Ethanol inhibition of M-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons

Ethanol-induced excitation of ventral tegmental area dopamine ( DA VTA) neurons is thought to be critical for the reinforcing effects of ethanol. Although ligand-gated ion channels are known to be the targets of ethanol, ethanol modulation of voltage-dependent ion channels of central neurons has not been well studied. We have demonstrated that ethanol excites DA VTA neurons by the reduction of sustained K+ currents and recently reported that M-current ( I-M) regulates action potential generation through fast and slow afterhyperpolarization phases. In the present study we thus examined whether ethanol inhibition of I-M contributes to the excitation of DA VTA neurons using nystatin-perforated patch current- and voltage-clamp recordings. Ethanol ( 20-120 mM) reduced I-M in a concentration-dependent manner and increased the spontaneous firing frequency of DA VTA neurons. Ethanol-induced increase in spontaneous firing frequency correlated positively with ethanol inhibition of I-M with a slope value of 1.3. Specific I-M inhibition by XE991 ( 0.3-10 mu M) increased spontaneous firing frequency which correlated positively with I-M inhibition with a slope value of 0.5. In the presence of 10 mu M XE991, a concentration that produced maximal inhibition of I-M, ethanol still increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner. Thus we conclude that, although ethanol causes inhibition of I-M and this results in some increase in the firing frequency of DA VTA neurons, another effect of ethanol is primarily responsible for the ethanol-induced increase in firing rate in these neurons.