ABSTRACT The ventral tegmental area (VTA) is a key CNS region involved in the reward and reinforcement of natural substances and drugs, such as cocaine. Hyperpolarization-activated cation current (Ih) is a key participant in the fundamental intrinsic properties of dopaminergic (DA) neurons of the VTA. The ion channels that carry Ih are comprised of HCN subunits, predominantly the HCN2 in the VTA. Alteration of Ih due to drug exposure has been shown after cocaine sensitization (CS). This change in Ih may be a common physiological mechanism in central reward/reinforcement pathways that contributes to addiction. Epigenetic mechanisms like histone deacetylation are responsible for some crucial neuronal changes that occur following chronic drug administration. This project will study the epigenetic regulation of the Ih function during the development of CS and on the Intermittent access self-administration (IntA) model. The IntA in our opinion better simulates human drug consumption. The specific aims will include: 1) To investigate the VTA epigenomic profile after CS, IntA and Histone Deacetylase inhibitor (HDACi); 2) Electrophysiological examination of Ih in VTA DA neurons after CS, IntA and HDACi; 3) To measure changes in HCN2 subunits in the VTA after CS, IntA and HDACi; 4) To investigate if in vivo shRNA targeting HDAC2 alters the development of CS, IntA and Ih properties of VTA DA neurons. Examination of cocaine-induced epigenetic changes in the VTA can provide key information about neuroadaptations that occur during the development of addiction. The reversal of these epigenetic modifications by histone deacetylase inhibition might provide possible avenues for therapeutic pharmacological intervention.

Narrative This project will test if the alteration of HCN channel function to progressive cocaine exposure is a critical element of drug action on the VTA resulting from epigenetic regulation acquired during the learning process using contingent and non-contingent animal models. One possible outcome of these studies is to identify risk factors for substance abuse disorders related to epigenetic regulation of an ionic channel that regulates neuronal biophysical properties. Knowledge of the epigenetic control of cocaine-induced biophysical neuronal changes ultimately will lead to the identification of new targets in the development of treatments for substance abuse disorders.