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NIH Public Access Author Manuscript Pharmacol Ther. Author manuscript; available in PMC 2012 February 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Pharmacol Ther. 2011 February ; 129(2): 149±171. doi:10.1016/j.pharmthera.2010.09.007. CHRONIC ALCOHOL NEUROADAPTATION AND STRESS CONTRIBUTE TO SUSCEPTIBILITY FOR ALCOHOL CRAVING AND RELAPSE GEORGE R. BREESE1, RAJITA SINHA2, and MARKUS HEILIG3 1 Bowles Center For Alcohol Research and the UNC Neuroscience Center, UNC School Of Medicine, Chapel Hill, NC 27599 2 Stress Center, Yale University School Of Medicine, New Haven, CT 06519 3 Clinical Division, National Institute of Alcoholism and Alcohol Abuse, 10 Center Drive, Bethesda MD 20892 Abstract Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis- like process occurs during the course of repeated chronic alcohol exposures that is critical for the negative symptoms observed during alcohol withdrawal. Basic studies have provided evidence for specific neurotransmitters within identified brain sites being responsible for the negative emotion induced by the persistent cumulative adaptation following intermittent-alcohol exposures. After an extended period of abstinence, the cumulative alcohol adaptation increases susceptibility to stress- and alcohol cue-induced negative symptoms and alcohol seeking, both of which can facilitate excessive ingestion of alcohol. In the alcoholic, stressful imagery and alcohol cues alter physiological responses, enhance negative emotion, and induce craving. Brain fMRI imaging following stress and alcohol cues has documented neural changes in specific brain regions of alcoholics not observed in social drinkers. Such altered activity in brain of abstinent alcoholics to stress and alcohol cues is consistent with a continuing ethanol adaptation being responsible. Therapies in alcoholics found to block responses to stress and alcohol cues would presumably be potential treatments by which susceptibility for continued alcohol abuse can be reduced. By continuing to define the neurobiological basis of the sustained alcohol adaptation critical for the increased susceptibility of alcoholics to stress and alcohol cues that facilitate craving, a new era is expected to evolve in which the high rate of relapse in alcoholism is minimized. 250 Keywords alcoholism; alcohol; adaptation; stress; corticotropin releasing factor; cytokines; brain sites; substance P; relapse; brain imaging Correspondence to: George R. Breese, Ph.D., Bowles Center for Alcohol Studies, UNC School of Medicine, Chapel Hill, NC 27599-7178. The authors have no conflicts. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. BREESE et al. Page 2 1. Introduction 1.1. Alcoholism as a disease—relationship to alcohol responsiveness, genetics, and stress NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Rhem et al. (2009) recently reviewed the extreme burden of alcohol use on society—a circumstance long recognized but inadequately addressed. Progress initiated in the middle of the 20th century began to provide views concerning the possible basis of alcoholism. One of the early conclusions was that offspring from a family with alcoholism were more likely to become alcoholic (Cadoret, 1980; Cotton, 1979; Devor and Cloninger, 1989; Schukit et al., 1985). One important biological clue linking this familial relationship to alcoholism was a lesser susceptibility for alcohol-induced ataxia and sway in sons of alcoholics compared to the response in individuals whose fathers were negative for alcoholism (Schukit, 1985, 1988Schukit, 1994, 2009ab. The logic gleaned from this work was that susceptible individuals become alcoholic because they can drink more alcohol before noting intoxication (Schukit, 1994). This view concerning the degree of alcohol intake received further support from knowledge that Asian individuals who became ill upon ingestion of small amounts of alcohol were less likely to become alcoholic (Peng et al., 2007). Thus, as a credible basis for the liability for alcoholism, this concept that sons of alcoholics could ingest more alcohol before observing symptoms of alcohol intoxication implicated a genetic susceptibility in alcoholism (Cloninger et al., 1981; Devor and Cloninger, 1989; Schuckit et al., 1985; Schweinsburg et al., 2004). A genetic basis is currently believed to be responsible for more than 50% of the individual risk for becoming alcoholic (Dick and Bierut, 2006). Ultimately such observations concerning a familial relationship to alcoholism have led to extensive investigations to identify specific gene changes that may relate to an increased susceptibility for this disease state (Bierut et al., 2010; Dick and Bierut, 2006; Edenberg and Foroud, 2006; Heilig, 2008; Ramchandani et al., 2010; Shuckit, 2009a). In recent years, another population identified with a greater susceptibility for alcoholism includes individuals who drink alcohol excessively during adolescence (Barr et al., 1998; Behrendt et al., 2008; Brown and Tapert, 2004; Clapper et al., 1995; Dawson et al., 2007, 2008; Dewit et al., 2000; Grant and Dawson, 1997; Hingson et al., 2006; Tapert et al., 2003). In an effort to understand this association, studies found that the excess drinking during adolescence that contributed to the increased vulnerability of this population for alcoholism involved such factors as a shared environment and genetic susceptibility (Dawson et al., 2008; Hopfer et al., 2003; McGue and Iacono, 2008; Nelson et al., 2010; Prescott and Kendler, 1999; Rangaswamy et al., 2007). Another generalization concerning susceptibility for alcoholism is that a stressful environment may contribute to excessive use of alcohol (Breese et al., 2004, 2005c; Brown et al, 1990; 1995; Kofoed et al., 1993; Koob, 2008; Sillaber and Henniger, 2004; Tate et al., 2005; Uhart and Wand, 2008). One of the earliest views to explain the role of stress in alcoholism was the tension-reduction hypothesis (Cappel and Herman, 1972; Conger, 1951; 1956). This concept proposed that individuals drank to reduce stress-induced tension and anxiety. While the pharmacology of alcohol can be viewed as demonstrating an “anti- tension” action (Gilman et al., 2008), the logic has long been questioned whether this property of alcohol to reduce “tension” alone relates to an excess of alcohol ingestion that ultimately produces an alcoholic state. In spite of the uncertainty of the tension-reduction hypothesis to alcoholism, the Marlatt laboratory examined the relationship of drinking to stress and consistently demonstrated that exposure to stress resulted in greater drinking in college students (Higgins and Marlatt, 1973; 1975; Marlatt and Gordon, 1980; Marlatt et al, 1975). Cooper et al. (1992) suggested that some vulnerable individuals drink as a coping mechanism to overcome the consequence of stress. In this respect, individuals who drink Pharmacol Ther. Author manuscript; available in PMC 2012 February 1. BREESE et al. Page 3 alcohol for self-medication of symptoms of stress associated with existing psychiatric disorders such as depression, generalized anxiety disorder, social phobia or post-traumatic NIH-PA Author Manuscript NIH-PA Author Manuscriptstress NIH-PA Author Manuscript disorder have a higher degree of alcoholism (Collimore et al., 2010; Conway et al. 2006; Gilbertson et al., 2008; Grant et al., 2004; McLeod et al., 2001; Petrakis et al., 2002; Pirkola et al., 2005; Schuckit, 2006, 2009b; Shivani et al., 2002). Like alcoholics (Haddad, 2004; Wand and Dobs, 1991), these disorders have a dysregulation of the HPA axis (Nestler et al., 2002; Yehuda, 2001); however, it is unknown whether this dysregulation could influence susceptibility for alcoholism. Further not clear is whether a pre-existing genetic background for alcoholism may also be a contributing factor to excessive alcohol use in this psychiatric population. In these subjects, onset of alcohol use is typically later in life, and is predominantly driven by an ability of alcohol to transiently alleviate negative emotional states. Alcohol intakes in this population who drink for self-medication of symptoms use alcohol initially to dampen negative emotions—a coping mechanism. Subsequent drinking becomes excessive resulting in adaptive change that sensitizes stress-relevant brain systems —a change which enhances the incentive for further increases in alcohol to diminish escalating negative symptoms to stress that occur during alcohol abstinence (Heilig, 2008). In a comprehensive model of stress as a factor in risk and relapse to alcoholism, Sinha (2001, 2008a, b, 2009) presents stress as a broader risk factor in the initiation and escalation of alcohol abuse that goes beyond self-medication of co-morbid psychiatric disorders, but rather discusses genetic risk and stress/adversity