title: N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.
abstract: The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.
authors.affiliation: Department of Neuroscience, Psychology and Behaviour, University of Leicester , Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Ersin
authors.initials: E
authors.lastname: Yavas
authors.affiliation: Department of Neuroscience, Psychology and Behaviour, University of Leicester , Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Andrew M J
authors.identifier: 0000-0002-2022-607X
authors.initials: AM
authors.lastname: Young
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055664:Electrochemical Techniques; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D004079:Dihydro-beta-Erythroidine; D004298:Dopamine; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D016202:N-Methylaspartate; D018733:Nicotinic Antagonists; D010622:Phencyclidine; D010852:Picrotoxin; D018094:Receptors, Metabotropic Glutamate
keywords: Brain slices; N-methyl-d-aspartate; dopamine; metabotropic glutamate receptors; nucleus accumbens; phencyclidine