The Hyperpolarization-Activated Cyclic Nucleotide-Gated Ion Channels in the Rewarding Effects of Ethanol

Abstract

Abstract An early target for ethanol-rewarding effects are the dopaminergic neurons of the ventral tegmental area (VTA), which are part of the dopamine mesolimbic system. Ethanol is able to activate VTA dopamine neurons by increasing their firing rate, thus, releasing dopamine in the nucleus accumbens. The excitability of VTA dopamine neurons is largely controlled by the depolarizing effect of hyperpolarization-activated cyclic nucleotide-gated (HCN) ionic channels. Experimental evidence shows that ethanol can activate HCN channels and that these activating actions of ethanol can be blunted by HCN blockers. Higher levels of the HCN2 isoform in the mesolimbic system have been associated with increased rewarding and stimulant effects of ethanol in animals. The mechanism by which ethanol activates HCN seems to be associated with the increase of intracellular cAMP levels. The development of drugs selective for neuronal HCN channels would provide a tool to determine the relevance of HCN channels in alcohol addiction.