Neurotransmission In Nucleus Accumbens Research Articles

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects’ times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects. We discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in OUD, that were largely distinct between OUD and unaffected subjects. Fewer rhythmic transcripts were identified in DLPFC of subjects with OUD compared to unaffected subjects, whereas in the NAc, nearly double the number of rhythmic transcripts was identified in subjects with OUD. In NAc of subjects with OUD, rhythmic transcripts peaked either in the evening or near sunrise, and were associated with an opioid, dopamine, and GABAergic neurotransmission. Associations with altered neurotransmission in NAc were further supported by co-expression network analysis which identified OUD-specific modules enriched for transcripts involved in dopamine, GABA, and glutamatergic synaptic functions. Additionally, rhythmic transcripts in DLPFC and NAc of subjects with OUD were enriched for genomic loci associated with sleep-related GWAS traits, including sleep duration and insomnia. Collectively, our findings connect transcriptional rhythm changes in opioidergic, dopaminergic, GABAergic signaling in the human brain to sleep-related traits in opioid addiction.

Chronic modafinil administration to preadolescent rats impairs social play behavior and dopaminergic system

Some clinical trials are investigating modafinil (Mod) as a treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. Mod increases dopamine (DA) levels in the reward system by blocking dopamine transporter (DAT). Social interactions are rewarding behaviors and evidence reveals the importance of reward circuitry in social interactions. Chronic psychostimulant treatments alter DA neurotransmission and associated behaviors. The aim of this work was to evaluate the effects of chronic Mod treatment during preadolescence on social play behavior, locomotor activity, and DA in nucleus accumbens (NAc). Preadolescent male Sprague-Dawley rats were injected with Mod (75 mg/kg i.p.) or vehicle for 14 days (PND22 to PND35). After that, we measured social play behavior, content and DA release in NAc by HPLC coupled to electrochemical detection, protein levels of DA type 2 receptor (D2) by Western blot and DA kinetic by fast-scan cyclic voltammetry (FSCV) in NAc. Regarding social play, the total number of pinning events decreased in the Mod group compared with the vehicle. The K+-stimulated DA release in NAc was significantly lower in Mod-treated rats compared with vehicle group. Also, Mod increases locomotor activity at the first injection, but this effect is almost completely lost at day 14 of Mod treatment. Chronic Mod treatment during preadolescence in rats impairs dopaminergic neurotransmission in NAc and decreases the capacity of rats to perceive rewarding effects of social play. Importantly, as Mod is being evaluated to treat ADHD in children and adolescents, potential effects on social behavior should be considered since this kind of behavior in this particular stage is crucial for neurodevelopment.

The involvement of accumbal glycine receptors in the dopamine-elevating effects of addictive drugs

The ability of drugs of abuse to increase mesolimbic levels of dopamine is a characteristic associated with their rewarding effects. Exactly how these effects are produced by different substances is not as well characterised. Our previous work in rats has demonstrated that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine-activating effects of ethanol, and in modulating ethanol intake. In this study the investigation of GlyR involvement was extended to include several different drugs of abuse. By using microdialysis and electrophysiology we compared effects of addictive drugs, with and without the GlyR antagonist strychnine, on dopamine levels and neurotransmission in nucleus accumbens. The dopamine-increasing effect of systemic ethanol and the drug-induced change in neurotransmission in vitro, as measured by microdialysis and field potential recordings, were dependent on GlyRs in nAc. Accumbal GlyRs were also involved in the actions of tetrahydrocannabinol and nicotine, but not in those of cocaine or morphine. These data indicate that accumbal GlyRs play a key role in ethanol-induced dopamine activation and contribute also to that of cannabinoids and nicotine.

The COMT Val158Met polymorphism is associated with novelty seeking in czech methamphetamine abusers: Preliminary results

Background and aims:Measurable traits of human personality may mark the predisposition to psychopathology. Increased novelty seeking plays an important role in the pathogenesis of substance abuse. Novelty seeking, one of the fundamental traits of the human temperament, is related to dopamine. Catechol-O-methyltransferase (COMT) is essential for dopamine inactivation. The aim of our study was to assess whether the COMT gene Val158Met functional polymorphism in patients dependent on methamphetamine is related to their novelty seeking score.Methods:Patients dependent on methamphetamine who had been treated at the Addiction Treatment Unit in Nechanice in 2004 and 2005 agreed to participate in the investigation. We administered the Temperament and Character Inventory (TCI) questionnaire, assessed their novelty seeking score and analysed their DNA samples for COMT Val158Met genotype.Results:The subjects were thirty-seven Czech Caucasians (women N = 10) dependent on methamphetamine with an average age of 23.6 ± 3.8 years. We found a significantly higher mean novelty seeking score among the patients with the Met allele (Met/Met homozygotes + Val/Met heterozygotes; N = 28) than in nine Val/Val homozygotes (27.4 vs 24.1; p = 0.042, Two-Sample T-Test).Conclusions:The Met allele of the COMT gene Val158Met polymorphism is associated with low COMT enzyme activity and high endogenous dopamine synaptic levels in the prefrontal cortex. This leads to a decrease in dopaminergic neurotransmission in nucleus accumbens and a need for an increased activity to stimulate it. Novelty seeking behavior corresponds with this need.

Therapeutic possibilities of cysteamine in the treatment of schizophrenia

Schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future.

Hippocampal Dopamine Receptors Modulate the Motor Activation and the Increase in Dopamine Levels in the Rat Nucleus Accumbens Evoked by Chemical Stimulation of the Ventral Hippocampus

A number of studies have shown that chemical stimulation (using N-methyl-D-aspartate (NMDA) infusions) or electrical stimulation of the ventral hippocampus (VH) elicits locomotor activation and sustained increases in nucleus accumbens (NAc) dopamine (DA) levels in rodents. How DA neurotransmission in NAc is involved in these effects has also been well established. However, the modulatory role of the DA receptors located in VH is not yet fully understood. The purpose of this study was to characterize the role played by VH D1 and D2 subtype receptors in both the locomotor activation and NAc DA increases induced by NMDA stimulation of the VH. This was assessed by studying how retrodialysis application of NMDA (50 mM, 10 min) affects motor activity and NAc DA levels during simultaneous retrodialysis administration of the D1/D5 receptor antagonist SCH 23390 (100 and 250 microM, 60 min) or the D2 receptor antagonist raclopride (100 and 250 microM, 60 min). SCH 23390 attenuated or completely abolished NMDA-evoked locomotor activation and the concurrent increase in NAc DA levels. On the other hand, raclopride was initially able to attenuate the effects of VH NMDA stimulation. However, in the last phase of the experiments, animals showed an important increase in clonic seizure activity with a simultaneous and dramatic increase in NAc DA levels. Our results show that the NMDA receptor-mediated effects in the VH require both D1 and, probably, D2 receptors and suggest that DA in VH strongly modulates the excitatory outputs from this brain area.

Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens.

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse perturb the normal functioning of this pathway. The nucleus accumbens (NAc) is a major terminal field of the mesolimbic dopamine neurons and modifications in neuronal structure and function in NAc accompany repeated exposure to psychomotor stimulants and other addictive drugs. Glutamatergic afferents to the NAc are thought to be crucial to the development of several aspects of addictive behavior, including behavioral sensitization and relapse to cocaine self-administration. Here we examine glutamatergic neurotransmission and synaptic plasticity in NAc neurons in vitro before and after repeated amphetamine treatment in vivo. We find that dopamine attenuates the response of NAc neurons to repetitive activation of glutamatergic afferents and thereby blocks long-term potentiation (LTP) induced by high-frequency afferent stimulation. Dopamine's effects are mimicked by dopamine receptor agonists and by amphetamine. In a second set of experiments, animals were treated with amphetamine daily for 6 days and brain slices were prepared after 8-10 days of withdrawal. In these slices, LTP in the NAc appears normal. However, acute exposure of such slices to amphetamine no longer modulates synaptic transmission or LTP induction. Thus, repeated exposure to amphetamine produces long-lasting changes in the modulation of glutamatergic synaptic transmission by amphetamine in the NAc. Our results support the notion that after psychostimulant exposure, excitatory synapses on NAc neurons alter their response to further psychostimulant for long periods of time.

Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors

Background: Phencycline (PCP, “angel dust”) and other noncompetitive antagonists of N-methyl- d-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. Methods: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. Results: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. Conclusions: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was perfomed through microdialysis probes into the rat ventral pallidum (10 μ1 of 0 2.6 4.0, 13.0, and 26.0 mM) or globus pallidus (10 μ1 of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.