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

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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.