COCA - Project 3. Tetrapartite Synapses Regulate Cue-induced Drug Seeking

COCA - 项目 3。四方突触调节提示诱导的药物寻求

• 批准号: 10404586
• 负责人: Peter W Kalivas
• 金额: $ 23.23万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404586
• 关键词: Acetylcysteine; Animal Model; Animals; Astrocytes; Calcium; Cells; Cellular Morphology; Chemosensitization; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; Cues; Data; Dendritic Spines; Drug Regulations; Event; Excitatory Synapse; Extracellular Matrix; Extracellular Space; Functional Magnetic Resonance Imaging; Genetic study; Glutamate Receptor; Glutamates; Goals; Heroin; Integrins; Isoxazoles; Link; Measures; Mediating; Metalloproteases; Molecular Target; Morphology; Mus; Neurons; Nucleus Accumbens; Opiate Addiction; Pathologic; Pharmaceutical Preparations; Physiological; Physiological Processes; Physiology; Population; Prefrontal Cortex; Process; Propionic Acids; Proteins; Rattus; Regulation; Relapse; Rodent; Rodent Model; Role; Self Administration; Signal Pathway; Signal Transduction; Structural Protein; Sucrose; Synapses; Synaptic plasticity; Training; Transcranial magnetic stimulation; Transgenic Organisms; Translating; Translations; Validation; Viral; Withdrawal; Work; addiction; cell behavior; cell type; cocaine self-administration; confocal imaging; cue reactivity; drug development; drug of abuse; drug withdrawal; epigenetic regulation; impaired capacity; in vivo; knock-down; neuroadaptation; neuroimaging; optogenetics; pre-clinical; prevent; protein expression; therapeutic development; transgene expression

PROJECT SUMMARY – Project 3 Addiction to drugs of abuse produces pathological changes in synaptic physiology that impair the capacity of the prefrontal cortex (PFC) to communicate with the nucleus accumbens, and impede the successful regulation of drug seeking. The Center for Opioid and Cocaine Addiction (COCA) studies the genetic, cellular and physiological mechanisms of relapse in the PFC and nucleus accumbens rodent models and bidirectionally translates this with COCA clinical studies using fMRI read-out of treatments with N-acetylcysteine (NAC) and PFC transmagnetic stimulation (TMS) for cue reactivity in cocaine users. Project 3 specifically explores the nucleus accumbens for synaptic adaptations after heroin and cocaine self-administration in mice and rats, and the adaptations that occur during cue-induced drug seeking. We find both enduring changes in withdrawal and transient changes during cue-induced heroin and cocaine seeking that are correlated with the intensity of the relapse event. These changes are present in all four compartments of the synapse (pre- and postsynapse, astroglia and extracellular matrix). By simultaneously examining the 4 synaptic compartments of the tetrapartite synapse, we are accessing processes heretofore poorly studied in relation to addiction, which may contain unique opportunities for therapeutic development. Animal & Validation Core B will provide rats and mice trained to self- administer heroin or cocaine. Our endpoints include cell morphology, cell signaling and physiological processes. Specifically, we will measure enduring and cue-induced transient changes in the morphology, synaptic glutamate-mediated currents and protein expression in specific cell types in the accumbens using transgenic rats and mice and cell-specific viral mediated expression of transgenes in the nucleus accumbens. Finally, pursuant to an overarching COCA goal to understand which cell type and neuronal subpopulation is mediating the effects of cue-induced heroin and cocaine seeking, we administer the treatments used in the clinical Project 4 (NAC and continuous theta burst stimulation) to provide bidirectional construct validity for the relapse-related discoveries in Project 3.

项目总结-项目3