Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

Abstract

Alcohol use is pervasive in the United States. In the transition from nonhazardous drinking to hazardous drinking and alcohol use disorder, neuroadaptations occur within brain reward and brain stress systems. One brain signaling system that has received much attention in animal models of excessive alcohol drinking and alcohol dependence is corticotropin-releasing factor (CRF). The CRF system is composed of CRF, the urocortins, CRF-binding protein, and two receptors - CRF type 1 and CRF type 2. This review summarizes how acute, binge, and chronic alcohol dysregulates CRF signaling in hypothalamic and extra-hypothalamic brain regions and how this dysregulation may contribute to changes in alcohol reinforcement, excessive alcohol consumption, symptoms of negative affect during withdrawal, and alcohol relapse. In addition, it summarizes clinical work examining CRF type 1 receptor antagonists in humans and discusses why the brain CRF system is still relevant in alcohol research.

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“…It is important to note that CRF peptide is both locally-generated and recruited from afferent CRF+ fibers originating from various areas, including the BNST (Schreiber and Gilpin, 2018), and the quantification of CRF concentrations within the CeM requires further targeted investigation.…”

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“…The highest densities of CRF neurons are found in the paraventricular nucleus (PVN) of the hypothalamus, where CRF is the main effector of the response to stress mediated by HPA activation (male rats) (Rivier and Vale, ). CRF‐positive cells are also abundant in extrahypothalamic structures of the extended amygdala, in particular the CeA, and the bed nucleus of the stria terminalis (BNST) (male mouse) (Peng et al, ), which mediate the behavioral and emotional response to stress (Schreiber and Gilpin, ). CRF binds to 2 types of Gs protein‐coupled receptors, CRF receptor type 1 (CRFR1) and type 2 (CRFR2).…”

“…Chronic alcohol exposure increases hypothalamic and extrahypothalamic CRF gene expression immediately after consumption. However, during withdrawal hypothalamic CRF and CRFR1 expression is reduced, with subsequent blunting of the HPA response, whereas extrahypothalamic CRF release is increased within the CeA and BNST (see Agoglia and Herman, , Roberto et al, and Schreiber and Gilpin, for review). It has been hypothesized that upregulation of CRF signaling may contribute to negative affect during withdrawal that motivates escalation of alcohol drinking (Zorrilla et al, ).…”

“…Likewise, CRFR1 antagonists reduced binge‐like EtOH drinking, drinking in dependent animals, and drinking in nondependent animals that consume large amounts of alcohol. CRF signaling in the CeA has been thought to play a critical role in this effect, given that antagonism of CRFR1 in the CeA, but not BNST or NAc, reduced alcohol self‐administration in dependent rats (Agoglia and Herman, ; Schreiber and Gilpin, ; Zorrilla et al, ).…”

“…CRFR1 is also involved in these processes; in fact, withdrawal‐induced anxiety is absent in CRFR1 knockout mice or can be blocked by CRFR1 antagonists in alcohol‐dependent animals. Further, CRFR1 antagonists attenuate stress and cue‐induced reinstatement of alcohol‐seeking behavior; the decrease in alcohol‐seeking behavior following stress is likely mediated by extrahypothalamic CRF, given that it is not influenced by adrenalectomy, while hypothalamic CRF may mediate cue‐induced reinstatement because metyrapone, an inhibitor of glucocorticoid synthesis, mimics the reduction in reinstatement induced by CRFR1 antagonists (Schreiber and Gilpin, ).…”