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Ethanol Inhibition of M-Current and Ethanol-Induced Direct Excitation of Ventral Tegmental Area Dopamine Neurons

Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Submitted 13 March 2006; accepted in final form 3 September 2006

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 µM) increased spontaneous firing frequency which correlated positively with I_M inhibition with a slope value of 0.5. In the presence of 10 µM 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.

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