GABA(A) receptors mediate the opposing roles of dopamine and the tegmental pedunculopontine nucleus in the motivational effects of ethanol.

Recent work has demonstrated that changes in ventral tegmental area (VTA) GABA(A) receptor ion conductance properties are responsible for switching morphine's positive reinforcing properties from a dopamine-independent to a dopamine-dependent pathway when an animal transitions from a non-deprived (minimal drug exposure) to a dependent (chronic drug exposure) and withdrawn state. Here we show that a double dissociation of ethanol's positive reinforcing properties is exactly opposite to that seen with morphine. In C57BL/6 mice, ethanol-conditioned place preferences were blocked in dopamine D2 receptor knockout non-deprived mice, but not by a lesion of the tegmental pedunculopontine nucleus (TPP). On the other hand, TPP lesions, but not a D2 receptor mutation, blocked ethanol-conditioned place preferences in ethanol-dependent and withdrawn mice. The opposite effects of ethanol and opiates can be explained by their proposed actions through a common VTA GABA(A) receptor switching mechanism.