Abstract
BackgroundThe 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 naïve rats and of rats pre-treated with nicotine.ResultsIn 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 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 μM) on the stimulated [3H]-monoamine overflow was abolished in rats pre-treated with nicotine as compared to saline-injected controls.ConclusionsOur 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.
Highlights
The activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine
Tetrodotoxin and calcium dependence of the stimulated [3H]-DA release from VTA slices The influence of tetrodotoxin (TTX) and calcium on the electrically evoked release of [3H]-DA from ventral tegmental slices of naïve rats was evaluated in order to determine its physiological significance under the experimental conditions used here
Effect of GABAB receptor activation on VTA [3H]-DA release Baclofen (0.1–100 μM), added to the superfusion buffer 36 min before the second stimulation, dose-dependently reduced the electrically evoked [3H]-DA release from VTA slices
Summary
The activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. The ventral tegmental area (VTA) represents the site of origin of the mesocorticolimbic dopaminergic pathway that has been implicated in mediating the reinforcing properties of drugs of abuse, including nicotine [1,2,3]. The majority of cells within the ventral tegmental area consist of dopaminergic, tyrosine-hydroxylase containing neurones, which send axon projections to forebrain structures such as the nucleus accumbens and the prefrontal cortex. The picture shows the orientation of the cuts (dark lines) for the dissection of the ventral tegmental area (VTA).
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