Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased γ-aminobutyric acid (GABA)-ergic activity produced by γ-vinyl GABA [D, L-4-amino-hex-5-enoic acid (Vigabatrin®)], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse.
Bibliographical noteFunding Information:
The authors thank Dr. Andrew Gifford, Dr. S. John Gatley, and Mr. David Alexoff for helpful discussions. We gratefully acknowledge Hoechst Marion Roussel for the generous supply of vigabatrin and ChiroTech Technology for providing 1 R ,4 S -ACC and 1 S ,4 R -ACC. This research was carried out under contract with the US Department of Energy Office of Biological and Environmental Research (USDOE/OBER DE-AC02-98CH10886) and by the National Institutes of Mental Health (NIMH MH49165 and NIMH R2955155).
- γ-Aminobutyric acid (GABA)
- γ-Aminobutyric acid (GABA) reuptake inhibitor
- γ-Vinyl GABA (vigabatrin)