Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knockout mice is reversed by chronic forced ethanol consumption

Background: The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R–DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol’s reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. Methods: We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2?/? mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [³H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. Results: We found that the lack of DRD2 leads to a marked upregulation (approximately 2‐fold increase) of CB1R in the cerebral cortex, the caudate‐putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. Conclusions: The results suggest that DRD2‐mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.