The regulatory role of endocannabinoid signaling on social fear

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Cannabis is the most commonly used recreational drug worldwide due to its relaxing effects. Profound pro-social effects of cannabis and delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been described, but mechanisms of action are largely unknown. Plant-derived cannabinoids, such as THC or cannabidiol, and synthetic analogs are increasingly prescribed in Germany to treat psychopathologies, anorexia or chronic pain, but the medical use of psychoactive components for treating social dysfunctions is less characterized. Here, we aim to investigate the involvement of the endogenous endocannabinoid (eCB) system in social preference behaviour versus social fear using an established mouse model of social fear, i.e. the social fear conditioning (SFC) paradigm. In this model, social fear is induced by operant conditioning, i.e. the mouse receives a mild shock when approaching and investigating a same-sex conspecific. Previous data highlight the robust involvement of brain oxytocin in promoting social fear extinction with specific involvement of the lateral septum, a region of the limbic system of the brain. Our preliminary data indicate that also eCB signaling within the septum is essential for social fear extinction. To investigate the role of eCBs in social fear extinction and reinstatement of social preference in detail, we will pharmacologically manipulate the activity of the septal eCB system including cannabinoid receptor-mediated actions and anandamide synthesis, and monitor effects on social fear extinction. We will further reveal the relevant eCB pathways and characterize septal afferents representing potential targets of eCB signaling possibly arising from the hippocampus. Then, these neuronal pathways will be chemogenetically silenced or their cannabinoid receptor (CB1) synthesis will be selectively inhibited and consequences on social fear acquisition and extinction will be monitored. As both eCB/THC and oxytocin seem to exert pro-social effects, promote social fear extinction and restore social functioning, their bidirectional interaction in the context of social fear is likely. Therefore, interactions between the eCB and the oxytocin systems within the septum will be studied using complementary methods including microdialysis, blood sampling, immunohistochemistry, pharmacological and chemogenetical approaches. Finally, as a translational approach, we will test the effects THC and cannabidiol applied either acutely or chronically on social fear acquisition and extinction, and whether these effects are - at least partly - mediated via the oxytocin system. With these series of experiments we aim to contribute to the still limited knowledge regarding the mechanisms of actions of cannabinoids especially in the context of social dysfunctions, such as social fear.