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Hyperpolarization-Activated Cation Current (I_h) Is an Ethanol Target in Midbrain Dopamine Neurons of Mice

Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology and Institute for Neuroscience, University of Texas, Austin, Texas

Submitted 30 June 2005; accepted in final form 2 September 2005

Ethanol stimulates the firing activity of midbrain dopamine (DA) neurons, leading to enhanced dopaminergic transmission in the mesolimbic system. This effect is thought to underlie the behavioral reinforcement of alcohol intake. Ethanol has been shown to directly enhance the intrinsic pacemaker activity of DA neurons, yet the cellular mechanism mediating this excitation remains poorly understood. The hyperpolarization-activated cation current, I_h, is known to contribute to the pacemaker firing of DA neurons. To determine the role of I_h in ethanol excitation of DA neurons, we performed patch-clamp recordings in acutely prepared mouse midbrain slices. Superfusion of ethanol increased the spontaneous firing frequency of DA neurons in a reversible fashion. Treatment with ZD7288, a blocker of I_h, irreversibly depressed basal firing frequency and significantly attenuated the stimulatory effect of ethanol on firing. Furthermore, ethanol reversibly augmented I_h amplitude and accelerated its activation kinetics. This effect of ethanol was accompanied by a shift in the voltage dependence of I_h activation to more depolarized potentials and an increase in the maximum I_h conductance. Cyclic AMP mediated the depolarizing shift in I_h activation but not the increase in the maximum conductance. Finally, repeated ethanol treatment in vivo induced downregulation of I_h density in DA neurons and an accompanying reduction in the magnitude of ethanol stimulation of firing. These results suggest an important role of I_h in the reinforcing actions of ethanol and in the neuroadaptations underlying escalation of alcohol consumption associated with alcoholism.

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