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Endocannabinoid regulation of the corticoaccumbens pathway and stress-enhanced cocaine-seeking behavior

内源性大麻素对伏隔皮质通路的调节和压力增强的可卡因寻求行为

基本信息

批准号：
10750394
负责人：
Andrew Gaulden
金额：
$ 4.51万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2026-08-08
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750394
关键词：
Abstinence Acute Affect American Area Attenuated Behavior Behavioral Behavioral Model Brain CNR1 gene Cocaine Cocaine use disorder Complex Corticosterone Data Dedications Disease Disinhibition Drug Interactions Endocannabinoids FDA approved Fiber Goals Health Human In Situ Hybridization Individual Intake Interneurons Knowledge Measurement Measures Mediating Modeling Molecular Neurobiology Neurons Neurotransmitters Nucleus Accumbens Outcome Output Pathologic Pathway interactions Pattern Personal Satisfaction Pharmaceutical Preparations Photometry Population Positioning Attribute Prefrontal Cortex Prevalence Rattus Recording of previous events Regulation Research Research Personnel Rewards Rodent Role Self Administration Signal Transduction Site Stimulus Stress Substance Use Disorder System Testing Time addiction antagonist attenuation behavior influence cell type cocaine craving cocaine seeking cocaine self-administration cocaine use drug seeking behavior endocannabinoid signaling endogenous cannabinoid system experimental study hippocampal pyramidal neuron in vivo innovation insight neuroadaptation neurophysiology neuroregulation neurotransmission pharmacologic pre-clinical skills stressor

项目摘要

Project Summary Cocaine use is a serious and growing concern for public wellbeing, yet there is no FDA-approved treatment option for individuals with cocaine use disorder (CUD), making it a critical unmet need. CUD is a complex disorder that is influenced by many external factors, such as stress. Despite the prevalence of stress throughout human populations, including individuals with CUD, most pre-clinical addiction research does not examine the impact of stress during drug intake. To understand how stress and drug intake interact to influence behavioral and neurobiological outcomes, we developed a rat model of cocaine self-administration (SA) that combines repeated stress at the time of cocaine self-administration in rats. This model causes an escalation of cocaine intake in otherwise stable responding rats and a long-lasting enhancement of cocaine- seeking behavior. We propose that this behavioral shift is regulated by changes in the endocannabinoid (eCB) system, which uniquely regulates stress and reward systems. In support of this, systemic administration of a cannabinoid receptor 1 (CB1R) antagonist attenuates cocaine-induced reinstatement only in rats with a history of stress. Furthermore, my preliminary data localizes this effect to the prelimbic cortex (PLc), a key site for regulation of stress and drug-seeking behavior. Importantly, eCB signaling, through attenuation of local inhibitory neurotransmission, is well-positioned to regulate PLc pyramidal neuron activity and output. One such PLc output is to the nucleus accumbens core (NAcc), which has been shown to regulate cocaine-seeking behavior. Therefore, this proposal tests the hypothesis that stress and cocaine-evoked changes in eCB signaling during cocaine SA permits enhanced cocaine seeking via disinhibition of the PLc to NAcc circuit. First, this proposal will use PLc-directed CB1R pharmacological manipulation to assess the role of eCB signaling in cocaine-primed reinstatement for rats with a history of cocaine SA and/or repeated stress. Next, we will use in vivo fiber photometry to record activity of the PLc→NAcc circuit during cocaine-primed reinstatement in rats with a history of stress or no stress. This will allow us to measure the individual or combined impact of a history of cocaine SA and/or repeated stress on cocaine-seeking behavior. Finally, using in situ hybridization, we will examine how cocaine SA and/or repeated stress produce long-term changes in the molecular machinery regulating eCB signaling at the PLc→NAcc circuit. These studies will expand our knowledge of stress-drug interactions and may yield new treatment options in individuals with CUD for whom stress is a predominant contributing factor.

项目总结