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The Role of Corticotrophin Releasing Factor in Alcohol and Nicotine Addiction

Our newest review, “Role of CRF in Alcohol and Nicotine Addiction” was recently published in a special collection on "The Role of Neuropeptides in Drug and Ethanol Abuse: Medication Targets for Drug and Alcohol Disorders", a collection assembled by guest editor, Dr. Jessica Barson, in the journal Brain Research.

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, substance use disorders (SUDs) consist of a problematic pattern of use that results in impairments in daily life and noticeable distress. The two most prevalent SUDs involve alcohol and nicotine, which are often co-abused. Chronic nicotine and alcohol use results in the dysregulation of brain regions that are involved in stress and emotional systems upon the initiation and cessation of use. Robust preclinical and translational evidence indicates that negative emotional states are key for the development of alcohol and nicotine addiction as subjects continue drug use to obtain relief from the negative emotional states of acute withdrawal and protracted abstinence.

In our review, we compared the role of Corticotropin-Releasing Factor (CRF) in dependent and non-dependent animals across a wide variety of pre-clinical rodent models. Since the stress response is crucial in the development of substance use disorders, we compared CRF modulation in Alcohol and Nicotine use, as well as provided commentary on the role it may have in potential sex differences. We also touched on the related Urocortins and CRF modulators such as CRF-binding protein.

After a deep dive into the foundational literature as well as recent innovations, we combined these our findings to create extensive tables comparing genetic, viral, optogenetic, and small molecule perturbations of the CRF system. We also updated the map of the distribution of CRF, CRF-1 and CRF-2 throughout the rat brain and created a figure displaying the intracellular CRF-1 and CRF-2 signaling pathways.

The majority of the brain CRF systems modulate behaviors that occur during drug abstinence/withdrawal, including anxiety-like behavior, dysphoria-like behavior, cognitive impairments, and stress-induced relapse. These behavioral effects have been attributed to actions of CRF on CRF-1 and CRF-2 receptors within a distributed network of brain regions, including the PFC, PVN, CeA, BNST, VTA, and IPN.

These studies indicate that the recruitment of a distributed brain CRF stress system may provide redundant circuits that promote negative affective states during alcohol and nicotine withdrawal. Further studies are needed to identify how specific manipulations of these CRF circuits can decrease alcohol and nicotine use while maintaining a focus on sexually dimorphic stress-related systems in SUDs.

We appreciate the opportunity to be a part of the special edition and we are looking forward to reading the other articles in the collection.

Article: Role of Corticotropin-Releasing Factor in Alcohol and Nicotine Addiction. Brain Research, 2020 Apr 21;1740:146850. doi: 10.1016/j.brainres.2020.146850

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