxidative stress in the lesioned striatum, and while both clorgyline and rasagiline reduced DA oxidative metabolism, rasagiline possesses an additional antioxidant property, not only that resulting from MAO inhibition.

Disruption of Drug Effects (Dopamine, Nicotine, Pilocarpine, κ-Opioid) in Planarians by UV Light

Based on previous work, it has been hypothesized that the energetics of ultraviolet (UV) light disrupts effects induced by receptor-binding ligands. If this hypothesis is true, then UV light should (i) disrupt a broad variety of endpoints and (ii) disrupt effects produced by ligands that bind to diverse receptor types. This was tested directly in the present study by using ligands selective for four different receptors (one ionotropic, three metabotropic) and three different behavioral endpoints. The selective dopamine D2 receptor antagonist (–)sulpiride (0.1 uM) dose-relatedly decreased spontaneous locomotor velocity, the selective nicotinic acetylcholine receptor agonist nicotine (1, 3, 5 mM) and the selective muscarinic acetylcholine receptor agonist pilocarpine (20, 30, 50 mM) induced seizure-like activity, and the selective-opioid receptor agonist U-50,488H (10 uM) produced physical dependence (manifested as abstinence-induced withdrawal) in planarian models. Each of these diverse ligand and receptor-mediated effects were attenuated by UV light (254 nm = 7.83 × 10–19 J = 4.89 eV). These findings provide further evidence that UV light disrupts ligand-receptor mediated interactions and that UV light might provide a useful tool for examining drug-receptor interactions.

Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia

BackgroundDYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.Methods and ResultsWe characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.ConclusionsThese results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.

Modulation of endocannabinoid-mediated long-lasting disinhibition of striatal output by cholinergic interneurons

The frequency and duration of glutamatergic inputs to the striatum are strong determinants of the net effect of retrograde endocannabinoid (eCB) signaling, and key factors in determining if long-term depression (LTD) has a net disinhibitory or inhibitory action in striatum. Low to moderate frequency stimulation in the dorsolateral striatum elevates eCB levels to an extent that primarily depresses transmitter release at inhibitory synapses, leading to a long-lasting disinhibition (DLL) of synaptic output. The aim of this study was to further characterize the basic features of endocannabinoid-mediated DLL of striatal output induced by moderate frequency stimulation (5 Hz, 60 s). DLL was inhibited in slices treated with the group 1 metabotropic glutamate receptor (mGluR) antagonists MPEP (40 μM) and CPCCOEt (40 μM), the dopamine D2 receptor antagonist sulpiride (5 μM), the L-type calcium channel blocker nifedipine (20 μM), the nicotinic receptor antagonist mecamylamine (10 μM), the muscarinic agonist oxotremorine sesquifumarate (10 μM), and strychnine (0.1 μM). Strychnine did not block DLL induced by WIN55,212-2 (250 nM), showing that glycine receptor-mediated modulation of eCB signaling occurs upstream from CB1R activation. Scopolamine (10 μM) restored DLL in strychnine-treated slices, suggesting that inhibition of glycine receptors on cholinergic interneurons could modulate eCB signaling by enhancing muscarinic receptor activation and reducing the opening of L-type calcium channels in response to depolarization. These data suggests that similar activation points are required for stimulation-induced DLL as for LTD at excitatory striatal synapses, and that cholinergic interneurons are key modulators of stimulation-induced eCB signaling in the striatum.

Human cognitive flexibility depends on dopamine D2 receptor signaling

RationaleAccumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans.ObjectivesWe aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility.MethodsTo this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the dopamine transporter gene, DAT1. ResultsBromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14).ConclusionsThese results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2340-2) contains supplementary material, which is available to authorized users.

Involvement of dopaminergic and glutamatergic systems of the basolateral amygdala in amnesia induced by the stimulation of dorsal hippocampal cannabinoid receptors

The present study intended to investigate the involvement of dopaminergic and glutamatergic systems of the basolateral amygdala in amnesia induced by the stimulation of dorsal hippocampal cannabinoid receptors in male Wistar rats. The animals were stereotaxically implanted with guide cannulas in the CA1 region of the dorsal hippocampus and basolateral amygdala (BLA), trained in a step-through type passive avoidance task, and tested 24 h after training to measure memory retrieval. Post-training intra-CA1 microinjection of the nonselective CB1/CB2 receptor agonist WIN55,212-2 (WIN) (0.1–0.5 μg/rat) dose-dependently induced amnesia. Post-training intra-BLA administration of the D1/D2 dopamine receptor agonist apomorphine (0.3 and 0.5 μg/rat) plus intra-CA1 administration of 0.1 μg/rat of WIN, which alone did not induce amnesia, inhibited memory formation. The inhibitory effect of 0.5 μg/rat of WIN (intra-CA1) on memory formation was significantly decreased by the D1 dopamine receptor antagonist SCH23390 (0.1–0.5 μg/rat, intra-BLA) or the D2 dopamine receptor antagonist sulpiride (0.02–0.5 μg/rat, intra-BLA) given 5 min before post-training intra-CA1 microinjection of WIN. It is important to note that single intra-BLA microinjection of the same doses of apomorphine, SCH23390 or sulpiride had no effect on memory retrieval in passive avoidance task. On the other hand, post-training co-administration of N-methyl-d-aspartate (NMDA; 0.03 and 0.05 μg/rat, intra-BLA) plus an ineffective dose of WIN (0.1 μg/rat, intra-CA1) induced amnesia. Furthermore, the inhibitory effect of 0.5 μg/rat of intra-CA1 microinjection of WIN on memory formation was significantly decreased by pre-treatment with intra-BLA microinjection of the NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 0.1 and 0.5 μg/rat, intra-BLA). Intra-BLA microinjection of the same doses of NMDA or d-AP5 by itself did not induce any response on memory retrieval. Taken together, these findings support the existence of a functional interaction between dorsal hippocampal and basolateral amygdaloid neural circuits during processing cannabinoid-induced amnesia.