Escalated cocaine self-administration and seeking in mice after repeated intermittent social stress: a corticotropin releasing factor mechanism

摘要

Social stress has been linked to drug use disorders in humans. This dissertation employs mouse models to examine how social defeat stress influences cocaine self-administration and seeking. One of the hypotheses underlying stress effects on drug use disorders is the interaction between stress neuropeptide corticotropin releasing factor (CRF) and mesolimbic dopamine system. To assess this hypothesis, I employed social defeat stress in male mice, mimicking some salient features of social stress in humans. In Aim 1 and 2, I evaluated the effects of social stress on cocaine self-administration and focused on the role of CRF and its type 1 receptors (CRF R1) in the ventral tegmental area (VTA, a dopamine-rich brain region). In Aim 3 and 4, I established a stress-induced reinstatement mouse model and further explored the potential stress effects on cocaine seeking behavior. The results demonstrated that repeated intermittent social defeat stress, contributed to the escalation of cocaine self-administration and seeking in male mice. Additionally, these behavior changes were concurrent with increased tonic CRF within the VTA. Moreover, pharmacological manipulations of CRF R1 in the VTA can block the social stress-escalated cocaine self-administration and seeking. However, escalation of cocaine-seeking behaviors was concurrent with decreased extracellular dopamine release in the nucleus accumbens shell (NAcSh). Together, these findings establish fundamental roles of CRF and CRF R1 in the VTA in mediating repeated social defeat stress escalated cocaine self-administration and cocaine seeking in male mice. CRF-R1 may be a mechanism for balancing the dysregulation of social stress and reward in drug use disorders.