Citation

Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, Ashby CR. Synapse 1999; 31(1): 76-86.

Copyright

(Copyright © 1999, John Wiley and Sons)

DOI

10.1002/(SICI)1098-2396(199901)31:1<76::AID-SYN10>3.0.CO;2-Y

PMID

10025686

Abstract

Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiting nicotine's biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine-induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine-induced increases in both naive and chronically nicotine-treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C-raclopride in primates, GVG (100 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction.

Language: en

Keywords

4-Aminobutyrate Transaminase; Animals; Enzyme Inhibitors; Female; gamma-Aminobutyric Acid; Male; Microdialysis; Papio; Rats; Rats, Sprague-Dawley; Tobacco Use Disorder; Tomography, Emission-Computed; Vigabatrin