To provide further knowledge of the neuroadaptations within the infralimbic cortex due to alcohol dependence with a focus on the hypocretin (Hcrt), dynorphin (Dyn) and corticotropin-releasing factor (CRF) transmission. This project will explore their participation to the compulsivity associated with the dark side of alcohol use disorder (AUD) and extend our understanding of the beneficial effects of targeting the Hcrt, Dyn, and CRF to prevent alcohol craving and relapse precipitated by stress.
The hypocretin (Hcrt; orexin) system regulates physiological processes, including feeding, energy metabolism, arousal, and stress, and is recruited by alcohol.
Chronic drug use dysregulates stress responses that are mediated by corticotropin-releasing factor (CRF) in both the hypothalamic-pituitary-adrenal axis and extrahypothalamic brain stress areas.
An Hcrt/CRF interaction exists that could participate in chronic relapsing and negative affective states that characterize drug use disorder.
Dynorphin (Dyn) promotes depressive-like behavior and mediates the aversive effects of stress via k-opioid receptor (KOR) signaling. Although Hcrt and Dyn are co-localized and co-released, they play opposing roles.
The infralimbic cortex (IL)—a mPFC subregion—exerts inhibitory control over alcohol seeking and shows long-term deficits in rats following alcohol dependence.
The Neuropharmacology component (Lead: Dr Martin-Fardon, Co-Lead: Dr. Flores-Ramirez) will test whether Hcrt/CRF and Hcrt/Dyn interactions in the IL change following dependence and whether these systems are pivotal in the stress-induced reinstatement of alcohol-seeking behavior in rats at late (2 weeks) abstinence.
Specific Aim 1: To test the hypothesis that following alcohol dependence Hcrt/CRF and Hcrt/Dyn interactions in the IL mediate stress-induced reinstatement of alcohol-seeking behavior. Specific Aim 1 will determine whether (1) Hcrt and CRF act concomitantly in the IL following alcohol dependence and (2) the opposing roles of Hcrt and Dyn during stress-induced alcohol-seeking behavior.
Specific Aim 2: To test the hypothesis that IL Hcrt-R/CRF1/KOR signaling in the IL is upregulated by alcohol dependence during abstinence. Specific Aim 2 will determine whether (1) molecular changes that are caused by alcohol dependence in the IL (Hcrt-R, CRF1, KOR, and CRF) and HYP (source of Hcrt and Dyn production) may explain alcohol seeking, and (2) the sensitivity of spontaneous GABAergic transmission in the IL to Hcrt-Hcrt-R, CRF-CRF1, and Dyn-KOR manipulations is altered following alcohol dependence (in collaboration with the Neurophysiology Component, [Dr. Roberto]).
Specific Aim 3: To confirm the importance of the HYP(Hcrt)->IL circuit during stress-induced reinstatement of alcohol-seeking behavior using an inhibitory Designer Receptors Exclusively Activated by Designer Drugs construct selective for Hcrt cells in Hcrt-Cre rats. Specific Aim 3 will test whether silencing Hcrt transmission in the IL blunts stress-induced reinstatement to confirm the importance of the HYP(Hcrt)->IL circuit during alcohol-seeking behavior.
This project will provide insights into the involvement of the IL Hcrt-R/CRF1/KOR signaling during pathological (alcohol-seeking) behavior and therefore may contribute to discovering effective therapies for the treatment of AUD.