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ALCOHOL RESEARCH: Current Reviews ALCOHOL RESEARCH: Current Reviews Effects of Alcohol Dependence and Withdrawal on Stress Responsiveness and Alcohol Consumption Howard C. Becker, Ph.D. A complex relationship exists between alcohol-drinking behavior and stress. Alcohol Howard C. Becker, Ph.D., has anxiety-reducing properties and can relieve stress, while at the same time acting is a professor of psychiatry as a stressor and activating the body’s stress response systems. In particular, chronic alcohol exposure and withdrawal can profoundly disturb the function of the body’s and neuro science at the neuroendocrine stress response system, the hypothalamic–pituitary–adrenocortical Charleston Alcohol Research (HPA) axis. A hormone, corticotropin-releasing factor (CRF), which is produced and Center, Department of Psychiatry released from the hypothalamus and activates the pituitary in response to stress, plays and Behavioral Sciences, a central role in the relationship between stress and alcohol dependence and Department of Neurosciences, withdrawal. Chronic alcohol exposure and withdrawal lead to changes in CRF activity Medical University of South both within the HPA axis and in extrahypothalamic brain sites. This may mediate the Carolina, and a medical emergence of certain withdrawal symptoms, which in turn influence the susceptibility research career scientist at to relapse. Alcohol-related dysregulation of the HPA axis and altered CRF activity within the Ralph H. Johnson Veterans brain stress–reward circuitry also may play a role in the escalation of alcohol Affairs Medical Center, both in consumption in alcohol-dependent individuals. Numerous mechanisms have been Charleston, South Carolina. suggested to contribute to the relationship between alcohol dependence, stress, and drinking behavior. These include the stress hormones released by the adrenal glands in response to HPA axis activation (i.e., corticosteroids), neuromodulators known as neuroactive steroids, CRF, the neurotransmitter norepinephrine, and other stress- related molecules. KEY WORDS: Alcohol consumption; alcohol dependence; chronic alcohol exposure; drinking behavior; withdrawal; relapse; stress; stress response; biological adaptation to stress; brain; brain stress pathway; hypothalamic– pituitary–adrenocortical axis; corticotropin-releasing factor; corticosteroids; norepinephrine; human studies; animal models lthough stress is known to be an 1999). On the other hand, alcohol itself The relationship between stress and important contributing factor to can serve as a stressor, activating the alcohol drinking is complicated by a A alcohol abuse and alcoholism, the hypothalamic–pituitary–adrenocortical host of alcohol-related factors (e.g., history interaction between stress and alcohol (HPA) axis, which constitutes a major of use, level and pattern of drinking, drinking behavior, as well as the mech- component of the hormonal (i.e., neu- or timing of accessibility of alcohol in anisms underlying this interaction in roendocrine) stress response (Smith and relation to stress experience) as well as the context of dependence are complex Vale 2006). Furthermore, chronic alcohol stress-related factors (e.g., type, chronicity, and not well understood. On the one intermittency, predictability, and con- hand, alcohol is an effective anxiety- exposure and withdrawal experiences not trollability) that intersect with a number reducing agent (i.e., anxiolytic). Hence, only produce robust perturbations in the of biological variables (e.g., genetics, motivation for drinking may be related HPA axis but also engage neuroendocrine- age, and sex). For example, clear indi- to its ability to alleviate stress, including independent (i.e., extrahypothalamic) vidual differences exist in sensitivity to, stress associated with periods of absti- brain stress systems that influence drink- perception of, and responsiveness to nence following bouts of heavy drinking ing behavior in a dynamic and complex stress and alcohol, and both clinical (Cappell and Greeley 1987; Sayette manner (Koob and Kreek 2007). and preclinical evidence indicate that 448 Alcohol Research: Current Reviews genetic factors help shape the nature motivation to drink. Finally, evidence iological symptoms, including rapid of the relationship between stress and will be presented that stress associated heartbeat (i.e., tachycardia), elevated alcohol drinking (Clarke et al. 2008; with alcohol dependence not only blood pressure (i.e., arterial hypertension), Uhart and Wand 2009). The dynamic compromises the ability to mount an excessive sweating (i.e., diaphoresis), interaction of these biological and appropriate behavioral response to a and body temperature dysregulation environmental variables along with subsequent stress challenge, but also alters (Becker 2000; Heilig et al. 2010). For experiential factors plays a critical role the ability of stress challenges to mod- example, studies in rats have demon- in defining subjective aspects of stress ulate drinking in the dependent state. strated increased activity of the adrenal (i.e., the perception and appraisal of a glands and sympathetic nervous system stressful event) and alcohol intoxication. (i.e., sympathoadrenal activity) during These subjective effects, in turn, shape Stress Associated With alcohol withdrawal, as evidenced by the impact of stress on alcohol drinking Chronic Alcohol Exposure elevated plasma levels of the epinephrine 2 and of alcohol consumption on stress and Withdrawal and norepinephrine (Rasmussen et al. responsiveness. 2006). Similarly, increased concentra- Despite the complex interaction As previously noted, alcohol activates tions of norepinephrine in cerebrospinal between stress and alcohol consumption, the HPA axis, with the magnitude and fluid were reported during acute alcohol it generally is acknowledged that stress- response profile influenced by a host withdrawal in alcoholics (Hawley et al. ful life events prominently influence of variables, including the individual’s 1994). Finally, elevated plasma levels alcohol drinking and, in particular, genetic makeup (i.e., genotype) and of epinephrine (Ehrenreich et al. 1997) relapse (Brady and Sonne 1999; Sinha sex as well as dosing parameters (Rivier and norepinephrine (Patkar et al. 2003, 2001, 2008). Several animal models 2000; Wand 2000). Alcohol stimulates 2004) have been reported in abstinent have been developed to study the influ- neuronal activity in the paraventricular alcoholics. ence of stress on alcohol consumption. nucleus of the hypotha lamus, thereby As is the case with most physiological However, reviews of this literature have inducing release of corticotropin-releasing features of alcohol withdrawal, auto- found equivocal results regarding the factor (CRF) (and vasopressin) from nomic-related symptoms typically wax circumstances and manner in which these cells. CRF, in turn, induces the and wane over the course of acute stress modulates alcohol drinking secretion of adrenocorticotrophic hor- withdrawal; however, some cardiovas- (Becker et al. 2011; Pohorecky 1990; mone (ACTH) from the pituitary, cular changes may persist, especially Sillaber and Henniger 2004). The dis- which subsequently acts on the adrenal when assessed following a stress chal- crepancies in results no doubt relate glands to cause an increase in the cir- lenge (Bernardy et al. 2003; Kahkonen to the aforementioned plethora of vari- culating levels of glucocorticoids (e.g., 2004; King et al. 1996). Likewise, ables that influence the reciprocal rela- cortisol in humans and corticosterone studies in humans and animals have tionship between stress and alcohol. in rodents) (Lee et al. 2001, 2004). shown that whereas heightened HPA Nevertheless, researchers continue to Both clinical and experimental studies axis activation associated with with- focus on stress associated with chronic have documented profound distur- drawal usually resolves within a few alcohol exposure and withdrawal bances in HPA axis function following days (Adinoff et al. 1991; Tabakoff et experiences and recently have directed chronic alcohol exposure and with- al. 1978), the blunted HPA axis attention to stress–alcohol interactions drawal. For example, studies in humans responsiveness, along with reduced in alcohol-dependent subjects (Becker (Errico et al. 1993; Wand and Dobs basal levels of circulating corticosteroids, appear to persist for a protracted period et al. 2011; Heilig et al. 2010; Pohorecky 1991), monkeys (Helms et al. 2012a, of time (Adinoff et al. 1990; Cuzon 1990; Sillaber and Henniger 2004). b), and rodents (Kakihana and Moore Carlson et al. 2011; Lovallo et al. This article provides an overview of 1976; Lee et al. 2000; Rasmussen et al. 2000; Rasmussen et al. 2000; Zorrilla clinical studies and studies involving 2000; Tabakoff et al. 1978) have shown et al. 2001). animal models of alcohol dependence that chronic alcohol consumption that demonstrate both prolonged alcohol produces general elevation in blood exposure and repeated periods of absti- glucocorticoid levels, flattening of normal 1 The autonomic nervous system controls involuntary functions of nence constitute potent stressors to the circadian fluctuations, and a dampened many internal organs. It can be divided into the sympathetic ner- organism. Studies conducted in rodents, HPA response to subsequent stress vous system, which promotes actions requiring quick responses (i.e., the fight-or-flight response), and the parasympathetic ner- monkeys, and humans are described challenge. Periods of abstinence
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