Project Summary The rationale for the current specific aims builds on the consistent epidemiological finding that social stress contributes critically to all phases of the addiction cycle, from initiation to escalation to relapse. The close link between social stress and drug use is based on reports from emergency rooms treating victims of violence and statistics from the criminal justice system on violent crimes committed by drug users as well as epidemiological evidence and neurobiological data. The overarching question to be answered by the proposed research is: what is the mechanistic link between social stress and escalated cocaine self-administration? Our special emphasis is on how corticotropin releasing factor (CRF, often referred to as CRH) modulates mesocorticolimbic dopamine (DA) systems. The CRF system is of continued interest, not only because it is critical to the initiation of the endocrine stress response, but its extra-hypothalamic localization and action are of significance in stress disorders and represent potential targets for therapeutic intervention. Specific Aim One tests the hypothesis that highly aversive social stress amplifies intensely rewarding cocaine self-administration by action on CRF and dopamine (DA) in microcircuits from the posterior ventral tegmental area (pVTA) to the dorsal raphe nuclei (DRN). Neuroanatomical tract tracing is employed to identify the synaptic contacts with DA neurons as a source of CRF input. In vivo microdialysis in the terminals of these microcircuits are used to characterize the dynamic neuroadaptions that contribute to the stress-induced escalation of cocaine self-administration (acquisition, maintenance, binge, relapse). Specific Aim Two tests the hypothesis that activation and inhibition of specific CRF cell groups in the VTA- DRN microcircuit modulate cocaine self-administration. In vivo optogenetics and, in parallel, Gq- or Gi- DREADD in mice expressing Channelrhodopsin specifically in CRF neurons (ChR/Crh mice) will be used to activate CRF inputs into the VTA or inhibit with archaerhodopsin. Microinjections CRFR1, CRFR2 and binding protein antagonists and agonists into the VTA-DRN microcircuit will identify targets for preventing and reversing effects of social defeat stress or optogenetic activation that escalate cocaine self-administration. A special feature of the proposed work is the test of the hypothesis that social stress-escalated cocaine self-administration is buffered in a sex-specific manner.