alcohol research: Current Reviews

overview: and alcohol Use Disorders revisited

robert M. anthenelli, M.D.

Nearly 13 years have passed since Alcohol Research & Health (now titled Alcohol robert M. anthenelli, M.D., Research: Current Reviews) first visited the topic of “Alcohol and Stress.” Since that is associate chief of staff for time, the field has advanced considerably. New terms have been developed to Mental Health, Veterans Affairs, describe the complex physiological interactions that occur when an individual is faced San Diego Healthcare System; with stressful events and more is known about how the brain and body work to offset the changes induced through stress-response mechanisms. An individual’s reactions professor and vice chair for to stress vary according to a number of factors, such as his or her genetic makeup, Veterans Affairs; and director, environment, life events, gender, age, and type and duration of stress. Drinking Pacific Treatment and Research alcohol has the unique ability to both relieve stress and to be the cause of it, creating Center, Department of Psychiatry, in a sense a double-edged sword. Understanding the link between alcohol drinking, School of Medicine, University of stress, and alcohol use disorders (AUDs) is a critical area for ongoing investigation. California, San Diego, California. Discoveries emanating from this field not only add to the burgeoning literature on stress and the risk for disease but also may provide answers to help prevent and intervene in the development of AUDs. Key worDs: alcohol consumption; alcohol use disorders; stress as a cause of alcohol and other drug use; stress; stressors; stress response; stress reactivity; physiological response to stress; brain; genetic factors; environmental factors; allostasis; ; allostatic state;

n the 13 years since Alcohol Research have occurred, spurring renewed inter- In their opening article to the 1999 & Health (now titled Alcohol Research: est in the role of uncontrollable acute Alcohol Health & Research edition on ICurrent Reviews) first visited the topic and chronic stressors on drinking “Alcohol and Stress,” Anisman and of “Alcohol and Stress” (see Vol. 23, behaviors in civilians and military per- Merali (1999) summarized the litera- No. 4, 1999), there has been a sustained sonnel alike. New fields have emerged ture to develop a working definition of flow of new information in the field (e.g., epigenetics), and their findings stress and stressors (i.e., stressful situa- prompting us to publish this updated tions) that we attempt to update in the demonstrate that early-life trauma can edition. Indeed, one could argue that present treatise. We also will embellish this second look at the topic is long leave an indelible stamp on an individ- upon several themes that these authors overdue. An entirely new lexicon of ual’s genetic makeup (i.e., genome) chose to highlight, including the terms1 has been developed to capture and stress circuitry. Gene–environment importance of sex differences and stressor our evolving conceptualization of stress interactions have been discovered that specificity. By introducing these themes, and its effects on health and disease partly quell the artificial argument as we hope to set the stage for the articles risk. Many of these terms (e.g., allostasis to whether nature or nurture most that follow, which delve into several of and allostatic load), which were becom- influences disease risk. Finally, new these topics more deeply. ing popular around the turn of the 21st integrated treatments have emerged century, were hardly mentioned in that (e.g., Najavits’ Seeking Safety), and previous edition, so there is a fair amount mechanisms of action partly defined what Is stress? of catching up to do. Unthinkable (e.g., naltrexone’s effects on stress axis events (e.g., the 9/11 terrorist attack and Webster’s Third New International function), that demonstrate how its aftermath—Operation Enduring Dictionary (1981, p. 2260) defined Freedom and Operation Iraqi Freedom) understanding the links between stress stress as “a physical, chemical, or emo- and alcohol drinking promotes improved tional factor (as trauma, histamine, 1 For terms and their definitions, see the Glossary beginning on treatment options for patients with or fear) to which an individual fails p. 522. alcohol use disorders (AUDs). to make a satisfactory adaptation, and

386 alcohol research: Current Reviews which causes physiologic tensions that release of anterior pituitary hormones; “wear and tear” can predispose the may be a contributing cause of disease.” a second, adaptation phase, wherein an individual to disease, especially in the Although this term now is widely used attempt is made to resist the stressor; context of chronic stress. in the common vernacular, it is inter- and a third, exhaustion phase, which, It is interesting to note that in this esting to note that the scientific con- at its extreme, could lead to death of seminal paper, the authors cite “the ceptualization of this phenomenon the organism (Goldstein and Kopin reciprocal relationship between stress dates back only about 150 years. 2007; Selye 1936). and alcohol consumption” as an example Most stress research historians agree Over time, scientists began challeng- of allostatic load: that the French physiologist, Claude ing two key concepts in this definition In short, whereas drinking may Bernard (1865), was the first to recognize of stress as any real or imagined threat help the person cope with stress in a key element in the stress response— to homeostasis (McEwen and Stellar the short-term, there is a longer-term the phenomenon now known as feed- 1993). First, Selye’s assertion that stress cost. As the person tries to balance the back regulation. Bernard noticed that responses were uniform and generalized reciprocal effects of stress and alcohol the internal environment of cells regardless of stressor type was modified consumption in this manner, the (“milieu intérieur”) is tightly regulated in recognition that certain types of upward spiral of both stress and drinking and largely dependent on feedback it stressors (e.g., physical versus emotional, increases this overall cost (allostatic load) receives from the periphery or “external see below) evoked activation of specific both behaviorally and biologically environment” (Goldstein and Kopin effector systems. For example, exposure (McEwen and Stellar 1993, p. 2096). 2007). Some 65 years later, Sir Walter to extreme cold produces a marked In summary, although the use of the Cannon coined the term “homeosta- activation of the sympathetic nora- term stress has become commonplace, sis” to capture the “coordinated physio- drenergic system in an effort to regulate the scientific conceptualization of this logical processes that maintain most core body temperature, yet it has minimal state is a relatively recent phenomenon of the steady states of the organism” effects on the endocrine or hormonal and is still evolving. Stress has been (Cannon 1929 as cited by Goldstein stress response (Goldstein and Kopin broadly defined “as a threat, real or and McEwen 2002, p. 55). From 2007). Thus, Selye’s doctrine of a uni- implied, to the psychological or physical Cannon’s perspective, which derived tary, nonspecific stress response gave integrity of an individual” (McEwen from his study of the sympathetic ner- way to a more refined view that indi- 2000, p. 108). Other terms, however, vous system (he also coined the phrase viduals activate stress systems more such as allostasis (“maintaining stability, “fight-or-flight responses”), all organ- selectively depending on the character- or homeostasis, through change” isms adjusted to challenges to their istics of the stressor. [Sterling and Eyer 1988 as cited in internal environments by making com- Second, scientists began recognizing McEwen 2000, p. 108]) and allostatic pensatory responses intended to restore that physiological regulatory systems load (“the price the body pays for homeostasis. By accomplishing such, spanned multiple domains, were dynamic being forced to adapt to adverse psy- the organism’s chances for survival and not static, and fluctuated constantly chosocial or physical situations” improved because the homeostatic based on the animal’s biological rhythms [McEwen 2000, p. 110]) are newly or steady state was viewed as optimal and physiological demands. Moreover, emerged and are helping to better and fixed at some preordained, stable the notion that there existed some define the relationships between stress level (Goldstein and Kopin 2007; static, ideal, homeostatic set point gave and disease risk, including the risk for Neylan 1998). way to thinking that, instead, these set AUDs, as described below. The Hungarian scientist, Hans Selye, points vary across a dynamic operating who was influenced by Cannon’s work, range which change over time. Thus, developed the concept of the General Sterling and Eyer ([1988] as cited in Stress and Addiction to Alcohol Adaptation Syndrome in 1936. Selye’s McEwen and Stellar 1993) coined the and Other Drugs theories, which dominated thinking term allostasis to describe this operat- on the nature of the stress response for ing range and the organism’s ability to Koob and Le Moal (1997, 2001) began more than 50 years, hypothesized that increase or decrease body functions to formally linking the brain’s stress and a classical syndrome developed in all a new steady state when challenged. reward systems in an allostatic model organisms “the symptoms of which are McEwen and Stellar (1993) embel- of alcohol and other drug addiction independent of the damaging agent or lished on the principle of allostasis that still holds sway over the field the pharmacological type of the drug by defining a new concept that these today. As described in detail elsewhere employed” (Selye 1936, p. 32). He authors labeled allostatic load. This (Koob and Le Moal 1997, 2001) and further hypothesized that this stress term connotes the toll placed on indi- alluded to in Koob and colleagues’ response had three stages: an initial viduals when they have to constantly contribution in this edition (see pp. alarm reaction (akin to Cannon’s fight- or repeatedly adjust the operating range 516–521), these scientists hypothe- or-flight response) that involved the to maintain fluctuating set points. This sized that alcohol and other drug

Overview: Stress and Alcohol Use Disorders Revisited 387 addiction represents an allostatic state induced stress hormone elevations. This among the first to demonstrate that whereby an individual’s hedonic set neuroadaptation underlies the allostatic organisms have evolved different stress point has drifted downward and been change associated with chronic heavy circuits to adapt to life’s variety of stres- recalibrated at a new point below the drinking and manifests as a blunted sors (Goldstein and Kopin 2007; Pacak normal, homeostatic range. The fluc- stress response in recently abstinent et al. 1998). This stressor-specific strat- tuating hysteresis of this proposed alcoholics (see Stephens and Wand, pp. egy certainly makes sense from an evo- downward sloping “mood” curve reflects 468–483). lutionary standpoint: it would be the operating range of the brain’s reward In summary, although low doses of extremely inefficient to mobilize the and stress systems, which engage in a alcohol in non–alcohol-dependent same effector systems to keep an animal’s struggle to adjust and readjust in the individuals produce rewarding effects core temperature up when exposed to setting of repetitive alcohol (or other that are perceived to attenuate stress, in cold weather as it would to respond to drug) use. Thus, in this allostatic model, actuality, the drug stimulates the release hemorrhagic hypotension. However, alcohol drinking can be viewed as both of CRF and stress hormones. Chronic, there also is an advantage to having a reward and a stressor—an interpretation heavy use of ethanol produces an allo- some redundancy across these effector which is consistent with observations static state wherein reinforcing and systems. For example, the hypothalamic– that acute doses of alcohol simultaneously stress-provoking effects of the drug battle pituitary–adrenal (HPA) axis, which increase brain concentrations of mesolim- and oppose each other but generally mediates the endocrine or hormonal bic dopamine and other reinforcing contribute to an altered set point below response to certain stressors, intercon- as well as brain levels that associated with normal mood states. nects with the adrenomedullary hor- of corticotropin-releasing factor (CRF) When repeated over many months to monal system and the sympathetic and blood levels of adrenocorticotropin years, this struggle exerts its toll (i.e., noradrenergic system (SNS). This does hormone (ACTH) and , the produces allostatic load) on the brain not mean, however, that specific stressors major stress hormones in the brain and and body, as there is a cost associated activate all three effector systems to the body (Rivier and Lee 1996). with the chronic efforts to adapt to same extent. Thus, when researchers At first glance, this notion of alcohol these stressors. Thus, drinking to relieve measure the outputs of these effector and other drugs of abuse working as stress proves to be a double-edged sword. systems (i.e., ACTH and cortisol in stressors (i.e., taxing to the individual) the bloodstream of humans to monitor flies in the face of the more commonly HPA axis reactivity versus heart rate held belief that ethanol has stress- Factors Influencing stress and blood pressure which reflect SNS response–dampening effects. However, reactivity activity) in response to various stress several characteristics of the drug may paradigms they may not necessarily explain this paradox. First, alcohol’s Casual readers of the alcohol and stress find unanimity of responses. rewarding properties may counterbalance literature can become frustrated by the Scientists have conceptualized different or mask its stress-provoking effects. apparent lack of uniformity of findings. categories of stressors to better capture This happens on a number of different For example, when analyzing studies this phenomenon. Thus, distinctions levels: (1) the drug produces brain attempting to determine whether stress such as “psychogenic versus neurogenic,” depressant effects by acutely enhancing leads to relapse to alcoholism (see the “processive versus systemic” (see the GABAergic tone, while inhibiting exci- article by Thomas and colleagues in this article by Herman, pp. 441–447), and tatory glutamatergic signaling; (2) ethanol edition, pp. 459–467), readers will “physical versus psychological versus acutely enhances the release of reinforc- observe that sometimes blunted hor- pharmacologic” stress have been used ing neurotransmitters (e.g., dopamine monal responses are associated with to describe the various stress induction and endogenous opiates) and neuro- increased relapse risk; whereas, in other paradigms used in experimental ani- modulators (e.g., endocannabinoids); instances, exaggerated hormonal responses mals and humans (for a partial list, see and (3) alcohol’s effects on the release predict the return to drinking. However, table 1). The stress-response patterns of the stress hormone, cortisol, in the when one considers that stress respon- generated by these different types of periphery triggers further rewarding sivity is governed by a host of factors stressors are not uniform, however, properties in the brain (see the article by related to (1) the characteristics of the which is a point frequently lost among Stephens and Wand, pp. 468–483). stressor and (2) the characteristics of casual observers. Second, consistent with the second the individual, some of this hetero- phase in Selye’s general adaptation syn- geneity in findings can be explained. drome, and the opponent-process other stressor characteristics model (Solomon and Corbit 1973) Stressor–Specificity evoked in Koob and Le Moal’s allo- In addition to the types of stressors static model of addiction, the brain Painstakingly detailed neuroanatomical influencing stress reactivity, there are resists or adapts to repeated, alcohol- studies in experimental animals were other features associated with the

388 alcohol research: Current Reviews stressful experience that affect an indi- tude of the stress response, as does its 484–491), early-life experiences (see vidual’s responsiveness (see table 1). duration (i.e., chronicity) (Anisman Brady and Back, pp. 408–413), envi- For example, the degree of controllabil- and Matheson 2005). ronmental exposures to stress (see ity of the stressor influences response, Keyes and colleagues, pp. 391–400), with uncontrollable stress creating a Individual-Level Variables and predilection to anxiety and other greater level of response compared with Affecting Stress Responsivity psychiatric disorders (see Smith and events considered to be under an indi- Randall, pp. 414–431 and Schumm vidual’s control (Anisman and Matheson Just as the type, predictability, and and Chard, pp. 401–407) can conspire 2005). It is interesting to note that controllability of the stressor influence to influence how adolescents and adults even this seemingly behavioral, subjective its response, an individual’s characteristics respond to stress and alcohol. phenomenon seems to be governed by also affect stress reactivity. Of particular Heavy drinking and repeated with- stressor-specific neural circuits. For relevance to human-stress researchers drawal from alcohol may result in instance, experiments in rodents have is the individual’s gender, and a better neuroendocrine changes that not only demonstrated that the brain’s serotonin understanding of this could help alter the body’s ability to respond to system seems to be of primary impor- explain why women seem to develop stressful challenges but also may tance in modulating uncontrollable AUDs following a stress-related condi- undermine efforts to stop or reduce versus controllable stress (Hammack tion, whereas the opposite temporal harmful drinking behavior (see articles 2002). Whether a stressor is predictable pattern applies for men (Kessler et al. by Alim and colleagues, pp. 506–515 or unpredictable influences the magni- 1997). Accumulating evidence indicates and Becker, pp. 448–458). that women and men have evolved Moreover, environmental insults can different stress-response activation affect a person’s genetic architecture, Table 1 Factors Influencing the Stress patterns during the reproductive years and these epigenetic phenomena appear Response (Kajantie and Phillips 2006) and that to influence the individual’s response women respond more robustly to cer- to stressful life experiences and alcohol stressor type Processive (neurogenic or psychogenic) tain stressors than men and vice versa. intake (see the article by Pandey and Systemic (immune insults) For example, using one of the most Moonat, pp. 459–467). When one popular psychological stress induction considers that other personal character- stressor characteristics paradigms, the Trier Social Stress Test,2 istics such as an individual’s coping Controllability several investigators have found that skills and social environment can modify Predictability how he or she reacts to stress, it should Ambiguity/uncertainty men react more robustly to this type of Chronicity stressor than do women (Uhart et al. come as no surprise that laboratory Intermittence 2006). Additional evidence for this paradigms in humans sometimes produce gender X stressor subtype interaction discrepant results (e.g., see Thomas organismic variables effect was found by Stroud et al. and colleagues, pp. 459–467) in the Genetics literature. Age (2002), who reported that women Sex mounted a greater stress response to a social evaluative stressor task (e.g., the experiential variables participant feeling shunned by two conclusions Previous stressor experiences confederate research associates feigning (sensitization) a spontaneous social interaction) than This brief overview sets the stage for Early life events (maternal factors, trauma) the articles and sidebars that follow. did men. Similarly, research has found In this issue, an esteemed group of resource characteristics gender- and stressor-specific effects to alcohol and stress researchers tackle various pharmacological stress tests; Personal characteristics compelling questions such as “How Coping skills women react more robustly to agents Does Stress Lead to Risk of Alcohol Self-esteem directly stimulating the pituitary gland Relapse?” (see the article by Sinha, pp. Self-efficacy or artificially lowering morning cortisol Personality (hardiness, optimism, 432–440). Although the answers to levels than do men, whereas men exhibit important questions such as this are neuroticism) comparatively blunted responses to And others not fully known, what should shine these manipulations (Anthenelli et al. through is how far the field has come social characteristics 2009). Therefore, gender is an important since Alcohol Research & Health last Social support (perceptions) variable to consider when evaluating tackled this topic. Understanding the Attachment (bonding) how individuals react to certain stressors. As described in other articles in this SOURCE: Adapted from Anisman and Matheson 2005. 2 Using the Trier Social Stress Test, the subject is asked to give a edition, an individual’s genetic makeup speech and perform a simple math task in front of an audience. (see Schumann and colleagues, pp. This test measures both social and cognitive stressors.

overview: stress and alcohol Use Disorders revisited 389 relationships among alcohol drinking, references KOOB, G.F., AND lE MOAl, M. Drug abuse: Hedonic homeo- static dysregulation. Science 278(5335):52–58, 1997. stress, and alcohol use disorders is a PMID: 9311926 critical area for ongoing investigation. ANISMAN, H., AND MATHESON, K. Stress, depression, and anhedonia: Caveats concerning animal models. MCEwEN, B.S. Allostasis and allostatic load: Implications Discoveries emanating from this field Neuroscience and Biobehavioral Reviews 29(4–5): for neuropsycopharmacology. Neuropsychopharm - not only add to the burgeoning litera- 525–546, 2005. PMID: 15925696 acology 22(2):108–124, 2000. PMID: 10649824 ture on stress and disease risk but ANISMAN, H., AND MERAlI, Z. Understanding stress: McEwen, B.S., and Stellar, E. Stress and the individual. also hold the promise to provide Characteristics and caveats. Alcohol Research & Health Mechanisms leading to disease. Archives of Internal answers on how to prevent and inter- 23(4):241–249, 1999. PMID: 10890820 Medicine 153(18):2093–2101, 1993. PMID: 8379800 ANTHENEllI, R.M.; BlOM, T.J.; HEFFNER, J.l.; ET Al. Sex differ- vene in this disorder. Here we offer a NEylAND, T.C. Hans Selye and the field of stress research. ences in the stress hormone response to the combined Journal of Neurospychiatry 10(2):230–231, 1998. foundation for the next decade of dexamethasone/CRH stimulation test in long-term absti- discovery! ■ nent alcoholics and controls. Poster presented at the PACAK, K.; PAlSOvITS, M.; yADID, G.; ET Al. Hetrogenous neu- 32nd Annual RSA Scientific Meeting, San Diego, rochemical responses to different stressors: A test of California, June, 2009. Selye’s doctrine of nonspecificity. American Journal of Physiology 275(4 Pt. 2):R1247–R1255, 1998. PMID: acknowledgements GOlDSTEIN, D.S., AND MCEwEN, B. Allostasis, homeostats, 9756557 and the nature of stress. Stress 5(1):55–58, 2002. Development of this manuscript was PMID: 12171767 RIvIER, C., AND lEE, S. Acute alcohol administration stimu- lates the activity of hypothalamic neurons that express supported, in part, by National Institute GOlDSTEIN, D.S., AND KOPIN, I.J. Evolution of concepts of corticotropin-releasing factor and vasopressin. Brain on Alcohol Abuse and Alcoholism stress. Stress 10(2):109–120, 2007. PMID: 17514579 Research 726(1–2):1–10, 1996. PMID: 8836539 HAMMACK, S.E.; RICHEy, K.J.; SCHMID, M.J.; ET Al. The role of (NIAAA) grant no. AA–019720, SElyE, H. A syndrome produced by diverse nocuous VA Merit Review grant no. NEUA– corticotropin-releasing hormone in the dorsal raphe agents. Nature 138(3479):32, 1936. nucleus in mediating the behavioral consequences of 003–08S, and by the Department of uncontrollable stress. Journal of Neuroscience SOlOMON, R.l., AND CORBIT, J.D. An opponent-process theory Veterans Affairs Research Service. 22(3):1020–1026, 2002. PMID: 11826130 of motivation. II. Cigarette addiction. Journal of Abnormal Psychology 81(2):158–171, 1973. PMID: 4697797 The author thanks Reene Cantwell KAJANTIE, E., AND PHIllIPS, D.I. The effects of sex and hor- and Marta La Belle for their technical monal status on the physiological response to acute STROUD, l.R.; SAlOvEy, P.; AND EPEl, E.S. Sex differences in support preparing this manuscript. psychosocial stress. Psychoneuroendocrinology stress responses: Social rejection versus achievement 31(2):151–178, 2006. stress. Biological Psychiatry 52(4):318–327, 2002. PMID: 12208639 KESSlER, R.C.; CRUM, R.M..; wARNER, l.A.; ET Al. lifetime co- Financial Disclosure occurrence of DSM-III-R alcohol abuse and dependence UHART, M.; CHONG, R.y.; OSwAlD, l.; ET Al. Gender differ- with other psychiatric disorders in the National ences in hypothalamic-pituitary-adrenal (HPA) axis reac- Comorbidity Survey. Archives of General Psychiatry tivity. Psychoneuroendocrinology 31(5):642–652, 2006. The author provides consulting and/or 54(4):313–321, 1997. PMID: 9107147 PMID: 16616815 advisory services to Pfizer. The Pacific KOOB, G.F., AND lE MOAl, M. Drug addiction, dysregulation webster’s Third New International Dictionary of the Treatment and Research Center of reward, and allostasis. Neuropsychopharmacology English language, Unabridged, Springfield, MA: receives grant support from Pfizer. 24(2):97–129, 2001. PMID: 11120394 Merriam-webster, 1981.

390 alcohol research: Current Reviews