Reduced inhibitory action of a GABAB receptor agonist on [3H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration.
BACKGROUND
The activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. However, the neurochemical mechanism that underlie this effect remains unknown. Since GABAB receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABAB receptor agonist baclofen on the release of [3H]-dopamine ([3H]-DA) from VTA slices of naive rats and of rats pre-treated with nicotine.


RESULTS
In naive rats, baclofen concentration-dependently inhibited the electrically evoked release of [3H]-DA from the isolated VTA (EC50 = 0.103 microM, 95% CI = 0.043-0.249), without affecting the basal [3H]-monoamine overflow. This effect was mediated by activation of GABAB receptors as it was blocked by the selective receptor antagonist CGP55845A. Chronic administration of nicotine (0.4 mg kg(-1), s.c., for 14 days) affected neither the basal nor the electrically evoked release of [3H]-DA from VTA slices. However, the inhibitory effect of baclofen (10 microM) on the stimulated [3H]-monoamine overflow was abolished in rats pre-treated with nicotine as compared to saline-injected controls.


CONCLUSIONS
Our results demonstrate that GABAB receptor activation reduces the release of DA from the rat VTA. In addition, a reduced sensitivity of VTA GABAB receptors appears to develop after chronic exposure to nicotine. The resulting disinhibition of VTA DA neurones might therefore contribute to the sensitised dopaminergic responses observed in the rat mesocorticolimbic system following repeated administration of nicotine.
Amantea
Diana
D
Department of Pharmacology, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. diana_amantea@yahoo.co.uk
Bowery
Norman G
NG
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D018755:GABA Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D018755:GABA Agonists; D014316:Tritium; D013779:Tetrodotoxin; D009538:Nicotine; D001418:Baclofen; D002118:Calcium; D004298:Dopamine