SHANK3 downregulation in the VTA accelerates the extinction of contextual associations induced by non-familiar conspecific interaction

Conditioned place preference (CPP) paradigms, traditionally adopted to study the reinforcing properties of drugs of abuse, have been developed to investigate the neurobiological mechanisms underlying the reinforcing properties of social stimuli. These protocols are largely based on single-housing before and/or during the social stimulus-contextual cues acquisition phase. Here, based on previously established social interaction-induced CPP paradigms, we characterize a place preference task relying on the reinforcing properties of free interaction with a non-familiar (novel) conspecific. The formation of contextual associations induced by the interaction with a novel social stimulus does not require single-housing, necessitates dopamine (DA) receptor 2/3 (D2/3R) activation and undergoes extinction. Interestingly, while extinction of CPP responses is reduced by single-housing, it is accelerated by the downregulation of the autism spectrum disorder (ASD)-related protein SHANK3 in the ventral tegmental area (VTA). Thus, inspired by the literature on drug of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and “social-seeking” dysfunctions in animal models of psychiatric disorders.