Dr. Marian Sepúlveda

Institution: Ponce Medical School

Email: msepulveda@psm.edu

Effects of exercise on fear- and cocaine-induced changes in the nucleus accumbens

In 2018, 7.8% of adults aged 18 or older (19.3 million adults) in the United States (US) suffered from substance use disorder (SUD) and 19.1% (47.6 million adults) exhibited mental illness. There is a comorbidity problem between SUD and mental illness, since 3.7% of adults exhibit both ailments (9.2 million adults) (1). The Veterans Affairs administration reported that 27% of veterans are diagnosed with PTSD and SUD, whereas 34% of veterans exposed to a traumatic experience also have a history involving substance abuse; more specifically, cocaine use disorder (CUD)(2-4). Despite the relationship between PTSD and SUD, it is unknown how trauma exposure and substance abuse interact to alter the probability of an individual to develop these disorders. Relapse to drug seeking is a central feature of substance use disorders, and relapse prevention is an area of research priority. Aerobic exercise is a promising nonpharmacological treatment currently under investigation as a therapeutic strategy to prevent PTSD symptoms and drug relapse, which could be incorporated into comprehensive treatment regimens for both
disorders. Understanding the mechanisms by which exercise can reduce PTSD symptoms and drug seeking is critical to maximize the therapeutic benefits and to identify relevant pharmacotherapeutic targets. The investigator proposes to determine the behavioral effects of aerobic exercise during cocaine extinction in male and female rats with prior exposure of fear conditioning (Aim 1a), on fundamental cellular features of cocaine addiction, specifically focusing on expression of specific neuronal and glial proteins (Aim 1b) of the NAc core – an important structure in cocaine reward. The investigator hypothesizes that cocaine seeking behavior will be diminished (Aim 1a) by restoring cocaine-induced changes (Aim 1b) in NAc core from rats of both sexes in rats with fear and cocaine history. The study team will measure expression of the neuronal (BDNF and Trk-B), and glial proteins (AQP4 and GLT1) in the NAc, which are downregulated after cocaine exposure in adolescent rats (2, 3) (Aim1b). We hypothesize that cocaine seeking behavior will be diminished (Aim 1a) by reversing cocaine-induced changes (Aim 1b) in NAc core, in rats of both sexes with fear and cocaine history. Taken altogether, the investigator hypothesizes that aerobic exercise during cocaine extinction will reduce reinstatement by restoring cocaine-induced changes in NAc neurons to pre-addiction levels in rats of both sexes with fear memories. To test the hypothesis, we will combine fear conditioning, short access cocaine self-administration, extinction, and reinstatement in a rat model with Western Blot protein analysis. Animals will be implanted with intra-jugular catheters and trained in fear conditioning prior short access cocaine self-administration and extinction with/out aerobic exercise. During extinction, rats will be placed in chambers with or without running wheels. Twenty-four hours after last extinction session, a cue-primed reinstatement test will be given (Aim 1b) or animals will be sacrificed for Western blotting protein analysis (Aim 1b) using saline as a control to measure levels of BDNF, TrkB, AQP4 and GLT1.