Addiction and corticotropin‐releasing hormone type 1 receptor antagonist medications

Abstract

Derangements in corticotropin-releasing hormone (CRH) through its type 1 receptor (CRHR1) have been identified in many pathologic conditions. Preclinical models of addiction find that small-molecule antagonists of CRHR1 can limit induction, maintenance, and relapse to drugs of abuse. Neuropsychiatric clinical trials of CRHR1 antagonists have shown mixed efficacy; treatment of addictive disorders has not been established, but finding effective treatments for addictive disorders is critical. Establishing effectiveness for substance abuse treatment will require a different design approach than was used for depression and anxiety trials. Focusing on active versus passive outcome measures, such as resilience to external stressful stimuli, may provide signals in curbing craving and relapse. Study design should include measures of abstinence and drug exposure, but additional elements of stress prevention should also be incorporated. Agents that could provide preemptive protection from drug use and relapse are novel and untested. An understanding of the evolutionary significance of the stress system and preclinical models suggests that these agents may provide protection in this manner. Investigators designing future trials might refocus their understanding of addiction and treatment in this new direction.

Ethnic-Specific Genetic Association of Variants in the Corticotropin-Releasing Hormone Receptor 1 Gene with Nicotine Dependence

“…Repeated stress exposure increases HPA axis dysregulation and can predict relapse in users of a variety of abused substances, including cocaine, alcohol, nicotine, and opiates, as well as in polysubstance abusers [ 18 – 21 ]. Over the past two decades, preclinical studies have demonstrated consistent effects of CRHR1 blockade on stress-mediated behavior, related neurochemistry, sympathetic nervous system activation, and neuroendocrine and immune function [ 34 ]. Further, variants in CRHR1 have been associated with depression [ 35 ], responses to antidepressants [ 36 ], and alcoholism [ 37 ].…”

Early Life Stress as a Risk Factor for Substance use Disorders: Clinical and Neurobiological Substrates

“…CRFR1 is the primary molecular site for stress activation. [ 6 ] CRFR1, a 415-amino acid protein, is the primary receptor subtype expressed in both brain and peripheral tissues. [ 7 ] In a genetically inactivated (CRFR1 −/− ) animal model, dopamine-mediated incentive behavioral manifestation of addiction, such as anxiety, is significantly increased.…”

Anti-stress neuropharmacological mechanisms and targets for addiction treatment: A translational framework

“…Several methodological factors could have led to poor translation ( Pomrenze et al, 2017 ; Shaham and de Wit, 2016 ); if these are properly addressed, there could still be a path forward for these agents but, in all likelihood, therapeutic application may be narrower than originally hoped ( Spierling and Zorrilla, 2017 ). Alternative study designs may be needed that measure not only direct effects of the medication on substance use, but also intermediate stress-related phenotypes, e.g., coping or resilience ( Contoreggi et al, 2013 ). One potential moderating factor is that some clinical studies were conducted exclusively with female volunteers, which could influence the generalizability of findings.…”