Project Grant R03DA060771

HIV EFFECTS ON ASTROCYTIC REGULATION OF STRESS-INDUCED COCAINE REINSTATEMENT - PROJECT SUMMARY HIV INFECTION IS COMMONLY CO-OCCURRING WITH DRUG USE. BOTH HIV INFECTION AND DRUG USE ARE ASSOCIATED WITH ADRENAL DYSFUNCTION AND HORMONAL DYSREGULATION, WHICH CAN DRIVE IMPAIRMENTS IN RESPONSE TO STRESS. STRESS IS A MAJOR FACTOR AFFECTING HIV DISEASE OUTCOMES AND SUSCEPTIBILITY TO RELAPSE, HOWEVER THERE IS A LACK OF UNDERSTANDING OF THE FACTORS THAT PROMOTE RELAPSE IN PEOPLE LIVING WITH HIV. RESPONSIVITY TO STRESS IS REGULATED BY THE GLUCOCORTICOID, CORTISOL. HIV CAN RESULT IN ENHANCED BASAL CORTISOL LEVELS, BUT REDUCED CORTISOL RESPONSES TO STRESS. IN CONTRAST, COCAINE DEPENDENCE IS ASSOCIATED WITH ENHANCED BASAL AND STRESS-INDUCED CORTISOL RESPONSES. HOWEVER, THE INTERACTION OF HIV INFECTION AND COCAINE USE ON CORTISOL LEVELS IS NOT WELL CHARACTERIZED. IN RODENT MODELS, COCAINE EXPOSURE ENHANCES THE CORTICOSTERONE RESPONSE TO STRESS IN MALE AND FEMALE RODENTS, WHILE TAT TRANSGENIC MALE, BUT NOT FEMALE, MICE EXHIBIT BLUNTED CORTICOSTERONE RESPONSES TO STRESS. THUS, HIV- INFECTED FEMALES MAY BE MORE VULNERABLE TO STRESS-INDUCED REINSTATEMENT OF COCAINE SEEKING DUE TO LACK OF BLUNTED CORTICOSTERONE RESPONSES BY TAT. GLUCOCORTICOID SIGNALING AT ASTROCYTES MAY BE AN IMPORTANT MEDIATOR OF THIS RESPONSE. THE GLUCOCORTICOID RECEPTOR CAN BE DOWNREGULATED IN RESPONSE TO STRESS, AND THIS EFFECT APPEARS TO BE SPECIFIC TO ASTROCYTES. ASTROCYTES ARE ALSO IMPORTANT MEDIATORS OF RELAPSE-RELATED BEHAVIORS AND ARE INDEPENDENTLY REGULATED BY COCAINE AND HIV INFECTION. FURTHER, MODULATION OF GLUCOCORTICOID RECEPTORS REGULATES ASTROCYTIC CALCIUM SIGNALING, SUGGESTING THAT STRESS MODULATES ASTROCYTIC ACTIVITY. OUR PRELIMINARY DATA INDICATE THAT STRESS-INDUCED REINSTATEMENT OF REWARD SEEKING IS ASSOCIATED WITH ENHANCED ASTROCYTIC CALCIUM SIGNALING IN THE REWARD-PAIRED CONTEXT. THUS, ASTROCYTIC GLUCOCORTICOID SIGNALING MAY BE A POTENTIAL REGULATOR OF THE STRESS RESPONSE AND STRESS-INDUCED RELAPSE-LIKE BEHAVIOR IN THE CONTEXT OF HIV INFECTION. AIM 1 WILL DETERMINE THE EFFECTS OF ECOHIV INOCULATION ON STRESS-INDUCED CORTICOSTERONE LEVELS AND ASTROCYTIC GLUCOCORTICOID RECEPTOR EXPRESSION FOLLOWING A HISTORY OF COCAINE EXPOSURE IN MALE AND FEMALE MICE. MALE AND FEMALE MICE WILL BE INOCULATED WITH ECOHIV AND UNDERGO COCAINE EXPOSURE AND WITHDRAWAL, AND THEN BE SUBJECTED TO FORCED SWIM STRESS. SERUM CORTICOSTERONE LEVELS AND IMMUNOFLUORESCENT LABELING OF ASTROCYTIC GR WILL BE ASSESSED TO DETERMINE IF FEMALE MICE EXHIBIT ENHANCED STRESS RESPONSES FOLLOWING ECOHIV INFECTION. AIM 2 WILL DETERMINE WHETHER ECOHIV INFECTION SEX-SPECIFICALLY PROMOTES STRESS-INDUCED REINSTATEMENT OF COCAINE SEEKING. MALE AND FEMALE MICE WILL BE INOCULATED WITH ECOHIV AND BE TRAINED IN A CONDITIONED PLACE PREFERENCE PARADIGM FOR COCAINE, FOLLOWED BY EXTINCTION AND REINSTATEMENT FOLLOWING FORCED SWIM STRESS EXPOSURE TO DETERMINE IF ECOHIV-INFECTED FEMALE MICE EXHIBIT ENHANCED STRESS-INDUCED REINSTATEMENT. THE RESULTS OF THESE EXPERIMENTS WILL IDENTIFY A POTENTIAL TARGET FOR REDUCING STRESS-INDUCED RELAPSE IN PEOPLE LIVING WITH HIV. FURTHER, WE WILL GAIN SIGNIFICANT KNOWLEDGE OF SEX- SPECIFIC REGULATION OF THE GLUCOCORTICOID SYSTEM BY ECOHIV INFECTION.