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 γ-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.
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Acknowledgements
This research was carried out at Brookhaven National Laboratory under contract with the U.S. Department of Energy Office of Biological and Environmental Research (USDOE/OBER DE-AC02-98CH10886), the National Institutes of Mental Health (NIMH MH49165 and NIMH R2955155), and the National Institute on Drug Abuse (5RO-DA06278). Partial funding provided by Eli Lilly Pharmaceuticals, Inc.
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Schiffer, W., Gerasimov, M., Hofmann, L. et al. Gamma Vinyl-GABA Differentially Modulates NMDA Antagonist-Induced Increases in Mesocortical Versus Mesolimbic DA Transmission. Neuropsychopharmacol 25, 704–712 (2001). https://doi.org/10.1016/S0893-133X(01)00268-8
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DOI: https://doi.org/10.1016/S0893-133X(01)00268-8
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