Elucidating Ih Biophysical Epigenetic Modifications in VTA Dopaminergic Neurons after Contingent and Non-Contingent Cocaine Administration

阐明偶然和非偶然可卡因给药后 VTA 多巴胺能神经元的 Ih 生物物理表观遗传修饰

• 批准号: 10797209
• 负责人: CARLOS A JIMENEZ-RIVERA
• 金额: $ 8.16万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797209
• 关键词: Animal Model; Biophysics; Cations; Chronic; Cocaine; Consumption; Development; Disease; Drug Exposure; Electrophysiology (science); Elements; Epigenetic Process; HDAC2 gene; Histone Deacetylase Inhibitor; Histone Deacetylation; Human; Intervention; Ion Channel; Knowledge; Learning; Measures; Modeling; Modification; Natural Substance; Neurons; Outcome Study; Participant; Pathway interactions; Pharmaceutical Preparations; Physiological; Process; Property; Psychological reinforcement; Rewards; Risk Factors; Self Administration; Substance abuse problem; Testing; Therapeutic; Ventral Tegmental Area; addiction; biophysical properties; cocaine exposure; cocaine sensitization; dopaminergic neuron; drug action; epigenetic regulation; epigenomics; histone modification; in vivo; neuroadaptation; pharmacologic; small hairpin RNA; substance abuse treatment; therapy development

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.

摘要