Cannabinoid receptor type 1 receptors on GABA ergic vs. glutamatergic neurons differentially gate sex‐dependent social interest in mice

Abstract Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism, and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important for a better understanding of numerous pathologies and improved treatments. Several findings have suggested that an alteration of cannabinoid receptor type 1 ( CB 1) receptor function could be involved in the pathophysiology of such disorders. However, the role of CB 1 receptors is still unclear, and their localisation on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB 1 receptors in different neuronal populations, we used male knockout mice and their respective control littermates [total deletion ( CB 1 −/− ); specific deletion on cortical glutamatergic neurons ( G lu‐ CB 1 −/− ) or on GABA ergic interneurons ( GABA ‐ CB 1 −/− ), and wild‐type ( WT ) mice treated with the CB 1 antagonist/inverse agonist SR 141716A (3 mg/kg). Mice were required to perform different social tasks – direct social interaction and social investigation. Direct interaction of two male mice was not modified in any group; however, when they were paired with females, G lu‐ CB 1 −/− mice showed reduced interaction. Also, exploration of the male stimulus subject in the three‐chamber social investigation test was almost unaffected. The situation was completely different when a female was used as the stimulus subject. In this case, G lu‐ CB 1 −/− mice showed reduced interest in the social stimulus, mimicking the phenotype of CB 1 −/− or WT mice treated with SR 141716A. GABA ‐ CB 1 −/− mice showed the opposite phenotype, by spending more time investigating the social stimulus. In conclusion, we provide evidence that CB 1 receptors specifically modulate the social investigation of female mice in a neuronal subtype‐specific manner.