Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice

Abstract

Background Cannabinoids and their principle psychoactive target, the cannabinoid type 1 receptor (CB1R), impact a number of alcohol‐related properties, and although alcohol and cannabis are often co‐used, particularly in adolescence, few animal models of this phenomenon exist. We modeled the co‐use of alcohol and ∆9‐tetrahydrocannabinol (THC) in adolescent mice using ingestive methods popular during this developmental period in humans, namely binge‐drinking and edible THC. With this model, we assessed levels of use, acute effects, and tolerance to each substance. Methods Adolescent male C57BL/6J mice had daily, limited access to 1 of 2 edible doughs (THC or control), to 1 of 2 fluids (ethanol (EtOH) or water), and in 1 of 2 orders (dough–fluid or fluid–dough). Home cage locomotor activity was recorded both during access and after access. On the day following the final access session, a subset of mice were assessed for functional and metabolic tolerance to alcohol using accelerating rotarod and blood EtOH concentrations, respectively. The remaining mice were assessed for tolerance to THC‐induced hypothermia, and whole‐brain CB1R expression was assessed in all mice. Results EtOH intake was on par with levels previously reported in adolescent mice. Edible THC was well‐consumed, but consumption decreased at the highest dose provided. Locomotor activity increased following EtOH intake and decreased following edible THC consumption, and edible THC increased fluid intake in general. The use of alcohol produced neither functional nor metabolic tolerance to an alcohol challenge. However, the use of edible THC impaired subsequent drug‐free rotarod performance and was associated with a reduction in THC's hypothermic effect. Conclusions Adolescent mice self‐administered both alcohol and edible THC to a degree sufficient to acutely impact locomotor activity. However, only edible THC consumption had lasting effects during short‐term abstinence. Thus, this adolescent co‐use model could be used to explore sex differences in self‐administration and the impact substance co‐use might have on other domains such as mood and cognition.