Abstract
Rationale
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.
Objective and methods
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 Cnr1fl/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.
Results
Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1fl/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 Cnr1fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task.
Conclusions
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.
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Acknowledgments
The floxed Cnr1 mouse was generated by the Gene-Targeted Mouse Core of the Integrative Neuroscience Initiative on Alcoholism (INIA)-stress consortium. Use of these mice requires a MTA from Eric Delpire (eric.delpire@vanderbilt.edu).
Funding
This study was supported by the National Institute on Drug Abuse R00 DA031699 (B.A.G.) and R01 DA040630. The Gene-Targeted Mouse Core is supported by NIH grant U01 AA013514 (to E.D.).
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Experimental design was performed by BDT and BAG. Animal breeding, behavioral testing, data analysis, and the construction of the manuscript were performed by BDT and NKS. ED contributed the Cnr1fl/fl mouse line. NKS, BTC, and KMM performed behavioral tests. All authors contributed to editing and revisions of the manuscript.
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Turner, B.D., Smith, N.K., Manz, K.M. et al. Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association. Psychopharmacology 238, 1121–1131 (2021). https://doi.org/10.1007/s00213-021-05759-1
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DOI: https://doi.org/10.1007/s00213-021-05759-1