N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.
Ersin Yavas, Andrew M J Young
ACS Chemical Neuroscience February 15, 2017 DOI: 10.1021/acschemneuro.6b00397 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study using brain slices Peer reviewed |
|---|---|
| Population | Rat nucleus accumbens brain slices; rodents pretreated in vivo with phencyclidine |
| Interventions | NMDA phencyclidine picrotoxin (RS)-α-methyl-4-sulfonophenylglycine |
| Duration | Phencyclidine pretreatment twice daily for 5 days, with a washout period of at least 7 days before experimentation |
| Keywords | Brain slices N-methyl-d-aspartate Dopamine Metabotropic glutamate receptors Nucleus accumbens Phencyclidine |
| Key findings | NMDA produced a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens slices. The effect was not blocked by picrotoxin but was reduced by the metabotropic glutamate receptor antagonist (RS)-α-methyl-4-sulfonophenylglycine, and was unchanged by subchronic phencyclidine pretreatment. The authors propose that NMDA depresses accumbal dopamine release via pre- or perisynaptic metabotropic glutamate receptors activated by extrasynaptic glutamate spillover, and that enduring phencyclidine-induced changes are downstream of chronic NMDA receptor blockade rather than direct NMDA receptor effects. |
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.