Stereoselective inhibition of dopaminergic activity by gamma vinyl-GABA following a nicotine or cocaine challenge: a PET/microdialysis study.
Elevation of endogenous GABA by the racemic mixture of gamma vinyl-GABA (GVG, Vigabatrin) decreases extracellular nucleus accumbens (NAc) dopamine (DA) levels and diminishes the response to many drugs of abuse known to elevate DA in the mesocorticolimbic system. We investigated the effects of the individual enantiomers (S(+)-GVG, R(-)-GVG) on cocaine-induced NAc DA in rodents as well as the effects of nicotine-induced increases in primates. In a series of microdialysis experiments in freely moving animals, S(+)-GVG (150 mg/kg), R(-)-GVG (150 mg/kg) or racemic (R, S) GVG (300 mg/kg) was administered 2.5 hours prior to cocaine (20 mg/kg) administration. When compared with cocaine alone, the R(-) enantiomer did not significantly inhibit cocaine induced NAc DA release. S(+)-GVG, at half the dose of the racemic mixture (150 mg/kg), inhibited cocaine-induced DA elevation by 40%, while the racemic mixture (300 mg/kg) inhibited cocaine-induced DA release by 31%. In addition, our PET studies in primates demonstrated that S(+)-GVG completely inhibits nicotine-induced increases in the corpus striatum, again at half the dose of the racemic mixture. The R(-) enantiomer was ineffective. Although the S(+) enantiomer has been well established as the active compound in the treatment of epilepsy, the efficacy of this enantiomer with regard to mesolimbic DA inhibition generates a complex series of clinical and neurochemical issues. Further investigations will determine the locus of action and physiologic properties of each enantiomer.
Schiffer
W K
WK
Department of Psychiatry, NYU School of Medicine, New York, NY, USA.
Gerasimov
M R
MR
Bermel
R A
RA
Brodie
J D
JD
Dewey
S L
SL
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed; D020888:Vigabatrin / Q000494:pharmacology*
D009538:Nicotine; D020888:Vigabatrin; D003042:Cocaine; D004298:Dopamine