Alcohol Action on Neurons in the Brain Reward Circuit

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DESCRIPTION (provided by applicant): Dopaminergic neurons in the ventral midbrain are the key component of the brain reward circuit. Acute administration of ethanol enhances the firing of dopamine neurons, whereas withdrawal from repeated ethanol exposure leads to a marked reduction in their activity. These effects are thought to contribute to the rewarding/reinforcing action of alcohol and the negative affective state experienced during abstinence. Dopamine neurons display a spectrum of firing patterns, ranging from pacemaker-like to burst-pause. The tonic, pacemaker firing represents the intrinsic activity of dopamine neurons, whereas the phasic, burst-pause firing is triggered by afferent inputs impinging on them. The overriding hypothesis of this proposal is that ethanol regulates both tonic and phasic activities of dopamine neurons via distinct postsynaptic mechanisms to produce its behavioral actions. This will be addressed with electrophysiological recording in acutely prepared midbrain slices from mice. The pacemaker activity of dopamine neurons is controlled by two key voltage-gated ionic conductances: the hyperpolarization- activated cation current (Ih) and the A-type potassium current (IA). These conductances play counteracting roles in that Ih facilitates and IA suppresses pacemaker firing. The first goal is to determine the effects of acute (Aim 1) and repeated (Aim 2) ethanol treatments on Ih and IA and identify their contribution to the modulation of pacemaker firing. The second goal is to determine the effects of acute (Aim 3) and repeated (Aim 4) ethanol treatments on the pause of firing accompanying bursts. In these aims, the pause of firing between bursts is posited to limit, or gate, the occurrence of bursts. Stimulation of glutamatergic inputs to dopamine neurons evokes a burst of firing followed by a pause. This pause is mediated by metabotropic glutamate receptors (mGluRs), which activate a calcium-sensitive potassium conductance via release of calcium from intracellular stores to cause membrane hyperpolarization. We will test the hypothesis that acute ethanol suppresses, while withdrawal from repeated ethanol exposure enhances the mGluR-mediated hyperpolarization/pause. Confocal calcium imaging and flash photolysis of caged compounds will be performed to delineate the postsynaptic targets mediating the action of ethanol. The role of Ih and IA in shaping the ethanol sensitivity of the mGluR-mediated hyperpolarization will also be determined. The information obtained from this study will advance our understanding of the neurobiological processes underlying alcohol-drinking behavior and hence will help develop better treatment strategies for alcoholism.