Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration

中脑 GABA 电路的改变可促进可卡因的自我管理

• 批准号: 10405526
• 负责人: John A. Dani
• 金额: $ 53.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405526
• 关键词: Abstinence; Animal Model; Attenuated; Behavior; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chlorides; Cocaine; Cocaine Abuse; Cocaine use disorder; Consumption; Data; Dependence; Dopamine; Dose; Down-Regulation; Drug Administration Routes; Extinction (Psychology); FDA approved; Goals; Hospitalization; Human; Infusion procedures; Maintenance; Measures; Membrane; Midbrain structure; Modeling; Molecular; Molecular Target; Neuraxis; Neurons; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Physiological; Protocols documentation; Public Health; Relapse; Research; Rodent Model; Self Administration; Testing; Therapeutic; Time; United States National Center for Health Statistics; Volition; addiction; base; cell type; chloride-cotransporter potassium; cocaine exposure; cocaine relapse; cocaine relapse prevention; cocaine self-administration; cocaine use; experimental study; gamma-Aminobutyric Acid; neuroadaptation; new therapeutic target; novel; prevent; promoter; side effect; stimulant abuse; therapeutic target

Project Summary. Cocaine is the most widely abused psychostimulant by a wide margin, and it remains a major public health problem in the US. Cocaine use was slowly declining, but in recent years there has been a resurgence in cocaine abuse accompanied by a sharp increase in cocaine-related hospitalizations and deaths. These facts highlight the need for effective medications for cocaine use disorder (CUD) because there are presently no FDA- approved pharmacologic treatments for CUD. Our exciting preliminary results highlight a novel molecular substrate that could be targeted to attenuate or prevent cocaine taking and seeking. Specifically, we show that cocaine exposure alters the expression of KCC2, a K+-Cl- cotransporter that defines the Cl- gradient in midbrain GABA neurons. Importantly, this cocaine-induced neuroadaptation is associated with circuitry changes in midbrain GABA neurons that promote and elevate further cocaine taking. These findings support the working hypothesis that initial cocaine taking alters midbrain GABAergic circuitry and increases the vulnerability for increased cocaine consumption over time. Thus, KCC2 represents a potential therapeutic target to treat CUD. KCC2 is expressed primarily in the central nervous system, and it is amenable to therapeutic manipulation in humans. KCC2 is highly attractive as a therapeutic target because it is usually constitutively highly active. Therefore, when normal subjects are treated with KCC2 activators, KCC2 activity is already high, such that attempts to increase its activity further do not produce deleterious side effects. Under normal physiological conditions, KCC2 maintains a low intra-neuronal Cl- concentration required for hyperpolarizing, inhibitory GABAergic currents. Our preliminary results indicate that cocaine dose-dependently downregulates KCC2 function in midbrain GABA neurons, thereby altering midbrain GABAergic circuitry. As a consequence of these circuitry changes, downregulation of KCC2 leads to increased cocaine self-administration. That is, cocaine use itself, by downregulating KCC2, perpetuates heavy cocaine self-administration. Our preliminary results indicate that if we prevent KCC2 downregulation or correct KCC2 function, then we decrease cocaine self-administration. The overall goal of this proposal is to characterize the functional state of the midbrain GABAergic circuitry and the disposition of KCC2 function during cocaine self-administration, extinction, and the reinstatement of cocaine seeking (Aims1 & 2). At each phase of the addiction cycle, we will determine the functional state of the midbrain GABAergic circuitry as a causal contributor to cocaine taking or seeking. Finally, we will apply two mechanistically different pharmacotherapies to boost KCC2 function to decrease cocaine self-administration and cocaine-seeking behavior during abstinence (Aim3). These translationally-relevant studies will test potential therapeutic drugs acting to boost KCC2 function to mitigate enhanced cocaine self-administration induced by cocaine itself. The proposed studies of KCC2 as a novel therapeutic target to mitigate CUD are timely, highly significant, and appropriately aimed at the factors underlying the transition to heavy cocaine use.

项目总结。