Research article

Reduced inhibitory action of a GABA_B receptor agonist on [³H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration

Diana Amantea^1,2 and Norman G Bowery¹

¹Department of Pharmacology, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

²Department of Pharmacobiology, University of Calabria, 87036 Rende, Cosenza, Italy

author email corresponding author email

BMC Pharmacology 2004, 4:24doi:10.1186/1471-2210-4-24

Published:	20 October 2004

Abstract

Background

The activation of GABA_B 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 GABA_B receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABA_B receptor agonist baclofen on the release of [³H]-dopamine ([³H]-DA) from VTA slices of naïve rats and of rats pre-treated with nicotine.

Results

In naïve rats, baclofen concentration-dependently inhibited the electrically evoked release of [³H]-DA from the isolated VTA (EC₅₀ = 0.103 μM, 95% CI = 0.043–0.249), without affecting the basal [³H]-monoamine overflow. This effect was mediated by activation of GABA_B 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 μM) 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 GABA_B receptor activation reduces the release of DA from the rat VTA. In addition, a reduced sensitivity of VTA GABA_B 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.