Core Region Of Nucleus Accumbens Research Articles

Extrapyramidal Side Effects with Chronic Atypical Antipsychotic Can Be Predicted by Labeling Pattern of FosB and phosphoThr34-DARPP-32 in Nucleus Accumbens.

Extrapyramidal side effects (EPS) can be induced by neuroleptics that regulate the expression of transcription factor FosB and dopaminergic mediator DARPP-32 in the striatum. However, the long-term neurobiological changes in striatal projection neurons resulting from a cumulative dosage of typical and atypical antipsychotics are poorly understood. The present study aimed to determine the differential and long-lasting changes in FosB distribution and DARPP-32 phosphorylation in the striatum and nucleus accumbens (NAc) associated with chronic antipsychotic-induced EPS. Male C57Bl/6J mice received daily injections of Olanzapine (Olz, 15 mg/kg), Clozapine (Clz, 20 mg/kg), or Haloperidol (Hal, 1 mg/kg), for a period of 11 weeks with a 4-day withdrawal period before the last dosage. Catalepsy for detection of EPS, along with open-field and rotarod tests, were assessed as behavioral correlates of motor responses. Additionally, FosB and phosphorylated-DARPP-32 immunohistochemistry were examined in striatal regions after treatment. All antipsychotics produced catalepsy and reduced open-field exploration, such as impaired rota-rod performance after Olz and Hal. The washout period was critical for Clz-induced side effects reduction. Both Olz and Clz increased FosB in NAc Shell-region, and phosphoThr34-DARPP-32 in NAc. Only Clz reduced phosphoThr75-DARPP-32 in the dorsal striatum and showed FosB/phosphoThr34-Darpp-32-ir in the NAc Core region. This study provides evidence that atypical antipsychotics such as Olz and Clz also give rise to EPS effects frequently associated with a cumulative dosage of typical neuroleptics such as Hal. Nevertheless, FosB/phosphoThr34-Darpp-32-ir in the NAc Core region is associated with hypokinetic movements inhibition.

α2δ-1 protein drives opioid-induced conditioned reward and synaptic NMDA receptor hyperactivity in the nucleus accumbens.

Glutamate NMDA receptors (NMDARs) in the nucleus accumbens (NAc) are critically involved in drug dependence and reward. α2δ-1 is a newly discovered NMDAR-interacting protein that promotes synaptic trafficking of NMDARs independently of its conventional role as a calcium channel subunit. However, it remains unclear how repeated opioid exposure affects synaptic NMDAR activity and α2δ-1-NMDAR interaction in the NAc. In this study, whole-cell patch-clamp recordings showed that repeated treatment with morphine in mice markedly increased the NMDAR-mediated frequency of miniature excitatory postsynaptic currents (mEPSCs) and amplitude of puff NMDAR currents in medium spiny neurons in the NAc core region. Morphine treatment significantly increased the physical interaction of α2δ-1 with GluN1 and their synaptic trafficking in the NAc. In Cacna2d1 knockout mice, repeated treatment with morphine failed to increase the frequency of mEPSCs and amplitude of puff NMDAR currents in the NAc core. Furthermore, inhibition of α2δ-1 with gabapentin or disruption of the α2δ-1-NMDAR interaction with the α2δ-1 C terminus-interfering peptide blocked the morphine-elevated frequency of mEPSCs and amplitude of puff NMDAR currents in the NAc core. Correspondingly, systemically administered gabapentin, Cacna2d1 ablation, or microinjection of the α2δ-1 C terminus-interfering peptide into the NAc core attenuated morphine-induced conditioned place preference and locomotor sensitization. Our study reveals that repeated opioid exposure strengthens presynaptic and postsynaptic NMDAR activity in the NAc via α2δ-1. The α2δ-1-bound NMDARs in the NAc have a key function in the rewarding effect of opioids and could be targeted for treating opioid use disorder and addiction.

Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity.

A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.

Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats.

Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions. To answer this question, we induced the expression of halorhodopsin in local PL-mPFC neurons projecting to NAcc, and then selectively inhibited the terminals of these neurons in the NAcc while recording neural activity during the performance of a delayed non-match to sample (DNMS) spatial WM task. Within-subject behavioural performance and PL-mPFC to NAcc circuit neural activity was assessed after the onset of a persistent rodent neuropathic pain model-spared nerve injury (SNI). Our results revealed that the induction of the neuropathy reduced WM performance, and altered the interplay between PL-mPFC and NAcc neurons namely in increasing the functional connectivity from NAcc to PL-mPFC, particularly in the theta-band spontaneous oscillations; in addition, these behavioural and functional perturbations were partially reversed by selective optogenetic inhibition of PL-mPFC neuron terminals into the NAcc during the DNMS task delay-period, without significant antinociceptive effects. Altogether, these results strongly suggest that the PL-mPFC excitatory output into the NAcc plays an important role in the deregulation of WM under pain conditions. Selective optogenetic inhibition of prefrontal-striatal microcircuit reverses pain-related working memory deficits but has no significant impact on pain responses. Neuropathic pain underlies an increase of functional connectivity between the nucleus accumbens core area and the prelimbic medial prefrontal cortex mediated by theta-band activity.

The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17β-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2–6 weeks) with 17β-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17β-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17β-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17β-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17β-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

A novel synthetic cathinone, α-pyrrolidinopentiothiophenone (PVT), produces locomotor sensitization in rat: Implications for GSK3β connections in the nucleus accumbens core

A novel psychoactive substance, α-pyrrolidinopentiothiophenone (α-PVT), is a structural analog to amphetamine. Recently, it has been shown that α-PVT has an abuse potential similar to psychomotor stimulants like cocaine or amphetamine. However, it has not been performed yet to determine whether α-PVT develops behavioral sensitization, a well-known phenomenon for psychomotor stimulants. In the present study, rats were first pre-exposed to either saline or α-PVT (20 mg/kg, IP) with a total of four injections in every 2–3 days of interval. Then, 2-weeks after withdrawal, locomotor activity was measured with a challenge dose (10 mg/kg, IP) of α-PVT and the nucleus accumbens core region was taken out. Similar to psychomotor stimulants, repeated administration of α-PVT produced locomotor sensitization. Further, the phosphorylation levels of GSK3β in the nucleus accumbens core were found to be decreased only in rats with sensitization developed, but not in those with acute or non-sensitized. Correlation analysis revealed that the phosphorylation levels of GSK3β have a strong negative correlation with locomotor activity only in rats with α-PVT pre-exposed, but not in those with its acute injection. These results suggest that a certain level of change in the phosphorylation levels of GSK3β in the nucleus accumbens core may involve in mediating the expression of locomotor sensitization by repeated injection of α-PVT in rats.

Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum.

The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function.

Functional and structural deficits at accumbens synapses in a mouse model of Fragile X.

Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings together reveal new structural and functional synaptic deficits in Fragile X.

Roles of hippocampal NMDA receptors and nucleus accumbens D1 receptors in the amphetamine-produced conditioned place preference in rats

There are glutamatergic projections from the hippocampus to the nucleus accumbens (NAc), which regulate DA transmission in this structure. To be precise, the ventral hippocampal (VH) glutamatergic neurons project to the nucleus accumbens shell region (NAcSh), whereas the dorsal hippocampus (DH) sends glutamatergic projections to the nucleus accumbens core region (NAcC). This study investigates the roles of hippocampal N-methyl- d-aspartate (NMDA) glutamate receptors and NAc type 1 dopamine receptor (D1) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. Our earlier reports showed that AMPH-CPP results in the enhancement of hippocampal CaMKII activity and it can be impaired by NMDA antagonist (AP5). In this study AMPH-CPP did not alter the NAc CaMKII activity, although AMPH-CPP was impaired by a blockade of D1 receptors (SCH23390) during conditioning. Moreover, inactivation of hippocampal area (dorsal hippocampus or ventral hippocampus) impaired AMPH-CPP, but its effect was diminished by the activation of D1 receptors in accumbal region (NAc core or NAc shell). By inactivating both DH and NAc core resulted in the disruption of rat’s CPP expression. However, the impaired CPP expression was recovered during the next testing session, suggesting the disruption of CPP expression was a short term effect. Moreover, the disruption of CPP expression was not exhibited if NAc core was not inactivated. Interestingly, the rats that received activation in VH but an inactivation in NAc shell before testing show impaired CPP expression compared to those received inactivation in both VH and NAc shell. DH activation plus an inactivation in NAc core before testing show a significantly higher rate of the weakening of AMPH-CPP expression. Similarly, an activation of VH plus an inactivation of NAc shell before testing also show a statistically significant lower CPP score on tests 3 and 4. These results, taken together, indicate that NMDA receptor activation in DH and VH have different enhancing effects on the AMPH-CPP as their innervations onto the different NAc regions are essential for AMPH-CPP establishment. If the deterioration of AMPH-CPP expression (or extinction process) resembles the formation of new learning, then this active process might have been facilitated by the hippocampal NMDA receptor activations during testing.

Involvement of extracellular signal-regulated protein kinase in acute cocaine-induced c-fos in nucleus accumbens

It is well known that acute cocaine administration increases c-Fos expression that is involved in cocaine-induced persistent changes in the central nervous system. In the present study, we investigated a possible involvement of extracellular signal-regulated protein kinase (ERK) in induction of c-fos expression in response to acute cocaine treatment in nucleus accumbens (NAc). We found that inhibition of ERK activation significantly attenuated cocaine-induced c-fos expression at both protein and mRNA levels in the NAc. Furthermore, using an immunofluorescent staining approach, we found that inhibition of ERK activation completely abolished cocaine-induced increase in number of c-Fos-positive cells in the core region of NAc, whereas, in shell region of NAc, inhibition of ERK activation partially attenuated cocaine-induced c-Fos expression. Our findings suggest that ERK might participate in cocaine-induced c-fos expression in the NAc, particularly in the core region of NAc.

Effect of agmatine on brain l-citrulline production during morphine withdrawal in rats: A microdialysis study in nucleus accumbens

Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or l-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular l-citrulline concentrations, an indirect sign of NO production since equal amounts of l-citrulline and NO are produced from l-arginine. l-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or l-NAME (100 mg/kg i.p.) in control rats. Both agmatine and l-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. l-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and l-NAME treatments significantly suppressed the increase in l-citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of l-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance.

Functional characterization of kainate receptors in the rat nucleus accumbens core region.

The nucleus accumbens, a brain region involved in motivation, attention, and reward, receives substantial glutamatergic innervation from many limbic structures. This excitatory glutamatergic input plays an integral role in both normal and pathophysiological states. Despite the importance of glutamatergic transmission in the nucleus accumbens, the specific receptor subtypes that mediate glutamatergic signaling in this brain region have not been fully characterized. The current study sought to examine the possible role of the kainate subclass of glutamate receptor in the nucleus accumbens. Kainate receptors are relatively poorly understood members of the ionotropic glutamate receptor family and are highly expressed in the nucleus accumbens. Recent studies have highlighted a number of novel pre- and postsynaptic functions of kainate receptors in several other brain regions. Using the whole cell patch-clamp technique, we report the first demonstration of functional kainate receptors on neurons within the core region of the nucleus accumbens. In addition, we present evidence that activation of kainate receptors in this brain region inhibits excitatory synaptic transmission via a presynaptic mechanism.

Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain.

Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D2-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA1 region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA1, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.

Maternal separation and early social deprivation in octodon degus: quantitative changes of nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons in the prefrontal cortex and nucleus accumbens

The influence of postnatal socio-emotional deprivation on the development of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reactive neurons in prefrontal cortical areas and in subdivisions of the nucleus accumbens was quantitatively investigated in the precocious rodent Octodon degus. Forty-five-days-old O. degus from two animal groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. Socially-deprived animals displayed a significant decrease of NADPH-diaphorase-containing neurons in anterior cingulate cortex (85.5%), the same tendency was observed in the infralimbic, precentral medial and prelimbic prefrontal areas. Similarly, the core region of nucleus accumbens expressed reduced NADPH-diaphorase-reactive neuron numbers in deprived animals (70%), whereas the shell region remained unchanged. Since during normal postnatal development the number of NADPH-diaphorase-reactive neurons gradually decreases in all prefrontal cortical and accumbal regions, the observed deprivation-induced changes may reflect either an excessive reduction of NADPH-diaphorase-positive neurons or a down-regulation of the enzyme in neurons that normally express it. Since some NADPH-diaphorase-containing neurons in the prefrontal cortex have been shown to be GABAergic, it is tempting to speculate that a reduction of these inhibitory neurons in the anterior cingulate cortex may result in an enhanced excitatory output activity of disinhibited projection neurons in this cortical region, including those that project to the core region of the nucleus accumbens. Our results indicate a link between early adverse socio-emotional experience and the maturation of NADPH-reactive neurons and further studies are required to analyse the functional implication for this experience-induced brain pathology.

Expression of Fos protein in rat brain following administration of a nicotinic acetylcholine receptor agonist epibatidine

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D 1 and D 2 receptors and the N-methyl- d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 μg/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D 1 receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5.0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 μg/kg). Pretreatment with sulpiride, a dopamine D 2 receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D 1 receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D 2 receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.

Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain.

The present study examined the effects of acute and repeated administration of three antidepressant drugs (imipramine, citalopram and (+)-oxaprotiline) on the levels of mRNA coding for dopamine D1 and D2 receptors in the rat brain. Quantitive in situ hybridization with 35S-labelled oligonucleotide probes has been utilised. The level of mRNA coding for dopamine D1 receptor (D1 mRNA) is decreased following repeated administration of imipramine, both in the nucleus accumbens and in the striatum. On the other hand, the repeated administration of citalopram, the selective inhibitor of serotonin reuptake, resulted in an increase in the level of D1 mRNA in the striatum and in the core region of nucleus accumbens. A similar tendency, i.e.: an increase in the level of D1 mRNA was observed after repeated administration of (+)-oxaprotiline, a selective inhibitor of noradrenaline reuptake. The level of mRNA coding for dopamine D2 receptors (D2 mRNA) was increased in all the brain regions studied, both after administration of imipramine and citalopram. (+)-Oxaprotiline did not produce any statistically significant changes in the level of D2 mRNA. The results obtained in this study indicate that the levels of mRNA coding for dopamine D1 and D2 receptors are regulated by the antidepressant drugs. The changes concerning the dopamine D2 receptors are more consistent and fit in with the previously described binding and behavioral effects and seem to be important for the mechanism of action of antidepressant drugs.

Changes in prepulse inhibition after local administration of NMDA receptor ligands in the core region of the rat nucleus accumbens

The dopamine and glutamate hypotheses are two pharmacological models for schizophrenia. In the present investigations, the prepulse inhibition paradigm was used to evaluate the role of the nucleus accumbens core region in both models. Prepulse inhibition is known to be decreased in schizophrenics, when compared with control patients, and in rats after systemic injection of dopamine receptor agonists and non-competitive antagonists of the NMDA receptor. In the present study injection of dopamine in the rat nucleus accumbens core region also decreased prepulse inhibition. Injections of NMDA decreased, whereas a low dose of the competitive NMDA receptor antagonist (±)-2-amino-5-phosphonopentanoic acid (AP-5) and the non-competitive NMDA receptor antagonist (5 R,10 S)-(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo[ a,d]cycloheten-5,10-imine hydrogen maleate (MK-801) increased prepulse inhibition. The results indicate an involvement of the accumbens core in mediating the systemic effects on prepulse inhibition of dopamine receptor agonists but not of non-competitive NMDA receptor antagonists.