Ventral tegmental area region governs GABA(B) receptor modulation of ethanol-stimulated activity in mice

Locomotor stimulation in response to ethanol in mice may model human ethanol-induced euphoria. The associated neural substrates, possibly relevant to alcoholism, have not been fully elucidated. Systemic injection of baclofen, a GABA(B) receptor agonist, attenuates ethanol's stimulant effects. GABA(B) receptors on dopamine cell bodies in the ventral tegmental area (VTA) may modulate ethanol-induced dopamine release, a postulated mechanism for ethanol's stimulant effects. However, baclofen's attenuating effects could be associated with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation, to test the hypotheses that (1) central GABA(B) receptors influence baclofen's effects on ethanol-stimulated activity, and (2) VTA GABA(B) receptors specifically modulate ethanol's stimulant effects. I.c.v. baclofen dose-dependently attenuated ethanol stimulation, supporting a central locus for baclofen's effects. Anterior VTA baclofen also attenuated ethanol stimulation. However, more posterior VTA infusions unexpectedly potentiated ethanol stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice. GABA(B) receptor autoradiography using (3)H]CGP 54626, a potent GABA(B) receptor antagonist, did not reveal line differences in binding density in the VTA, or in the substantia nigra pars compacta, a nearby brain structure associated with motor control. These results suggest that anterior VTA GABA(B) receptors play a role in baclofen's attenuation of ethanol's stimulant effects, and that posterior VTA GABA(B) receptors serve an opposite role that is normally masked. Selection for differential ethanol stimulant sensitivity has altered VTA GABA(B) systems that influence locomotor behavior. However, differences in GABA(B) receptor densities in the VTA or substantia nigra pars compacta cannot explain the selected line difference.