Pharmacological reduction of small conductance calcium-activated potassium current (SK) potentiates the excitatory effect of ethanol on ventral tegmental area dopamine neurons

Abstract

Dopaminergic neurons in the ventral tegmental area (VTA) are important for the rewarding properties of drugs of abuse, including ethanol. We previously demonstrated that ethanol excites VTA neurons and that ethanol reduces the amplitude of the after hyperpolarization (AHP) that follows spontaneous action potentials. Because the small conductance calcium-activated potassium current (SK) is a component of the AHP of VTA neurons, we assessed the effect of the SK blockers apamin and d-tubocurarine (d-TC) on the action of ethanol on dopaminergic VTA neurons with intracellular and extracellular recording in rat brain slices. Apamin (1-200 nM) and d-TC (100 and 400 microM) caused concentration-dependent reductions in the AHP amplitude. Ethanol (80 mM) caused a small reduction in the AHP. In the presence of apamin (40 nM), ethanol (80 mM) caused a much larger reduction in AHP amplitude. Extracellular studies showed that apamin (20, 40, and 100 nM) and d-TC (400 microM) had no significant effect on the spontaneous firing rate of dopaminergic VTA neurons but enhanced the potency of ethanol to increase their firing rate. These results indicate that the ethanol-induced reduction of the AHP and excitation of VTA neurons is not due to a reduction in SK current. Furthermore, blockade of SK current by apamin or d-TC enhances the excitatory effect of ethanol on dopaminergic VTA neurons. These data suggest that the amount of SK current present affects the sensitivity of dopaminergic VTA neurons to ethanol excitation and that neurotransmitters that reduce SK current may increase the reward potency of ethanol.