Alcohol Dependence, Withdrawal, and Relapse

Howard C. Becker, Ph.D.

Continued excessive alcohol consumption can lead to the development of dependence that is associated with a withdrawal syndrome when alcohol consumption is ceased or substantially reduced. This syndrome comprises physical signs as well as psychological symptoms that contribute to distress and psychological discomfort. For some people the fear of withdrawal symptoms may help perpetuate alcohol abuse; moreover, the presence of withdrawal symptoms may contribute to relapse after periods of abstinence. Withdrawal and relapse have been studied in both humans and animal models of alcoholism. Clinical studies demonstrated that alcohol­dependent people are more sensitive to relapse­ provoking cues and stimuli than nondependent people, and similar observations have been made in animal models of alcohol dependence, withdrawal, and relapse. One factor contributing to relapse is withdrawal­related anxiety, which likely reflects adaptive changes in the brain in response to continued alcohol exposure. These changes affect, for example, the body’s stress response system. The relationship between withdrawal, stress, and relapse also has implications for the treatment of alcoholic patients. Interestingly, animals with a history of alcohol dependence are more sensitive to certain medications that impact relapse­like behavior than animals without such a history, suggesting that it may be possible to develop medications that specifically target excessive, uncontrollable alcohol consumption. KEY WORDS: Alcoholism; alcohol dependence; alcohol and other drug (AOD) effects and consequences; neuroadaptation; AOD withdrawal syndrome; AOD dependence relapse; pharmacotherapy; human studies; animal studies

he development of alcohol expectations about the consequences of drinking (Koob and Le Moal 2008). dependence is a complex and alcohol use. These expectations, in turn, Indeed, for some dependent individuals, Tdynamic process. Many neuro­ shape an individual’s decision about the fear that withdrawal symptoms biological and environmental factors engaging in drinking behavior. might emerge if they attempt to stop influence motivation to drink (Grant The nature of and extent to which or significantly curtail drinking may 1995; Samson and Hodge 1996; these factors are operable in influenc­ prominently contribute to the perpet­ Vengeliene et al. 2008; Weiss 2005). ing decisions about drinking not uation of alcohol use and abuse. At any given time, an individual’s propen­ only vary from one individual to This article will provide an overview sity to imbibe is thought to reflect a another but also depend on the stage of the basic features of alcohol depen­ balance between alcohol’s positive rein­ of addiction—that is, whether the dence and the associated withdrawal forcing (i.e., rewarding) effects, such drinker is at the stage of initial expe­ syndrome, emphasizing those compo ­ as euphoria and reduction of anxiety rience with alcohol, early problem

(i.e., anxiolysis), and the drug’s aversive drinking, or later excessive consump­ 1 To be diagnosed with alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders, effects, which typically are associated tion associated with dependence. the 4th Edition (DSM–IV) (American Psychiatric Association with negative consequences of alcohol Although many people abuse alcohol 1994), an individual must meet at least four of the follow­ consumption (e.g., hangover or with­ without meeting the criteria for alcohol ing criteria: drinking more alcohol than intended, unsuc­ 1 dependence, continued excessive cessful efforts to reduce alcohol drinking, giving up other drawal symptoms). Memories associ­ activities in favor of drinking alcohol, spending a great ated with these rewarding and aversive alcohol consumption can lead to deal of time obtaining and drinking alcohol, continuing to qualities of alcohol, as well as learned the development of dependence. drink alcohol in spite of adverse physical and social associations between these internal states Neuroadaptive changes that result effects, and the development of alcohol tolerance. and related environmental stimuli or from continued alcohol use and abuse contexts, influence both the initiation (which manifest as tolerance and HOWARD C. BECKER, PH.D., is a profes­ and regulation of intake. These experi­ physiological dependence) are thought sor in the Departments of Psychiatry and ential factors, together with biological to be crucial in the transition from Neuroscience, Medical University of and environmental influences and social controlled alcohol use to more fre­ South Carolina & VA Medical Center, forces, are central to the formation of quent and excessive, uncontrollable Charleston, South Carolina.

348 Alcohol Research & Health Alcohol Dependence, Withdrawal, and Relapse nents of withdrawal that especially are emotional changes such as irritability, Events that potently trigger relapse thought to contribute to the problem agitation, anxiety, and dysphoria, as drinking fall into three general cate­ of relapse. It will present evidence well as sleep disturbances, a sense of gories: exposure to small amounts of from both clinical and experimental inability to experience pleasure (i.e., alcohol (i.e., alcohol­induced prim­ studies that highlights long­lasting anhedonia), and frequent complaints ing), exposure to alcohol­related (i.e., physiological and emotional changes about “achiness,” which possibly may conditioned) cues or environmental which are characteristic of dependence reflect a reduced threshold for pain contexts, and stress. Clinical laboratory and have been postulated to play a sensitivity. Many of these signs and studies have found that compared key role in persistent vulnerability symptoms, including those that reflect with control subjects, alcohol­dependent to relapse. In particular, it will review a negative­affect state (e.g., anxiety, people are more sensitive to the ability animal models of alcohol dependence distress, and anhedonia) also have of these stimuli and events to elicit and withdrawal, as well as models of been demonstrated in animal studies craving and negative affect, which in self­administration, that have helped involving various models of depen­ turn presumably drives an increased researchers elucidate brain mechanisms dence (Becker 2000). desire to drink (Fox et al. 2007; underlying relapse and excessive Although many physical signs and Sinha et al. 2008). The combination drinking associated with dependence. symptoms of withdrawal typically of these clinical laboratory procedures abate within a few days, symptoms with neuroimaging techniques has associated with psychological distress proven to be a powerful tool allowing Alcohol Withdrawal and dysphoria may linger for pro­ investigators to identify brain regions tracted periods of time (Anton and that are more strongly activated in When an alcohol­dependent individual Becker 1995; De Soto et al. 1985; alcohol­dependent subjects than in abruptly terminates or substantially Martinotti et al. 2008). The persis­ control subjects when they are exposed reduces his or her alcohol consumption, tence of these symptoms (e.g., anxi­ to these stimuli/events (George et a characteristic withdrawal syndrome ety, negative affect, altered reward al. 2001; Myrick et al. 2004; Wrase ensues. In general, alcohol acts to sup­ set point manifesting as dysphoria et al. 2002). Similar experimental press central nervous system (CNS) and/or anhedonia) may constitute a procedures have been employed to activity, and, as with other CNS depres­ significant motivational factor that evaluate the ability of pharmacothera­ sants, withdrawal symptoms associated leads to relapse to heavy drinking. peutics to quell craving and temper with cessation of chronic alcohol use the brain activation provoked by are opposite in nature to the effects of alcohol­related cues in humans (Anton intoxication. Typical clinical features of Studying Alcohol Relapse et al. 2004; George et al. 2008; alcohol withdrawal include the follow­ Behavior Myrick et al. 2007, 2008; O’Malley ing (Becker 2000; Hall and Zador et al. 2002). 1997; Saitz 1998): Relapse may be defined as the resump­ More detailed insight regarding tion of alcohol drinking following a mechanisms underlying fundamental • Signs of heightened autonomic prolonged period of abstinence. Clinically, changes in brain function that occur nervous system2 activation, such as vulnerability to relapse commonly is as a consequence of dependence and rapid heartbeat (i.e., tachycardia), associated with an intense craving or which relate to enduring relapse vul­ elevated blood pressure, excessive desire to drink. Although a precise nerability have been gained through sweating (i.e., diaphoresis), and definition for craving remains elusive research in animals. Several animal shaking (i.e., tremor); (Anton 1999; Koob 2000; Littleton models have been used to study alco­ 2000), and there even is some debate hol self­administration behavior and • Excessive activity of the CNS (i.e., about the role of craving in relapse the issue of relapse (for reviews, see CNS hyperexcitability) that may (Miller and Gold 1994; Rohsenow Le and Shaham 2002; Sanchis­Segura culminate in motor seizures; and and Monti 1999; Tiffany and Carter and Spanagel 2006; Weiss 2005). In 1998), there is no question that relapse one type of model, animals with a • Hallucinations and delirium tremens represents a prevalent and significant long history of daily access to alcohol in the most severe form of withdrawal. problem in alcoholism. In fact, given the are abruptly denied access to the high rate of recidivism in alcoholism, drug. When alcohol is reintroduced In addition to physical signs of relapse clearly is a major impediment after this period of “forced” (i.e., withdrawal, a constellation of symptoms to treatment efforts. Consequently, experimenter­induced) abstinence, contributing to a state of distress and substantial research efforts have been the animals exhibit a transient psychological discomfort constitute directed at modeling relapse behavior, a significant component of the with­ as well as elucidating neural substrates 2 The autonomic nervous system is that division of the drawal syndrome (Anton and Becker and environmental circumstances that nervous system which regulates the functions of the inter­

nal organs and controls essential and involuntary bodily 1995; Roelofs 1985; Schuckit et al. are associated with or promote exces­ functions, such as respiration, blood pressure and heart

1998). These symptoms include sive drinking. rate, or digestion.

Vol. 31, No. 4, 2008 349 increase in alcohol consumption. ior. This renewed alcohol­seeking the dependent individual, this allostatic This alcohol deprivation effect has behavior can be observed even after a state is fueled by progressive dysregula­ been demonstrated using both mea­ long period of time has elapsed since tion of the brain’s reward and stress sys­ sures of voluntary alcohol consump­ the animals last were given an oppor­ tems beyond their normal homeostatic 3 tion and operant procedures (Heyser tunity to self­administer alcohol, sug­ limits (Koob 2003; Koob and Le Moal et al. 1997; Sinclair 1979; Spanagel gesting that these contextual cues can 2001). These neuroadaptive changes and Holter 1999). Another model serve as powerful triggers for relapse­ associated with dependence and with­ frequently used to study alcohol (and like behavior (Ciccocioppo et al. drawal are postulated to impact the other drug) relapse behavior involves 2001; Katner and Weiss 1999; rewarding effects of alcohol and, conse­ operant reinstatement procedures Katner et al. 1999). Additional stud­ quently, contribute to the transition

(Shaham et al. 2003). In this model, ies (Chaudhri et al. 2008; Zironi et from controlled alcohol use to more animals first are trained to respond al. 2006) found that reexposure of excessive, uncontrollable drinking. the animals to the general environ­ for access to alcohol (i.e., to receive Manifestations of these perturbations mental context in which they could the reinforcement provided by alco­ in brain reward and stress systems also self­administer alcohol not only hol). Then, the response­contingent appear to mediate the myriad symptoms enhanced subsequent alcohol reinforcement is interrupted with of alcohol withdrawal, as well as under­ extinction training—that is, even if responding but also modulated the lie persistent vulnerability to relapse. the animals perform the required ability of alcohol­conditioned cues to As noted above, clinical laboratory response, they do not receive alcohol; reinstate alcohol­seeking behavior. studies have shown that alcohol­ as a result, the animals eventually Finally, and perhaps most impor­ dependent people are more sensitive reduce or even completely stop tantly, animals used in all of these responding. When the animals then models generally have demonstrated to relapse­provoking cues/stimuli are exposed again to small alcohol sensitivity to treatment with various compared with control subjects. By doses, environmental stressors, or medications that have been shown to definition, alcohol­dependent sub­ stimuli previously associated with be clinically effective in preventing jects also are heavier drinkers and delivery of alcohol (i.e., conditioned and/or retarding alcohol relapse (too) often experience an insidious cues), they resume responding (to (Burattini et al. 2006; Heilig and Egli return to excessive levels of alcohol varying degrees)—as if “seeking” 2006; Le and Shaham 2002; Marinelli consumption once a “slip” occurs alcohol reinforcement (Le et al. et al. 2007b; Spanagel and Kiefer after abstinence. Not surprisingly, 1998, 2000; Weiss et al. 2001). This 2008). From a clinical standpoint, this numerous rodent and primate models renewed alcohol­seeking behavior is important because it underscores have been employed to examine the becomes even more robust when sev­ the value of these models in identify­ influence of dependence on relapse. eral of these relevant stimuli are pre­ ing and evaluating new treatment Early studies using these animal models sented in combination (Backstrom strategies that may be more effective generally yielded equivocal findings, and Hyytia 2004; Liu and Weiss in battling the problem of relapse. most likely because investigators used 2002b). Interestingly, this reinstate­ procedures that neither sufficiently ment of alcohol responding occurs established alcohol’s positive reinforcing even though the animals still do not Alcohol Dependence, effects prior to dependence induction receive alcohol reinforcement. Withdrawal, and Relapse nor optimized the development of This experimental design can be alcohol’s negative reinforcing capacity further modified by the use of dis­ As mentioned earlier, alcohol addiction (i.e., the animals did not have an criminative contextual cues. This is a complex and dynamic process (see opportunity to associate alcohol means that certain contextual cues figure 1). Prolonged excessive alcohol drinking with alleviation of with­ (e.g., a unique odor or testing envi­ consumption sets in motion a host of drawal symptoms) (Meisch 1983; ronment) will indicate to the animal neuroadaptive changes in the brain’s Meisch and Stewart 1994). that responding will pay off with reward and stress systems (for reviews, More recent studies that have delivery of alcohol reinforcement, see Hansson et al. 2008; Heilig and incorporated these procedural consid­ whereas a different contextual cue is Koob 2007; Koob and Le Moal 2008; erations, however, have demonstrated used to signal that responding will Vengeliene et al. 2008). The develop­ increased alcohol responding and/or not result in access to alcohol. If the ment of alcohol dependence is thought drinking in dependent compared responding is extinguished in these to reflect an allostatic state—that is, a with nondependent mice (Becker animals (i.e., they cease to respond state in which the chronic presence of

alcohol produces a constant challenge 3 In operant procedures, animals must first perform a cer­ because they receive neither the alco­ tain response (e.g., press a lever) before they receive a hol­related cues nor alcohol), presen­ to regulatory systems that attempt (but stimulus (e.g., a small amount of alcohol). By modifying tation of a discriminative cue that ultimately fail) to defend the normal the required response (e.g., increasing the number of

lever presses required before the alcohol is delivered) previously signaled alcohol availability equilibrium of various internal pro­ researchers can determine the motivational value of the cesses (i.e., homeostatic set points). In will reinstate alcohol­seeking behav­ stimulus for the animal.

350 Alcohol Research & Health Alcohol Dependence, Withdrawal, and Relapse

and Lopez 2004; Chu et al. 2007; 2002b; Sommer et al. 2008). In Role of Withdrawal­ Dhaher et al. 2008; Finn et al. 2007; many instances, these effects were Related Stress and Lopez and Becker 2005) and rats observed long after the animals had Anxiety in Relapse (O’Dell et al. 2004; Rimondini experienced chronic alcohol exposure et al. 2003; Roberts et al. 2000; (Lopez and Becker 2005; Rimondini As previously noted, increased anxiety Sommer et al. 2008; Valdez et al. et al. 2003; Valdez et al. 2002). Finally, represents a significant component of 2002). Moreover, in some studies, experience with repeated cycles of the alcohol withdrawal syndrome. the enhanced alcohol consumption chronic alcohol exposure and with­ Importantly, this negative­affect state in dependent animals during with­ drawal not only led to an exacerba­ may contribute to increased risk for drawal produced blood and brain tion of the physiological symptoms of relapse as well as perpetuate continued alcohol levels that nearly reached lev­ withdrawal but also to enhanced sus­ use and abuse of alcohol (Becker 1999; els attained during the initial chronic ceptibility to relapse (for more infor­ Driessen et al. 2001; Koob 2003; Roelofs alcohol exposure which had produced mation on this issue, see the sidebar, 1985). Indeed, both preclinical and clini­ the dependent state (Griffin et al. “Repeated Alcohol Withdrawals: cal studies suggest a link between anxiety 2008; Roberts et al. 2000). Also, con­ Sensitization and Implications for and propensity to self­administer alcohol sistent with the findings of clinical Relapse”). Thus, a growing body of (Henniger et al. 2002; Spanagel et al. studies, animals with a history of evidence indicates that alcohol depen­ 1995; Willinger et al. 2002). alcohol dependence exhibited exag­ dence and withdrawal experiences sig­ Various experimental procedures gerated sensitivity to alcohol­related nificantly contribute to enhanced have been used to demonstrate cues and various stressors that lead relapse vulnerability as well as favor increased behavioral anxiety in ani­ to enhanced alcohol­seeking behavior sustained high levels of alcohol drink­ mal models of alcohol dependence (Gehlert et al. 2007; Liu and Weiss ing once a “slip” occurs. and withdrawal (Becker 2000; Kliethermes 2005). Many of these models involve procedures that exploit the natural tendency of rodents to avoid environments (e.g., Social drinking bright open spaces) that may be con­ sidered dangerous or threatening, Problem/abusive drinking thereby eliciting an internal state of fear or anxiety. Other models assess an animal’s propensity to engage in Dependence social interaction with another (unfa­ Altered brain function miliar) animal of the same species (Overstreet et al. 2002) or response Excessive & uncontrollable drinking under conflict situations (Sommer et al. 2008). Finally, some models use operant discrimination proce­ Abstinence dures to train animals to discern sub­ jective (i.e., interoceptive) cues associ­ Acute/protracted withdrawal symptoms ated with an anxiety­inducing (i.e., anxiogenic) state experienced during withdrawal (Gauvin et al. 1992; Lal Relapse et al. 1988). Alcohol withdrawal–related anxiety is thought to reflect manifestations Figure 1 of numerous adaptive changes in the Schematic illustration of how problem drinking can lead to the development brain resulting from prolonged alcohol of dependence, repeated withdrawal experiences, and enhanced vulnera­ exposure, most notably alterations in bility to relapse. Alcohol dependence is characterized by fundamental the stress systems active in the brain changes in the brain’s reward and stress systems that manifest as withdrawal and the body’s hormone (i.e., endocrine) symptoms when alcohol consumption is stopped or substantially reduced. circuits. The hormonal stress response These changes also are purported to fuel motivation to reengage in exces­

sive drinking behavior. Repeated bouts of heavy drinking interspersed is mediated by a system known as the

with attempts at abstinence (i.e., withdrawal) may result in sensitization of hypothalamic–pituitary–adrenocortical

withdrawal symptoms, especially symptoms that contribute to a negative (HPA) axis. Within this system, stress

emotional state. This, in turn, can lead to enhanced vulnerability to relapse induces the release of the hormone

as well as favor perpetuation of excessive drinking. corticotrophin­releasing factor (CRF) (continued on page 356)

Vol. 31, No. 4, 2008 351 Repeated Alcohol Withdrawals Sensitization and Implications for Relapse

Given that alcoholism is a chronic however, researchers have been involving animal models. For exam­ relapsing disease, many alcohol­ turning their attention to the eval­ ple, animals with a history of dependent people invariably expe­ uation of changes in withdrawal chronic alcohol exposure and rience multiple bouts of heavy symptoms that extend beyond repeated withdrawal experiences drinking interspersed with periods physical signs of withdrawal—that were shown to exhibit enhanced of abstinence (i.e., withdrawal) is, to those symptoms that fall withdrawal­related anxiety, as mea­ of varying duration. A convergent within the domain of psychological sured in a variety of behavioral tasks body of preclinical and clinical distress and dysphoria. This new (Overstreet et al. 2002, 2004; evidence has demonstrated that focus is clinically relevant because Sommer et al. 2008; Zhang et al. a history of multiple detoxifica­ these symptoms (e.g., anxiety, neg­ 2007). Moreover, such a history tion/withdrawal experiences can ative affect, and altered reward enhanced the animals’ sensitivity to result in increased sensitivity to set point) may serve as potent various stressors, as measured by the the withdrawal syndrome—a pro­ instigators driving motivation to stressors’ ability to activate the body’s cess known as “kindling” (Becker drink (Koob and Le Moal 2008). stress response system (i.e., the and Littleton 1996; Becker 1998). Sensitization resulting from repeated hypothalamic–pituitary–adrenocor­ For example, clinical studies have withdrawal cycles and leading to tical [HPA] axis) (Becker 1999), indicated that a history of multiple both more severe and more persis­ to produce anxiety­like behavior detoxifications increases a person’s tent symptoms therefore may con­ (Breese et al. 2005; Sommer et al. susceptibility to more severe and stitute a significant motivational 2008), and to trigger relapse­like medically complicated withdrawals factor that underlies increased risk behavior (Ciccocioppo et al. 2003). in the future (e.g., Booth and for relapse (Becker 1998, 1999). In all these cases, increased activity Blow 1993). Similarly, animal Furthermore, multiple with­ of a signaling molecule called corti­ studies have demonstrated sensiti­ drawal episodes provide repeated cotropin­releasing factor (CRF) was zation of electrographic and opportunities for alcohol­dependent found to be a critical mediating fac­ behavioral measures of withdrawal individuals to experience the negative tor. This finding lends support to seizure activity in mice following reinforcing properties of alcohol— the idea that enhanced CRF activity multiple withdrawals compared with that is, to associate alcohol con­ represents a key neuroadaptive change animals tested after a single with­ sumption with the amelioration that is fueled by repeated with­ drawal episode, even if both groups of the negative consequences (e.g., drawal experience and which drives of animals had been exposed to the withdrawal­related malaise) experi­ (at least in part) the motivation to same total amount of alcohol (e.g., enced during attempts at abstinence. drink as well as amplifies responsive­ Becker and Hale 1993; Becker 1994; This association not only may serve ness to stimuli/events that provoke Veatch and Becker 2002, 2005). as a powerful motivational force relapse (Heilig and Koob 2007; that increases relapse vulnerability, Koob and Le Moal 2008). (For Effects of Repeated but also favors escalation of alcohol more information on the body’s Withdrawals on Emotional drinking and sustained levels of stress response, including the HPA State and Stress Response potentially harmful drinking. Thus, axis and CRF, see the main article.) for many dependent individuals, Additional evidence indicates Most studies demonstrating this repeated withdrawal experiences that behavioral measures indicating sensitization or “kindling” of may be especially relevant in shaping a reduced sensitivity to rewarding alcohol withdrawal primarily have motivation to seek alcohol and stimuli (i.e., anhedonia) are exaggerated focused on withdrawal­related engage in excessive drinking behavior. in rats that experience withdrawal excessive activity (i.e., hyperex­ Support for the notion that from repeated alcohol injections citability) of the central nervous repeated withdrawal experience pro­ compared with rats tested during system (CNS), as indicated by gressively intensifies withdrawal withdrawal from a single alcohol seizure activity, because this symptoms—which, in turn, impacts injection (Schulteis and Liu 2006). parameter is relatively easy to relapse vulnerability and facilitates Finally, a history of multiple with­ observe in experimental as well transition to uncontrollable drinking— drawal experiences can exacerbate as clinical settings. More recently, primarily has come from studies cognitive deficits and disruption of

352 Alcohol Research & Health Alcohol Dependence, Withdrawal, and Relapse

sleep during withdrawal (Borlikova particular, control over the amount receive alcohol reinforcement was et al. 2006; Stephens et al. 2005; consumed during a given drinking significantly increased following Veatch 2006). Taken together, these occasion, these observations may repeated withdrawal experience. This results indicate that chronic alcohol be relevant to the problem of suggests that the reinforcing value of exposure involving repeated with­ relapse and excessive drinking. alcohol may be enhanced as a result drawal experiences exacerbates with­ Indeed, clinical studies have indi­ of experiencing repeated opportuni­ drawal symptoms that significantly cated that heavy drinkers exhibit a ties to respond for access to alcohol contribute to a negative emotional reduced capacity to detect (dis­ in the context of withdrawal. state, which consequently renders criminate) internal cues associated Enhanced alcohol responding/ dependent subjects more vulnerable with alcohol intoxication (Hiltunen intake in dependent animals occurred to relapse. 1997; Jackson et al. 2001; Schuckit well beyond the period of acute and Klein 1991). Future studies withdrawal, and escalation of alcohol Effects of Repeated Withdrawals will need to further explore the self­administration was especially on Tolerance to Subjective potential relationship between facilitated when dependence was Alcohol Effects and Alcohol increased tolerance to subjective induced by delivering chronic alcohol Self­Administration effects of alcohol produced by in an intermittent rather than con­ repeated withdrawal experience and tinuous fashion (Lopez and Becker Researchers also have explored enhanced propensity to imbibe. 2005; O’Dell et al. 2004). This the effects of repeated withdrawal More direct evidence supporting latter finding suggests that elevated episodes on the perceived subjective increased alcohol consumption as a alcohol self­administration does not effects of alcohol. In animal stud­ consequence of repeated withdrawal merely result from long­term alco­ ies using operant discrimination experience comes from animal hol exposure per se, but rather that procedures,1 the animals’ ability to studies linking dependence models repeated withdrawal experiences detect (perceive) the subjective cues with self­administration procedures. underlie enhanced motivation for associated with alcohol intoxication For example, rats exposed to chronic alcohol seeking/consumption. was diminished during withdrawal alcohol treatment interspersed with Additionally, the more cycles of from chronic alcohol exposure, and repeated withdrawal episodes con­ chronic alcohol exposure and with­ this tolerance effect was enhanced sumed significantly more alcohol drawal the animals were exposed to, in mice that experienced multiple than control animals under free­ the more alcohol they ingested and withdrawals during the course choice, unlimited access conditions the longer (i.e., for several weeks) of the chronic alcohol treatment (Rimondini et al. 2002, 2003; the enhanced alcohol intake was (Becker and Baros 2006). Similarly, Sommer et al. 2008). Similar results sustained following the final with­ rats with a history of repeated have been reported in mice, with drawal episode compared with a cycles of chronic alcohol exposure voluntary alcohol consumption separate group of nondependent and withdrawal exhibited long­ assessed using a limited access mice (Lopez and Becker 2005). lasting tolerance to the sedative/ schedule (Becker and Lopez 2004; This effect apparently was specific hypnotic effects of alcohol Dhaher et al. 2008; Finn et al. 2007; to alcohol because repeated chronic (Rimondini et al. 2008). Because Lopez and Becker 2005). Likewise, alcohol exposure and withdrawal changes in sensitivity as well as studies using operant procedures experience did not produce alter­ in the ability to detect (perceive) have demonstrated increased alcohol ations in the animals’ consumption subjective effects associated with self­administration in mice (Chu et of a sugar solution (Becker and alcohol intoxication may influence al. 2007; Lopez et al. 2008) and rats Lopez 2004). More detailed analyses decisions about drinking and, in (O’Dell et al. 2004; Roberts et al. of the pattern of alcohol consump­ 1996, 2000) with a history of repeated tion revealed that dependent mice

1In operant procedures, animals must first perform a chronic alcohol exposure and with­ not only consumed more alcohol

certain response (e.g., press a lever) before they drawal experience. Further, the than nondependent animals over receive a stimulus (e.g., a small amount of alcohol).

By modifying the required response (e.g., increasing amount of work mice (Lopez et al. the entire 2­hour period during

the number of lever presses required before the alco­ 2008) and rats (Brown et al. 1998) which they had access to alcohol, hol is delivered) researchers can determine the moti­ were willing to expend in order to but that the rate of consumption vational value of the stimulus for the animal.

Vol. 31, No. 4, 2008 353 was faster and progressively increased lower relapse vulnerability and/or Pharmacology and Experimental Therapeutics with successive withdrawal test periods a reduced amount consumed 319:871–878, 2006. PMID: 16914560 (Griffin et al. 2008). once drinking was (re)­initiated BECKER, H.C., AND HALE, R.L. Repeated In both mice and rats, enhanced (Ciccocioppo et al. 2003; Finn et episodes of ethanol withdrawal potentiate the alcohol self­administration follow­ al. 2007; Funk et al. 2007; Walker severity of subsequent withdrawal seizures: An animal model of alcohol withdrawal “kindling.” ing repeated cycles of withdrawal and Koob 2008). These findings Alcoholism: Clinical and Experimental Research was associated with significantly have clear clinical relevance from a 17(1):94–98, 1993. PMID: 8452212 higher resultant blood alcohol levels treatment perspective. Indeed, clin­ compared with the levels achieved ical investigations similarly have BECKER, H.C., AND LITTLETON, J.M. The alco­ hol withdrawal “kindling” phenomenon: Clinical by nondependent animals (Becker reported that a history of multiple and experimental findings. Alcoholism: Clinical and Lopez 2004; Roberts et al. detoxifications can impact respon­ and Experimental Research 20:121A–124A, 1996. 2000). The greater (and faster) alco­ siveness to and efficacy of various BECKER, H.C., AND LOPEZ, M.F. Increased hol intake exhibited by dependent pharmacotherapeutics used to man­ ethanol drinking after repeated chronic ethanol mice also lead to significantly higher age alcohol dependence (Malcolm exposure and withdrawal experience in C57BL/6 peak and more sustained alcohol et al. 2000, 2002, 2007). Future mice. Alcoholism: Clinical and Experimental concentrations in the brain com­ studies should focus on elucidating Research 28:1829–1838, 2004. PMID: 15608599 pared with the levels achieved after neural mechanisms underlying BECKER, H.C., AND VEATCH, L.M. Effects of alcohol consumption in nondepen­ sensitization of symptoms that lorazepam treatment for multiple ethanol with­ dent animals (Griffin et al. 2008). contribute to a negative emotional drawals in mice. Alcoholism: Clinical and Finally, greater voluntary alcohol state resulting from repeated with­ Experimental Research 26:371–380, 2002. consumption in dependent mice drawal experience. Such studies PMID: 11923591 produced brain alcohol concentra­ will undoubtedly reveal important BOOTH, B.M., AND BLOW, F.C. The kindling tions that approximated those levels insights that spark development hypothesis: Further evidence from a U.S. of new and more effective treatment national study of alcoholic men. Alcohol & experienced during the chronic Alcoholism 28:593–598, 1993. PMID: 8274184 intermittent alcohol exposure which strategies for relapse prevention had rendered the animals dependent as well as aid people in controlling BORLIKOVA, G.G.; ELBERS, N.A.; AND in the first place (see figure 2, main alcohol consumption that too STEPHENS, D.N. Repeated withdrawal from ethanol spares contextual fear conditioning and section). Although it is tempting to often spirals out of control to spatial learning but impairs negative patterning speculate that dependent animals excessive levels. and induces over­responding: Evidence for increase voluntary alcohol drinking effect on frontal cortical but not hippocampal function? European Journal of Neuroscience to attain blood and brain alcohol —Howard Becker, Ph.D. levels in a range consistent with sus­ 24:205–216, 2006. PMID: 16882017 taining dependence, the extent to BREESE, G.R.; OVERSTREET, D.H.; KNAPP, which resultant brain alcohol con­ D.J.; AND NAVARRO, M. Prior multiple ethanol centrations help drive as well as References withdrawals enhance stress­induced anxiety­like behavior: Inhibition by CRF1­ and benzodi­ perpetuate enhanced alcohol drink­ American Psychiatric Association. Diagnostic azepine­receptor antagonists and a 5­HT1a­ th ing in dependent animals remains and Statistical Manual of Mental Disorders, 4 receptor agonist. Neuropsychopharmacology

to be determined. Edition. Arlington, VA: American Psychiatric 30:1662–1669, 2005. PMID: 15726114 Association, 1994. BROWN, G.; JACKSON, A.; AND STEPHENS, BECKER, H.C. Positive relationship between the Effects of Repeated Withdrawals D.N. Effects of repeated withdrawal from chronic number of prior ethanol withdrawal episodes ethanol on oral self­administration of ethanol on a on Sensitivity to Treatment and the severity of subsequent withdrawal progressive ratio schedule. Behavioural Pharmacology seizures. Psychopharmacology 116:26–32, 1994. 9:149–161, 1998. PMID: 10065934 Some studies using animal models PMID: 7862927 involving repeated withdrawals CHU, K.; KOOB, G.F.; COLE, M.; ET AL. BECKER, H.C. Kindling in alcohol withdrawal. have demonstrated altered sensitivity Alcohol Health & Research World 22:25–33, Dependence­induced increases in ethanol self­ to treatment with medications 1998. PMID: 15706729 administration in mice are blocked by the designed to quell sensitized with­ CRF1 receptor antagonist antalarmin and by drawal symptoms (Becker and BECKER, H.C. Alcohol withdrawal: Neuro­ CRF1 receptor knockout. Pharmacology, adaptation and sensitization. CNS Spectrums Biochemistry & Behavior 86:813–821, 2007. Veatch 2002; Knapp et al. 2007; 4:38–65, 1999. PMID: 17482248 Overstreet et al. 2007; Sommer et al. 2008; Veatch and Becker 2005). BECKER, H.C., AND BAROS, A.M. Effect of CICCOCIOPPO, R.; LIN, D.; MARTIN­FARDON, duration and pattern of chronic ethanol expo­ R.; AND WEISS, F. Reinstatement of ethanol­ Moreover, after receiving some of sure on tolerance to the discriminative stimulus seeking behavior by drug cues following single these medications, animals exhibited effects of ethanol in C57BL/6J mice. Journal of versus multiple ethanol intoxication in the rat:

354 Alcohol Research & Health Alcohol Dependence, Withdrawal, and Relapse

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Vol. 31, No. 4, 2008 355 (continued from page 351) basal levels of circulating corticosteroids and CRF2 receptors that are located (Marchesi et al. 1997; Rasmussen et in the membrane surrounding the from a brain area called the hypotha­ al. 2000; Zorrilla et al. 2001). target cells on which CRF acts. lamus. CRF acts on the pituitary In addition to these HPA axis– Outside of the hypothalamus, CRF gland located directly below the related effects, alcohol alters CRF and its receptors are found in an hypothalamus, where it initiates activity independent of the HPA axis extensive network of interconnected the production of a molecule called (Heilig and Koob 2007; Koob and Le neural structures that are intimately proopiomelanocortin (POMC). This Moal 2001). CRF is a 41–amino acid associated with the brain’s reward and compound is processed further into neuropeptide that is widely distributed stress pathways, such as the amygdala, smaller molecules, such as β­endorphin throughout the mammalian brain bed nucleus of stria terminalis (BNST), and adrenocorticotropic hormone and plays a critical role not only in and prefrontal cortex. Following (ACTH). ACTH is carried via the regulating HPA axis activity but also chronic alcohol exposure, increased blood stream to the adrenal glands in orchestrating other behavioral and CRF release, along with an increase (which are located atop the kidneys), physiological responses to stress. To in the number (i.e., upregulation) where it induces the release of stress exert these effects, CRF interacts with of CRF1 receptors, can be observed, hormones (i.e., glucocorticoids) that two types of receptors called CRF1 especially in these brain areas. These then act on target cells and tissues throughout the body (including the brain). The main glucocorticoid in humans and other primates is corti­ sol; the main glucocorticoid in Alcohol access rodents is corticosterone. It is well known that alcohol acti­ vates the HPA axis, with the magni­ tude and response profile influenced (mM) by a host of variables, including the individual’s specific genetic makeup (i.e., genotype) and sex as well as the alcohol alcohol dose ingested (Rivier 2000;

Wand 2000). Both clinical and exper­ Brain imental studies have documented profound disturbances in HPA axis concentration function following chronic alcohol exposure and withdrawal. For example, in humans and rodents, chronic alco­ hol consumption results in a general 20­minute samples elevation in blood corticosteroid levels, with a typical flattening of changes in corticosteroid levels that normally is Figure 2 observed throughout the day (Kakihana Enhanced voluntary alcohol drinking in dependent mice produced brain and Moore 1976; Rasmussen et al. alcohol concentrations similar to those achieved during the chronic alco­

hol exposure that initially rendered the animals dependent. Samples 2000; Tabakoff et al. 1978; Wand and were collected from the nucleus accumbens of alcohol­dependent mice Dobs 1991). At the same time, para­ that had undergone three cycles of chronic intermittent alcohol vapor doxically, HPA response to subsequent exposure (red symbols) and nondependent controls (black symbols). stress challenge consistently is dampened Samples were taken before, during, and after the 2­hour drinking ses­ (i.e., blunted) (Errico et al. 1993; Lee sion, when the mice had the opportunity to voluntarily drink alcohol (15 et al. 2000). Whereas the overall height­ percent vol/vol) or water. Alcohol intake during the drinking session was ened HPA axis activation associated 3.04 ± 0.15 g/kg for dependent mice and 2.32 ± 0.28 g/kg for nondepen­ with withdrawal usually resolves within a dent mice. The red bar indicates the 2­hour drinking session. Horizontal few days (Adinoff et al. 1991; Tabakoff lines and shaded area represent brain alcohol levels (means ± SEM) et al. 1978; Willenbring et al. 1984), measured in the dependent mice during chronic intermittent alcohol expo­ the blunted responsiveness of the HPA sure (28.4 ± 3.5 mM). axis to subsequent challenges appears to NOTE: Brain alcohol concentrations (mM) were measured in microdialysis samples collected from the nucleus persist for a protracted period of time accumbens. Values are corrected for calculated recovery rates (~10 percent) for microdialysis probes. SEM =

(Adinoff et al. 1990; Costa et al. 1996; standard error of the mean.

Lovallo et al. 2000). In some cases, SOURCE: Data are adapted from Griffin et al. 2008. this may be accompanied by reduced

356 Alcohol Research & Health Alcohol Dependence, Withdrawal, and Relapse variations represent an important propensity to drink through an inter­ Treatment Implications neuroadaptive change (Heilig and action with the brain’s main reward Koob 2007; Koob and Le Moal circuitry (i.e., mesocorticolimbic Relapse represents a major challenge to 2001) that is thought to be key in the dopamine system) (Fahlke et al. treatment efforts for people suffering emergence of withdrawal­related anx­ 1996; Piazza and Le Moal 1997). A from alcohol dependence. To date, no iety and dysphoria, both of which CRF antagonist that acts on both the therapeutic interventions can fully pre­ likely are intimately tied to alcohol CRF1 and CRF2 receptors (i.e., a vent relapse, sustain abstinence, or drinking and relapse (Becker 1999; nonselective peptide CRF antagonist) temper the amount of drinking when a Koob 2003). The contribution of called D­Phe­CRF12–42 reduced exces­ “slip” occurs. For some people, loss of CRF to withdrawal­related anxiety sive drinking in dependent animals control over alcohol consumption can is supported by findings that agents when administered into the brain lead to alcohol dependence, rendering which interfere with the normal ventricles (Finn et al. 2007; Valdez et them more susceptible to relapse as actions of CRF (i.e., CRF antago­ al. 2002) or the central nucleus of the well as more vulnerable to engaging in nists) can reduce the anxiety if they amygdala (Funk et al. 2006). drinking behavior that often spirals out are administered into the blood (i.e., Similarly, systemic administration of of control. Many of these people make systemically) (Breese et al. 2005; antagonists that selectively act at the numerous attempts to curtail their Sommer et al. 2008) or directly into alcohol use, only to find themselves the CNS—that is, either into the CRF1 receptor also reduced upregu­ lated drinking in dependent mice reverting to patterns of excessive fluid­filled spaces of the brain (i.e., consumption. (Chu et al. 2007) and rats (Funk et brain ventricles) (Baldwin et al. 1991; Significant advancements have al. 2007; Gehlert et al. 2007). Valdez et al. 2003) or into the central been made in understanding the nucleus of the amygdala (Rassnick et Different stressors likewise robustly neurobiological underpinnings and al. 1993). This effect appears to be reinstated extinguished alcohol­ environmental factors that influence reinforced responding in different mediated by CRF1 receptors because motivation to drink as well as the CRF antagonists that selectively operant reinstatement models of consequences of excessive alcohol use. block CRF1 receptors result in anxi­ relapse (Funk et al. 2005; Gehlert Given the diverse and widespread ety reduction (Overstreet et al. 2004). et al. 2007; Le et al. 2000, 2005; neuroadaptive changes that are set in Conversely, activation of CRF2 recep­ Liu and Weiss 2002b). This effect motion as a consequence of chronic tors may attenuate withdrawal­related appears to involve CRF activity alcohol exposure and withdrawal, it anxiety (Valdez et al. 2004). Thus, because CRF antagonists block stress­ perhaps is not surprising that no sin­ chronic alcohol exposure and with­ induced reinstatement of alcohol­ gle pharmacological agent has proven drawal experiences can be viewed as seeking behavior (Gehlert et al. 2007; to be fully successful in the treatment potent stressors that disrupt the func­ Le et al. 2000; Liu and Weiss 2002b). of alcoholism. The challenge of tional integrity of the HPA axis and Moreover, extrahypothalamic CRF choosing the most appropriate agent also act on the extrahypothalamic CRF activity appears to contribute to this for the treatment of alcoholism is systems. This perturbation in the brain effect because surgical removal of the compounded by the complexity and and hormonal (i.e., neuroendocrine) adrenal gland (i.e., adrenalectomy), heterogeneity of this relapsing disease stress axes may have significant impli­ which renders the HPA axis nonfunc­ as well as by the host of other variables cations for motivation for alcohol tional, did not affect the stress­induced (e.g., genotype, coexisting disorders, self­administration behavior. reinstatement of alcohol­seeking treatment regimens, and compliance)

Although the circumstances and behavior (Le et al. 2000).4 Finally, that must be considered in the con­ manner in which stress influences direct infusion of CRF antagonists text of treatment interventions (e.g., drinking behavior are complex and into a brain region called the median McLellan et al. 2000). Further, the not fully understood, it generally is raphe nucleus5 blocked stress­induced efficacy of treatment may depend on acknowledged that stressful life events temporal factors, such as the stage of alcohol­seeking behavior, possibly by prominently influence alcohol drink­ addiction (e.g., whether the patient interacting with CRF receptors (Le ing and, in particular, may trigger 1 seeks treatment or not) as well as relapse (Brady and Sonne 1999; et al. 2002; Marinelli et al. 2007a). drinking pattern (e.g., binge­like Sillaber and Henniger 2004; Sinha Taken together, a substantial body intake) (Anton et al. 2004), especially 2001; Weiss 2005). Activation of the of evidence suggests that changes in when both amount and frequency of HPA axis and CRF­related brain CRF function within the brain and

neuroendocrine systems may influ­ 4 stress circuitry resulting from alcohol This effect was observed with or without corticosterone dependence likely contributes to ence motivation to resume alcohol supplementation. self­administration either directly amplified motivation to drink. For 5 The median raphe nucleus is an area in the brain stem example, animal studies have indicat­ and/or by mediating withdrawal­ that contains a large proportion of the brain’s serotonin

neurons and therefore significantly supplies the brain with ed that elevation of corticosteroid related anxiety and stress/dysphoria this important neurotransmitter. Serotonin can influence hormone levels may enhance the responses. CRF activity both within and outside the HPA axis.

Vol. 31, No. 4, 2008 357 alcohol consumption is assessed to prospect that therapeutics may be drawal play a key role not only in determine drinking behavior/phenotype developed which specifically target altering the rewarding effects of alco­ (Feunekes et al. 1999). excessive uncontrolled alcohol drink­ hol, but also in mediating the expres­ Nevertheless, numerous pharma­ ing without producing nonspecific sion of various withdrawal symptoms cotherapies have been employed to effects (i.e., without reducing certain that, in turn, impact motivation to treat alcoholism, guided principally by behaviors in dependent as well as resume drinking. Although currently advancing knowledge about alcohol’s nondependent subjects). Further few treatments are available for tack­ interactions with various components advances in understanding the neuro­ ling this significant health problem of the brain’s reward and stress path­ biological factors that bear on the and providing relief for those suffer­ ways (Heilig and Egli 2006; Litten et complex problem of relapse will no ing from the disease, there is hope. al. 2005; Spanagel and Kiefer 2008). doubt continue to enlighten and As new and exciting discoveries in To date, two medications targeting facilitate discovery of new and more neuroscience, genetics, neuroimaging, these brain systems—naltrexone effective treatment strategies for con­ and biological psychiatry/psychology (Revia®) and acamprosate (Campral®)— trolling excessive drinking associated continue to advance understanding have been approved by the Food and with alcohol dependence. of the complexities of alcohol depen­ Drug Administration (FDA) for dence, new insights will emerge that treatment of alcoholism.6 The efficacy point to novel targets for the next of naltrexone and acamprosate in Summary generation of therapeutics, which treating alcohol dependence and hopefully will be more effective in relapse is based on numerous clinical A complex interplay among numerous preventing relapse and/or tempering studies, although support is not uni­ biological and environmental factors alcohol intake in people attempting to versal (Anton et al. 2006; Heilig and governs the motivational aspects of control their drinking problems. ■ Egli 2006; Mann et al. 2008; Spanagel alcohol­seeking and drinking behavior and Kiefer 2008). Naltrexone oper­ throughout the addiction process. ates as an antagonist of certain recep­ Chronic excessive alcohol consumption Financial Disclosure tors (principally µ and δ receptors) can lead to the development of depen­ for brain­signaling molecules (i.e., dence. When drinking is terminated, a The author declares that he has no neurotransmitters) called endogenous characteristic withdrawal syndrome competing financial interests. opiates that are involved in reward ensues that includes potentially life­ systems, whereas acamprosate is threatening physical symptoms as well thought to modulate signal transmis­ as a constellation of symptoms that References sion involving another neurotrans­ contribute to psychological distress, mitter called glutamate. It has been anxiety, and negative affect. Many American Psychiatric Association. Diagnostic and postulated that naltrexone may blunt withdrawal symptoms associated with Statistical Manual of Mental Disorders, 4th Edition. Arlington, VA: American Psychiatric Association, 1994. the rewarding effects of alcohol, this negative emotional state persist for whereas acamprosate may attenuate a long period of time and constitute a ADINOFF, B.; MARTIN, P.R.; BONE, G.H.; ET AL. adaptive changes during abstinence powerful motivational force promoting Hypothalamic­pituitary­adrenal axis functioning that favor relapse (Heilig and Egli the perpetuation of alcohol use/abuse and cerebrospinal fluid corticotropin releasing hor­ 2006; Litten et al. 2005). mone and corticotropin levels in alcoholics after as well as enhancing vulnerability to recent and long­term abstinence. Archives of As previously indicated, a variety relapse. Both clinical studies and basic General Psychiatry 47:325–330, 1990. PMID: of animal models have been used to research studies using animal models 2157379 study the ability of these and other have demonstrated that alcohol­related ADINOFF, B.; RISHER­FLOWERS, D.; DE JONG, J.; medications to reduce alcohol con­ (conditioned) cues and contexts as well ET AL. Disturbances of hypothalamic­pituitary­ sumption as well as prevent and/or as stressful stimuli and events can trigger adrenal axis functioning during ethanol withdrawal retard relapse. Of particular interest are relapse. Moreover, a history of depen­ in six men. American Journal of Psychiatry studies demonstrating that animals dence appears to amplify responsive­ 148:1023–1025, 1991. PMID: 1853950 with a history of dependence exhibit ness to such relapse­provoking stimuli ANTON, R.F. What is craving? Models and implica­ greater sensitivity to some medica­ and events. tions for treatment. Alcohol Research & Health tions that impact alcohol relapse– Alcohol dependence is thought to 23:165–173, 1999. PMID: 10890811 like behavior compared with animals represent a persistent dysfunctional ANTON, R.F., AND BECKER, H.C. Pharmacotherapy without such a history (Ciccocioppo (i.e., allostatic) state in which the and pathophysiology of alcohol withdrawal. In: et al. 2003; Funk et al. 2007; Gehlert Kranzler, H.R., Ed. The Pharmacology of Alcohol organism is ill­equipped to exert Abuse. Berlin: Springer­Verlag, 1995. pp. 315–367. et al. 2007; Liu and Weiss 2002a, b). appropriate behavioral control over These findings raise the promising alcohol drinking. Functional changes ANTON, R.F.; DROBES, D.J.; VORONIN, K.; ET AL. in brain and neuroendocrine stress Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: Temporal effects of 6 A third FDA­approved medication to treat alcohol and reward systems as a result of drinking. Psychopharmacology (Berlin) 173:32–40, dependence (disulfiram; Antabuse®) targets alcohol metabolism. chronic alcohol exposure and with­ 2004. 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