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Bernardes Terzian, Ana Luisa (2014): Behavioral phenotypes of mice lacking cannabinoid CB1 receptors in different neuronal subpopulations: focus on sex-related social interest. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



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 to better understand numerous pathologies and improve treatments. Several evidences suggest that an alteration of cannabinoid CB1 receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptor is still unclear and its localization on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptor on different neuronal population, male mice were used – knockout mice and their respective control littermates [total deletion (CB1-/-); specific deletion on cortical glutamatergic neurons (GluCB1-/-); on GABAergic neurons of the forebrain (GABACB1-/-); or on dopaminergic D1 receptor expressing neurons (D1CB1-/-)], and wild-type (WT) mice treated with CB1 antagonist/inverse agonist SR141716A (3mg/kg). To elucidate the behavioral effects of specific CB1 receptor deficiency, D1CB1-/- mice were submitted to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, and fear-related memory paradigms. It was demonstrated that D1CB1-/- mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within-session extinction. Also, when all mice lines were submitted to different social tasks, involving male or female as the stimulus subject, GluCB1-/- mice showed reduced interest for the social stimulus, as CB1-/- or WT treated with SR141716A mice. D1CB1-/- showed moderate changes in social interest, and GABACB1-/- mice showed the opposite phenotype by spending more time investigating the social stimulus. In conclusion, specific reduction of endocannabinoid signaling in D1-expressing neurons is able to affect acute fear adaptation. Moreover, CB1 receptors specifically modulate social investigation of female mice in a cell-specific manner. These findings support the involvement of cannabinoid signaling in social alterations in psychiatry disorders.