The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

Abstract

Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol-dependent subjects, stress-induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress-induced alcohol craving. Here, we examine these studies to explore potential limitations and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of AUD.

Keywords: Alcohol Craving; Alcohol Seeking; Alcohol Use Disorder; Corticotropin Releasing Factor Receptor Type 1; Neuropeptide.

Figure 1

CRFR1 antagonists and the addiction cycle. (A) CRFR1 plays a role in all phases of the addiction cycle. Thickness of red arrows indicates the relative involvement of CRFR1. (B) Summary flow chart for verucerfont and pexacerfont clinical trials. Future trials of verucerfont may be informative if they incorporate parameters such as alcohol consumption in non-treatment seeking individuals with AUD, patient stratification by genotype or other features, or combinations of promising drugs (e.g. those that target dynorphin, NPY, or CRFR2).