gamma-Aminobutyric acid mimetic drugs differentially inhibit the dopaminergic response to cocaine

Dopaminergic activity in the mesocorticolimbic system is associated with re inforcing properties of psychostimulant drugs. We previously demonstrated t hat increased gamma-aminobutyric acid (GABA)-ergic activity produced by gam ma-vinyl GABA [D,L-4-amino-hex-5-enoic acid (Vigabatrin(R))], an irreversib le inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, al cohol, and methamphetamine-induced increases in extracellular nucleus accum bens dopamine as well as behaviors associated with three biochemical change s. In the present study, using in vivo microdialysis techniques, we compare d three different strategies to increase GABAergic activity in order to mod ulate cocaine-induced increase in extracellular dopamine. Our data demonstr ate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2, 5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GAB A u ptake inhibitor, dose and time dependently diminished increases in extracel lular dopamine following acute cocaine challenge. Furthermore, we demonstra ted that cyclized analogue of vigabatrin, a competitive reversible GABA-tra nsaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversibl e inhibition of GABA transaminase, inhibition of GABA uptake represent anot her potentially effective, indirect strategy for the treatment of cocaine a buse. (C) 2000 Published by Elsevier Science B.V. All rights reserved.