IDENTIFYING BEHAVIORAL AND BIOLOGICAL PREDICTORS OF CANNABIS VAPOR SELF-ADMINISTRATION IN FEMALE AND MALE RATS

Ginny I. Park

doi:10.7273/000006965

Approximately 9% of first-time cannabis users will become dependent on cannabis, yet there are no FDA-approved pharmacotherapies for managing cannabis use disorder (CUD). This is in part due to flawed diagnostic nosology resulting in a lack of understanding of the mechanisms that give rise to CUD, as well as a conspicuous lack of translationally relevant animal models of cannabis use. To address these gaps, we have developed a model of cannabis self-administration that delivers vaporized cannabis extract in a response-contingent manner via the pulmonary route of administration that is most common in humans. We used this model to identify behavioral and biological predictors of motivation to self-administer vaporized cannabis in rats. We conducted an extensive battery of behavioral assays in female and male Long Evans rats (N=48) prior to initiation of cannabis self-administration training and characterized endophenotypes using endpoints that correspond to the behavioral dimensions of the NIMH Research Domain Criteria (RDoC). We then used a series of linear regression analyses to determine whether behavioral and physiological parameters in the five RDoC dimensions (positive and negative valence systems, cognition, social processes, and arousal/regulatory systems) significantly predicted the number of cannabis vapor deliveries earned during a 3-hr progressive ratio test after four weeks of cannabis self-administration. The Positive Valence model was significant, accounting for 21.1% of the variance in cannabis self-administration, with greater motivation for sucrose reinforcement predicting higher rates of cannabis self-administration (p=.008). The Cognition model was significant, accounting for 17.9% of the variance in cannabis self-administration. Specifically, better visual cue discrimination and poorer set shifting performance each predicted higher rates of cannabis self-administration (p’s = .015 and .030, respectively). The Arousal/Regulatory Systems model was also significant, accounting for 59.3% of the variance in cannabis self-administration. Specifically, higher concentrations of basal corticosterone (CORT) predicted higher rates of cannabis vapor self-administration (p = .005), while lower concentrations of plasma anandamide (AEA) content predicted higher rates of self-administration (p = .008). Finally, the Social Processes and Negative Valence models were not significant predictors of cannabis self-administration. Our data indicate that basal CORT, circulating AEA content, high motivation for sucrose reinforcement, and greater reliance on visual cue-based strategies were all significant predictors of motivation to self-administer cannabis vapor in adulthood. Thus, these endophenotypes may precede the onset of problematic cannabis use, which could be leveraged to identify individuals with increased susceptibility for developing CUD.

IDENTIFYING BEHAVIORAL AND BIOLOGICAL PREDICTORS OF CANNABIS VAPOR SELF-ADMINISTRATION IN FEMALE AND MALE RATS

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