Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission.
ABSTRACT To explore the role of endogenous GABA in NMDA antagonist induced dopamine (DA) release, we used in vivo microdialysis to study the effects of pretreatment with gamma-vinyl GABA (GVG) on phencyclidine (PCP)-induced DA release in terminal regions of midbrain DA neurons. GVG, an irreversible inhibitor of the GABA catabolizing enzyme GABA-AT, significantly reduced the DA response to PCP (7.0 mg/kg) in freely moving animals. Preferential increases in PCP-induced DA release in the PFC (four-fold those of NAcc) were dose-dependently inhibited by acute pretreatment with GVG at doses of 150 (51% inhibition), 300 (68% inhibition), and 500 (82% inhibition) mg/kg, whereas NAcc PCP-induced DA activity was unresponsive to 150 mg/kg and only partially inhibited by 300 and 500 mg/kg. Subchronic treatment with GVG did not enhance the inhibitory capacity of the GABAergic system. While GVG evidently modulates PCP-induced increases in mesocorticolimbic DA transmission, the character of this modulation is regionally specific, with cortical NMDA-antagonist induced increases appearing more sensitive to inhibition by endogenous GABA than subcortical areas.
Article: Significance of dysfunctional glutamatergic transmission for the development of psychotic symptoms.[show abstract] [hide abstract]
ABSTRACT: It has been postulated that disturbances in glutamatergic transmission may contribute to the pathophysiology of schizophrenia. This view is based on several findings: (1) the noncompetitive NMDA receptor antagonists, phencyclidine and ketamine, induce both positive and negative psychotic symptoms in humans, which closely resemble those observed in schizophrenia; (2) a number of animal studies have shown that neuroleptics that ameliorate symptoms of schizophrenia (e.g. clozapine) also inhibit the effects of NMDA antagonists; (3) postmortem and in vivo studies have revealed alterations in ionotropic glutamate receptors (NMDA, AMPA, KA) and their modulatory sites in schizophrenia; (4) compounds enhancing the function of NMDA receptors potentiate the antipsychotic effects of neuroleptics in schizophrenic patients.Polish journal of pharmacology 55(2):133-54.