Project Summary Despite strides towards understanding circuit and molecular mechanisms of addiction, treatment options remain largely unchanged. This impasse is at least partly due to limitations in the construct and predictive validity of animal models of addiction, which rarely incorporate social factors. In both humans and laboratory animals, adverse social interactions and social isolation promote drug self-administration and relapse, while social interactions tend to be protective. I recently developed an operant rat model of choice between drugs and social interaction and showed the profound protective effects of the latter on addiction. My research revealed two major findings: (1) rats strongly prefer operant social interaction over drugs, and (2) social choice- induced voluntary abstinence prevents incubation of methamphetamine (Meth) craving. This protective effect was associated with activation of PKCδ in central amygdala lateral part (CeL) (assessed by double-labeling of Fos with PKCδ). In contrast, after homecage forced abstinence, incubation of craving was associated with selective recruitment of CeL-somatostatin (SOM) neurons. Therefore, the aim of this proposal is to study (1) the circuit mechanisms underlying the protective effect of social reward on incubation of Meth craving, and (2) the neural encoding mechanisms of the social interaction versus Meth choice. During the K99 phase, I will investigate a CeL mechanism of the protective effect of social reward on incubation of Meth craving. This will be achieved using shRNAs viral constructs to selectively knockdown PKCδ or SOM recently developed by my collaborator Dr. Messing. Additionally, under the guidance of Dr. Schoenbaum (my co-mentor), I will use single-unit recording to investigate the neural substrates underlying the preference for social reward over Meth. I will focus on the orbitofrontal cortex because of its critical role in associative learning and decision-making. During the R00 phase, I will use the techniques I have learned during my post-doctoral training and the K99 phase to further characterize the circuit mechanisms of the protective effect of social interaction on incubation of drug craving and drug choice. The proposed training will allow me to develop a future independent research program geared towards identifying mechanisms underlying the role of social factors in drug addiction.