Summary: Despite the high rate of co-occurrence between substance use disorders (SUDs) and other mental illness the neurophysiological mechanisms that underlie the stress/drug abuse comorbidity are not well understood. In addition, some mental illnesses, such as anxiety, depression, trauma and stressor-related disorders, are identified as risk factors for developing drug addiction. Studies have also shown gender-related health disparities and health care disparities, with women having higher rates of comorbidity between SUDs and other mental illnesses than men, but lower rates of treatment. Taken together, these studies highlight the need to recognize how traumatic experiences affect neural responses to drug use in males and females. Research in our laboratory combines validated rat models of severe stress and drug self-administration, which allow us to disentangle the relationships between a history of stress and behavioral responses to cocaine. Preliminary results show that inescapable footshocks (IFS) – a form of chronic stress - prior to cocaine self-administration (SA), decrease cocaine consumption in female rats, but not in males. On the other hand, stressed-female rats show an increase in cue reactivity after 30 days of forced abstinence, which is not observed in male rats. These results suggest that chronic stress prior to cocaine exposure enhances the rewarding effects of cocaine during drug acquisition, leading to increased craving incubation. Based on the need to understand the relationship between stress and drug use, as well as these preliminary data, the goal of this study is to understand how a history of prior chronic stress can influence behavioral and neurophysiological responses to cocaine in both males and females. Two brain structures that contribute to the development of both severe stress and cocaine use disorders (CUD) are the basolateral amygdala (BLA) and the nucleus accumbens (NAc). However, the effects of chronic stress and cocaine exposure on synaptic plasticity of BLA neurons projecting to the NAc in males are still unclear and, in females, completely unknown. Accordingly, we propose to specifically assess how IFS prior to extended access cocaine self-administration differentially affects the neurophysiology of BLA neurons projecting to the NAc core of females versus males, in connection with cocaine-related behaviors. We will utilize a chronic stress and CUD comorbidity rodent model and whole cell patch-clamp recordings to measure synaptic plasticity in the NAc core after self-administration (Aim 1), and BLA to NAc core synaptic changes after forced abstinence (Aim 2). Additionally, a designer receptor exclusively activated by manipulations with designer drugs (DREADDs) will be used to assess functional contributions of the BLA-NAc core circuitry during self-administration and cue reactivity (Aim 3). Understanding how stress affects neural plasticity in a way that leads to increased cocaine-seeking behavior in femal...