Abstract From a developmental milestone, adolescence is a very critical phase since there are a plethora of changes occurring on different tiers - physical, cognitive, emotional, social, and behavioral. Any negative experiences at this critical developmental period can significantly impact the outcomes with serious ramifications that could persist into adulthood. This problem is further aggravated in HIV+ adolescents due to the associated stigma, negative attitudes, and prejudice in society. Social defeat (SD) employing a resident-intruder paradigm mimics bullying in humans and is considered a relevant animal model of psychosocial stress in defeated individuals. While previous literature has reported the experience of social stress to correlate with a higher incidence of stress-related psychiatric and addictive disorders, molecular mechanisms contributing to these outcomes still remain unclear. Our goal is on discerning molecular mechanisms and focuses on decoding the role of extracellular vesicles (EV) in exacerbating synaptic function and precipitating prescription opioid use in HIV+ adolescents post SD. Our preliminary studies using a preclinical model: HIV transgenic rats have revealed alterations in brain derived EV (BDEV) sizes with HIV infection. Based on this premise, our overarching central hypothesis is SD in HIV+ adolescent rats further exacerbate BDEV dynamics that aggravate synaptic injury and precipitates prescription opioid use. Under Aim 1, we seek to elucidate if SD in HIV+ adolescent rats dysregulate dynamics of BDEV biogenesis and increases vulnerability to prescription opioid use. In Aim 2 we will delineate mechanisms associated with adolescent HIV+ BDEVs post SD elicit higher inflammation and exacerbate synaptic injury. Upon completion of these goals, we expect to significantly enhance our knowledge of the role of BDEVs to regulate brain function post SD in HIV+ adolescents and identification of novel BDEV protein markers. Such information gleaned will further fuel mechanistic studies and eventually help develop future strategies to treat and improve neurological outcomes in this vulnerable population.