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 all link social stress and drug use. Furthermore, approximately 43% of cocaine addicts also meet the DSM-IV criteria for posttraumatic stress disorder and experience of symptoms associated with this disorder is often concurrent with increased cocaine use. Only specific types of social stress can promote drug abuse and each stressor activates discrete neurobiological mechanisms. However, the precise neural mechanisms responsible for this connection have yet to be determined. Therefore, deciphering this underlying neurocircuitry will contribute to the discovery of pharmacological therapies for the treatment of addiction. Corticotrophic releasing factor (CRF) is a neuropeptide that mediates adaptive and maladaptive responses to social stress. We focus on CRF receptor subtype 1 (CRF-R1), based on the growing evidence and our own preliminary data that implicate this system in the mechanisms of social stress escalation in drug abuse- related behavior. We utilize a well-established social defeat method to stress rats because it is an ethologically relevant stressor for the rat. Furthermore, social defeat has been shown to increase several different aspects of cocaine self-administration that are indicative of addiction-like behaviors in the rat. This proposal seeks to characterize the link between CRF, social stress and escalated cocaine self- administration at the behavioral level and proceed to the study of critical nodes at the level of neurocircuitry. Initially, we will utilize pharmacological agents to activate or inhibit CRF-R1 action in specific brain regions and test for effects on cocaine-induced behavior. We focus on subregions of the ventral tegmental area (VTA) as a most relevant anatomical site for the modulation of dopamine by CRF. Dopamine cells are located in the VTA and are most often implicated in abused substance abuse behaviors. Prior social defeat experiences cause subsequent increased dopamine release in brain regions specifically implicated in addiction. Therefore we also will determine if CRF-R1 agents acting in the VTA just prior to defeat stress can block or potentiate later cocaine-induced increases of dopamine in specific brain regions using in vivo microdialysis techniques. Social defeat stress also increases later cocaine self-administration behaviors. Therefore, we hypothesize that CRF- R1 antagonists infused directly into the VTA prior to each social defeat stress experience will prevent the escalation of cocaine self-administration. We investigate aspects of self-administration that have, in the past, contributed substantially to the development of pharmacological therapies for drug addiction. Importantly, the current proposal advances our understanding of the stress-CRF-cocaine link through its focus on the social dimension of stress. Furthermore, we focus on stress-escalated cocaine self-administration as a preferential target for CRF-R1 modulation specifically in the VTA dopamine cell body region.
The experiments proposed will give valuable insight into the brain mechanisms responsible for addiction. Stress is known to cause increased vulnerability to drug addiction, increased likelihood of beginning to take drugs again after a period of abstinence from the drug, and escalated intake of the drug during periods of intense drug taking or binges. At present, there are few, if any, pharmacologically available treatments for these characteristics of addiction and the proposed research will test the ability of certain pharmacological agents to reverse the effect that stress can have on uncontrollable drug intake.
