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Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats

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Abstract

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine self-administration requires the CB1 cannabinoid receptor. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min self-administration components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine self-administration that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist/inverse agonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine self-administration, regardless of stress history, increased CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during self-administration. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1Rs are required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use regulates mesolimbic CB1R activity through a currently unknown mechanism.

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Fig. 1: Chronic electronic footshock administered daily at the time of self-administration induces a persistent escalation of cocaine intake.
Fig. 2: Cannabinoid receptor type 1 antagonism in the nucleus accumbens shell and ventral tegmental area attenuate cocaine intake in rats that underwent stress-induced escalation of cocaine intake.
Fig. 3: Cocaine self-administration increases cannabinoid receptor type 1 binding in the ventral tegmental area but not nucleus accumbens shell.
Fig. 4: A history of stress-induced escalation of cocaine intake results in increased cocaine-induced reinstatement that is dependent upon CB1R activation.

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Acknowledgements

We thank Luke Urbanik for assistance with surgeries.

Funding

This work was supported by National Institute on Drug Abuse Grants R01-DA015758 to JRM, R01-DA038663 to JRM and CJH, and K01-DA045295 to JRMc.

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Author notes

  1. Jayme R. McReynolds

    Present address: Department of Pharmacology & Systems Physiology and Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Authors and Affiliations

  1. Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA

    Jayme R. McReynolds, Colten P. Wolf, Dylan M. Starck, Jacob C. Mathy, Rebecca Schaps & John R. Mantsch

  2. Department of Pharmacology & Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Leslie A. Krause, Cecilia J. Hillard & John R. Mantsch

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Contributions

JRMc, CJH, and JRM designed the project and experiments. JRMc and JRM supervised all of the experiments. JRMc, CPW, and DMS conducted the surgeries and JRMc ran the behavioral experiments with assistance from CPW, DMS, RS, and JCM. CPW and RS completed the histology. JRMc ran the behavior and collected tissue for the CB1R binding assay and CJH supervised and LAK completed the binding assays and analysis of the binding data. JRMc analyzed and graphed all data. JRMc and JRM wrote the first draft of the manuscript with editing and reviewing by CJH. Funding was acquired by JRMc, CJH, and JRM.

Corresponding author

Correspondence to Jayme R. McReynolds.

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Competing interests

JRMc, CPW, DMS, JCM, LAK, and RS declare no potential competing interest. CJH is a member of the scientific board of directors of Phytecs, Inc; has equity in Formulate Biosciences, Inc and has received consultation fees from Pharmavite, LLC. JRM is a co-founder of and has equity in Promentis Pharmaceuticals, Inc.

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McReynolds, J.R., Wolf, C.P., Starck, D.M. et al. Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats. Neuropsychopharmacol. 48, 1121–1132 (2023). https://doi.org/10.1038/s41386-023-01589-1

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