Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association

Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain's reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders.

We sought to determine how cell type-specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1^fl/fl mice and striatal output pathway cre lines (Drd1a -cre; D1, Adora2a -cre; A2a) to generate cell type-specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays.

Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1^fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1^fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task.

This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.