Alcoholism, Corticotropin-Releasing Factor, and Molecular Genetic Allostasis

Abstract

Alcoholism, or Substance Dependence on alcohol, is a chronic relapsing disorder characterized by loss of control over intake (compulsive use) and the emergence of a negative emotional state during abstinence. Stress long has been considered a key element in the etiology of alcohol dependence, yet the exact mechanisms by which stress exacerbates and interacts with alcohol dependence have remained elusive. Recent work on the brain neurotransmitter corticotropinreleasing factor (CRF) [see footnote on nomenclature] has provided new insights into the stressalcohol dependence interaction. Two papers in this issue of Biological Psychiatry (1,2) provide an exciting molecular mechanism for this interaction that may have heuristic value for future translational advances.CRF is a 41 amino acid polypeptide with a wide distribution throughout the brain but high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus, the basal forebrain (notably the amygdala and bed nucleus of the stria terminalis) and the brainstem. Central administration of CRF mimics the behavioral response to activation and stress in rodents, and administration of competitive CRF receptor antagonists generally have anti-stress effects (3). Two major CRF receptors have been identified, with CRF 1 receptor activation associated with increased stress responsiveness and CRF 2 receptor activation associated with decreases in feeding and decreased stress responsiveness, although there is some controversy in this area depending on the location of the CRF 2 receptors in question.In the current issue of Biological Psychiatry, Sommer et al. (1) studied rats using an animal model of alcohol dependence and showed that CRF and expression of the crh1 transcript within the amygdala are upregulated in postdependent animals. Animals trained to self-administer alcohol in a two-bottle, free-choice procedure and exposed to intermittent ethanol vapors to induce dependence showed a doubling of ethanol intake and increased sensitivity to stress which was reversed by a CRF receptor antagonist. CRF mRNA was increased in the central nucleus of the amygdala, and crh1 transcript expression was increased in the basolateral amygdala, with a concomitant decrease in crh2 transcript expression in the basolateral amygdala.These new results fit well with a burgeoning dataset implicating an increase in extrahypothalamic CRF function with the excessive drinking associated with alcohol

Mindfulness-Oriented Recovery Enhancement versus CBT for co-occurring substance dependence, traumatic stress, and psychiatric disorders: Proximal outcomes from a pragmatic randomized trial

“…Consequently, substance use becomes compulsive, resulting in a powerful conditioned response mediated by the mesocorticolimbic dopamine system that is subjectively experienced as craving (Skinner & Aubin, 2010). In turn, craving coupled with negative affect may promote chronic substance use, which in turn renders the individual increasingly sensitized to stress and desensitized to pleasure from naturally-rewarding objects and events (Koob, 2008; Koob & Le Moal, 2001). This process, known as allostasis, results in an overall hedonic deficit, manifested in negative affective states which impel the individual to imbibe increasingly higher doses of the substance to achieve a dwindling sense of well-being.…”

Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling

“…Also in this module, corticotropin releasing hormone receptor 1 ( Crhr1 ), significantly up-regulated due to wheel running, has been shown to mediate GABAergic signaling in response to ethanol consumption (Chen et al, 2010; Funk et al, 2007), was up-regulated in rats bred for high ethanol consumption (McBride et al, 2013), and down-regulated after ethanol consumption in mice (Marballi et al, 2015). The corticotrophin signaling pathway plays an important role in the addiction process (Koob, 2008). …”

Stressful Life Events and Relapse Among Formerly Alcohol Dependent Adults

“…It is not surprising that the termination of a major life relationship would lead to relapse, given the potential for loss of social support and increased stress. Stress has long been associated with risk for alcohol use disorders, yet the exact mechanism is not known (Koob, 2008a). Recent work suggest that the brain neurotransmitter corticotropin-releasing factor (CRF) may play an important role in increasing the risk of alcohol use disorders associated with stress (Koob, 2003, 2008a, 2008b, 2009; Koob & Kreek, 2007).…”

“…Stress has long been associated with risk for alcohol use disorders, yet the exact mechanism is not known (Koob, 2008a). Recent work suggest that the brain neurotransmitter corticotropin-releasing factor (CRF) may play an important role in increasing the risk of alcohol use disorders associated with stress (Koob, 2003, 2008a, 2008b, 2009; Koob & Kreek, 2007). This includes animal work suggesting that changes in the CRF receptor may lead to heavy alcohol use following exposure to repeated stress (Sommer et al, 2008), and work showing that adolescents who experienced multiple stressful life events were more likely to drink heavily than those not experiencing such events, provided that they were homozygous for a gene that influences the expression of the CRF receptor (Blomeyer et al, 2008).…”