Neuropharmacology Component - Martin-Fardon

Relapse vulnerability is a challenge for the successful treatment of alcohol use disorder (AUD), making relapse prevention a central focus of treatment and medication development efforts. Stress is a major factor that contributes to the chronic relapsing and compulsive nature of drug addiction. The hypocretin (Hcrt; orexin) system regulates physiological processes including feeding, energy metabolism, arousal, and stress, and is recruited by alcohol. Hypocretin neurons are only located in the hypothalamus (HYP) that includes the lateral HYP (LH), dorsomedial HYP (DMH), and perifornical area (PFA) and project to major components of neurocircuitry that mediates drug seeking including the medial prefrontal cortex (mPFC). Chronic drug use dysregulates stress responses that are mediated by corticotropin-releasing factor (CRF) in both the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress areas outside the HPA axis (e.g., central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]). An Hcrt/CRF interaction exists that could participate in chronic relapsing and negative affective states that characterize drug addiction. Dynorphin (Dyn) promotes depressive-like behavior and mediates the aversive effects of stress via k opioid receptors (KORs) signaling. Even though Hcrt and Dyn are co-localized and co-released, in the ventral tegmental area (VTA) and the paraventricular nucleus of the thalamus (PVT), they play opposing roles in the mediation of drug-directed behavior. The Martin-Fardon component will test whether Hcrt/CRF and Hcrt/Dyn interaction in the infralimbic cortex (IL) -- a subregion of the mPFC that exerts inhibitory control over alcohol seeking and shows long-term deficits in rats following a history of alcohol dependence -- changes following dependence and whether these systems are pivotal in stress-induced reinstatement of alcohol-seeking behavior in male and female rats at late (2 weeks) abstinence. This will be achieved by (1) exploring whether the Hcrt/CRF and Hcrt/Dyn interactions in the IL mediate stress-induced reinstatement of alcohol-seeking behavior in alcohol-dependent animals during abstinence; (2) establishing whether the IL Hcrt-r/CRF1/KOR signaling in the IL is upregulated due to alcohol-dependence during abstinence; and (3) confirming the importance of the HYP(Hcrt)®IL circuit during stress-induced reinstatement of alcohol-seeking behavior using an inhibitory Designer Receptor Exclusively Activated by Designer Drugs construct selective for Orx cells in Orx-Cre rats. This project will provide insights into the involvement of the IL Hcrt-r/CRF1/KOR signaling during pathological (alcohol-seeking) behavior and may identify novel targets for alcohol craving and relapse prevention.