Abstract

The opioid crisis remains a critical public health concern, with relapse presenting a major challenge in the treatment of opioid use disorder. Stress during abstinence, such as hunger from caloric restriction, increases relapse vulnerability, yet the neural mechanisms underlying stress- induced relapse, particularly in the context of food deprivation, remain unclear. This thesis investigated behavioral and neural contributors to heroin use and relapse in rats, focusing on the orbitofrontal cortex (OFC) and prelimbic (PrL) cortex. First, we evaluated whether a 5-minute seek-take protocol effectively models intermittent access and compulsive heroin use in both male and female rats. After validating the model, we asked two key research questions: whether chemogenetic inhibition of (1) the OFC or (2) the PrL reduces stress-induced heroin seeking following punishment-imposed abstinence. Using an established intravenous heroin self- administration paradigm followed by punishment-imposed abstinence (via footshock), rats were tested for heroin seeking in either a sated or food-deprived state. Chemogenetic inhibition was achieved by expressing inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the OFC or PrL and activating them with systemic deschloroclozapine dihydrochloride (DCZ). We hypothesized that inhibiting these cortical regions would attenuate stress-induced relapse. Our results show that the 5-minute seek-take protocol successfully models intermittent and compulsive heroin use in both sexes. However, chemogenetic inhibition of the OFC or PrL cortex did not reduce heroin seeking during stress-induced relapse. These
findings suggest that the OFC and PrL might not be critically involved in stress-induced relapse to heroin seeking following punishment-imposed abstinence.