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Neuropharmacology

At the heart of TSRI-ARC's quest to combat alcohol use disorder (AUD) lies our innovative exploration into the complex world of Neuropharmacology. This area of research focuses on understanding the brain changes due to alcohol dependence, specifically in a region known as the infralimbic cortex. Here, we are studying three critical components—hypocretin (Hcrt), dynorphin (Dyn), and corticotropin-releasing factor (CRF)—and their role in the compulsive nature of AUD. Hcrt is involved in various vital processes such as arousal and stress response, which alcohol affects. Dynorphin contributes to stress-related negative behaviors and CRF plays a key role in our body's stress response, which is altered by chronic alcohol use. By exploring how these elements interact in the brain, particularly after dependence has developed, we aim to shed light on the 'dark side' of AUD - the compulsive craving and relapse triggered by stress. This understanding could lead to new treatments that target these interactions, offering hope for those battling the urge to drink and helping prevent relapses. Our research is not just about mapping the brain's response to alcohol but about finding practical, impactful ways to treat and potentially cure AUD.

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Neuropharmacology

Aims

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.

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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.

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Remi Martin-Fardon

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Francisco Flores Ramirez

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