Understanding Stress: Characteristics and Caveats

Hymie Anisman, Ph.D. and Zul Merali, Ph.D.

Exposure to stressful situations is among the most common human experiences. These types of situations can range from unexpected calamities to routine daily annoyances. In response to stressors, a series of behavioral, neurochemical, and immunological changes occur that ought to serve in an adaptive capacity. However, if those systems become overly taxed, the organism may become vulnerable to pathology. Likewise, the biological changes, if sufficiently sustained, may themselves adversely affect the organism’s well-being. Several factors may dictate an individual’s response to environmental stressors, including characteristics of the stressor (i.e., type of stressor and its controllability, predictability, and chronicity); biological factors (i.e., age, gender, and genetics); and the subject’s previous stressor history and early life experiences. Research on the physiological and psychological responses to different types of stressful stimuli is presented, focusing particularly on processes that may be relevant to the development of alcohol use disorders. Stressful events may profoundly influence the use of alcohol or other drugs (AODs). For example, the resumption of AOD use after a lengthy period of abstinence may reflect a person’s attempt to self-medicate to attenuate the adverse psychological consequences of stressors (e.g., anxiety). Alternatively, stress may increase the reinforcing effects of AODs. KEY WORDS: psychological stress; physiological stress; sensory stimuli; conditioned response; unconditioned response; coping skills; neurotransmitters; brain; neurochemistry; biological adaptation; animal model; genetics and heredity; gender differences; age differences; life event; AODD (AOD use disorders); literature review

xposure to stressful situations is the adverse psychological consequences as being aversive in that it elicits a stress among the most common human of stressors (e.g., anxiety). Alternatively, response which taxes a person’s physio- Eexperiences. These types of stress may increase the reinforcing effects logical or psychological resources as situations can range from unexpected of AODs. well as possibly provokes a subjective calamities (e.g., bereavement, natural This article provides a working defi- disaster, or illness) to routine daily nition of stress and describes research annoyances. Regardless of their degree on the physiological and psychological HYMIE ANISMAN, PH.D., is a professor of severity, however, stressors may pro- responses to different types of stressful at the Institute of Neuroscience, Carleton mote physiological and behavioral dis- stimuli, focusing particularly on processes University, Ottawa, Canada. turbances, ranging from psychiatric that may be relevant to the development disorders (Brown 1993) to immune of alcohol use disorders. ZUL MERALI, PH.D., is a professor at system dysfunction (Herbert and Cohen the School of Psychology and Department 1993). Stressful events also may pro- of Cellular and Molecular Medicine, foundly influence the use of alcohol or Stress: A Working University of Ottawa, Canada. other drugs (AODs). For example, the Definition resumption of AOD use after a lengthy This research was supported by the Natural period of abstinence may reflect a person’s As commonly used, the term “stressor” Sciences and Engineering Council of attempt to self-medicate to attenuate indicates a situation or event appraised Canada.

Vol. 23, No. 4, 1999 241 state of physical or mental tension. As sequences, the elevated cortisol levels response to the potential onslaught of relevant scientific data have accumulated, persist for an extended period, then the nutrients, which require digestion and however, a simple, universally accepted adaptive nature of the response may be absorption. In addition, food may nat- definition of stress has become increas- lost and adverse effects may ensue. Thus, urally contain or be contaminated by ingly elusive. what we consider to be an adaptive any number of toxic compounds that This article focuses on some of the short-term response may subsequently must be eliminated or destroyed (e.g., factors that may influence the mecha- provoke long-term pathophysiological by immune system activity or enzy- nisms by which a person responds to consequences (Sapolsky et al., 1986). matic degradation in the liver). Further- stressful situations (i.e., stressors). Much Because stressful stimuli often elicit more, in the wild, an animal approach- of the information presented here is based cortisol secretion, some researchers have ing a food source may experience some on animal research, which can provide proposed the use of cortisol levels as an risk from either predators or competitors. essential information not obtainable index of the stress response. However, The evaluation of these hypotheses is from human studies. However, the not all events perceived as stressful lead complicated by individual differences human stress response is influenced by in the perception and appraisal of a a host of personality characteristics and stimulus as stressful. life experiences that cannot be dupli- cated in animal studies. Other articles in this issue provide more specific The human stress Characteristics information on possible interactions of the Stressor between stress and human behavioral response is influenced responses, such as alcohol consumption. by a host of personality Several factors serve a fundamental role Many researchers view the stress in determining the nature and conse- response as an adaptive mechanism characteristics and quences of the stress response (see side- designed to maintain the relative stability bar). These factors include inherent of the body’s overall physiological func- life experiences that features of a given type of stressor as well tioning (i.e., homeostasis) in response cannot be duplicated as the conditions under which the stressor to a challenge. However, not all stress is encountered (i.e., the stressor regimen). responses are clearly adaptive. Some in animal studies. physiological reactions to stress that Evaluating the Stress Response appear to confer short-term benefits are followed by adverse long-term repercus- In general, stressors may be psychogenic sions. In other instances, changes that to the release of hormones specifically and/or neurogenic. Psychogenic stres- appear to have adverse consequences associated with stress. Indeed, several sors are purely of psychological origin may, on closer examination, turn out other hormones and similar chemical (e.g., anticipating an adverse event, to be beneficial. Finally, some changes messengers are extremely responsive to experiencing the death of a loved one, that may have little positive value and stressful stimuli and may influence the or caring for a chronically ill person). no adaptive significance may yet com- cascade of events activated by stress. Neurogenic stressors involve a physical prise part of the overall stress response. Furthermore, positive stimuli may elicit stimulus (e.g., a headache, bodily injury, The ambiguity of the stress response physiological responses comparable in or recovery from surgery). can be illustrated by examining the func- many respects to those provoked by In addition, environmental stressors tions of cortisol, a hormone released by adverse events, and increased cortisol can be classified as either processive or the adrenal glands in response to stressful release is not uniquely provoked by events systemic. Processive stressors are those stimuli (see sidebar, page 247). Among perceived as stressful. For example, rats that require appraisal of a situation or other functions, cortisol helps promote that were offered food in the laboratory involve high-level cognitive processing the release of energy stores essential for exhibited activation of the hypothalamic- of incoming sensory information. Exam- coping with stress. Yet, cortisol may pituitary-adrenal axis (HPA) (see sidebar) ples of processive stressors among animals suppress the normal functioning of the identical to that elicited by stressful include exposure to new environments, immune system, a response that could stimuli, such as physical restraint predators, or situations that trigger fear theoretically render the body more sus- (Merali et al. 1998). HPA activation because of previous association with ceptible to infectious diseases. However, could arguably represent an anticipa- unpleasant stimuli (i.e., fear cues). In cortisol-induced immune suppression tory response to any strong stimulus, contrast, systemic stressors are of physi- also may serve a protective function preparing the animal to respond appro- ological origin (e.g., disturbances of nor- (Munck et al. 1984), preventing the priately. Alternatively, the presentation mal bodily metabolism resulting from development of illnesses characterized of food, at least in animals, may actu- bacterial or viral infection). by immune attack on the body’s own ally threaten to disrupt homeostasis. Herman and Cullinan (1997) have tissues (e.g., rheumatoid arthritis). Even In that case, the stress response may suggested that both processive and sys- when cortisol release has adaptive con- help mobilize the body’s physiological temic stressors might activate the HPA

242 Alcohol Research & Health Understanding Stress: Characteristics and Caveats

axis through distinct but converging stressor and the stressor regimen. This may increase (e.g., financial burden neurological circuits. Specifically, pro- fact is illustrated by the phenomenon and loss of social support). In addition, cessive stressors may primarily activate of adaptation (i.e., a diminished response the stress response itself may function the limbic system, a region of the brain after prolonged or repeated exposure to as a stressor. For example, symptoms of comprising interconnected structures a stressor). For example, within a single depression induced by stress may lead that are associated with arousal, emotion, experimental session, the brain’s chemi- to interpersonal conflict or, conversely, and goal-directed behavior. Conversely, cal response exhibits adaptation to some social withdrawal, further exacerbating systemic stressors may more directly stressors (e.g., restraint) but is less likely depression (Hammen 1991). influence the hypothalamus, a brain to occur in response to others (e.g., With respect to behavioral outcomes, structure with multiple regulatory func- footshock or tailshock). Although the some stressors (e.g., loss of social sup- tions that interacts extensively with the reason for this finding is unknown, one port) are more likely than others to limbic system. In the absence of experi- possibility is that restraint is continu- provoke depressive symptoms (Monroe mental evidence, it seems reasonable to ous, whereas footshock is intermittent. and Simons 1991), whereas other stres- speculate that processive stressors might Thus, drawing firm conclusions about sors (e.g., threats or impending stress) be more closely associated with increased the adverse effects of a stressor based on are more closely associated with anxiety alcohol consumption than would sys- a specific stressor regimen can some- symptoms (Finlay-Jones and Brown temic stressors. times be difficult. The variability of the 1981). Surprisingly, stress-induced psy- When evaluating the impact of adverse stress response may provide important chiatric pathology is often elicited not events on an individual, a researcher or clues to the identification of the psy- by a major adverse life event but by a health professional must consider the chological and physical processes that series of relatively mild stressors (i.e., specific nature of the stressor involved. govern voluntary alcohol consumption. day-to-day hassles). Furthermore, the Although most stressors elicit some Stressor effects in humans are more effects of the minor stressors may be common neurochemical and behavioral complex than in animals. Some investi- especially profound if they occur fol- effects, their responses are not always gations of the human stress response lowing a major stressful event (Lazarus identical. have been conducted under contrived 1990; Ravindran et al. 1997). In animal studies, researchers have conditions in the laboratory, and the The severity of stress-induced effects employed a wide range of stressors to meaningfulness of such studies may be may be related to characteristics of the assess behavioral and biological outcomes. limited. Studies that attempt to simu- individual coupled with the nature of Some of these stressors are ethologically late natural conditions are more likely the stressor. Relevant stressor character- sound (i.e., they represent situations to produce realistic outcomes. Some istics include the following: (1) the that the animal would ordinarily en- of the latter studies rely on a person’s degree to which stress can be mitigated counter in its natural environment and recollection of past events (i.e., retro- or eliminated by an appropriate response for which it may have developed natu- spective studies). The disadvantage of (i.e., controllability), (2) the predictability ral, evolutionary defenses). Ethological retrospective studies, however, includes of onset of the stressor, (3) the duration stressors may include the sight or odor the potential distortion of recall result- or chronicity of exposure (i.e., either of predators, confrontation with unfa- ing from subsequent experience or acute or over a relatively protracted miliar members of the same species, or the subject’s current mental state. Pro- period), and (4) the timing and fre- fear cues. spective studies, which are less com- quency of exposure (e.g., intermittent). Other commonly employed experi- monly employed, involve an initial mental stressors include exposure to baseline examination of the subject Controllability and Coping cold air, immersion in cold water, and with subsequent followup evaluations mild electric shocks administered to the (Sklar and Anisman 1981). Perceived controllability clearly influ- animal’s foot or tail. In various studies, Irrespective of the experimental ences some (but not all) stress responses. investigators have administered footshock approach, research clearly indicates that For example, uncontrollable stressors and tailshock at varying intensities, thereby stressors, which are usually multidi- provoke behavioral disturbances in ani- obtaining information on the effects of mensional, produce not only immedi- mals that are not induced by control- controllable (i.e., escapable) versus uncon- ate actions but also protracted effects lable stressors of comparable severity. trollable (i.e., inescapable) stressors. How- secondary to the primary stressor. For Some investigators interpret these dif- ever, the generalizability of experimental instance, stressful experiences are often ferences as the consequences of “learned results involving some stressors is limited. followed by persistent brooding (i.e., helplessness” (Seligman 1975). Other For example, the effects of exposure rumination) that may in itself be stress- researchers interpret these findings in to cold air or cold water may reflect ful, and some events (e.g., bereavement) terms of the strain that such events place physiological processes specific to the may have secondary effects (e.g., finan- on the neurotransmitter systems in the generation of body heat rather than the cial burden and loss of social support). brain (see textbox, p. 244) (Anisman et psychological consequences of stress. Whereas some stressor effects may al. 1991; Weiss and Simson 1985). The nature of the stress response diminish over time (e.g., sadness, remorse, The excessive strain on, or the varies depending on the nature of the or guilt), the effects of other stressors resulting variations of, neurotransmit-

Vol. 23, No. 4, 1999 243 ters may increase an individual’s vulner- lenge may have greater adaptive value illusory. Rather than assessing stressor ability to pathological states. Indeed, than the ability to assess controllability. controllability, researchers may find it studies in rodents have indicated that in Moreover, determining whether a given more profitable to consider the specific some brain regions (e.g., the hypothala- stressor is controllable may require sus- coping mechanisms that are available mus), the response of the neurotrans- tained or repeated exposure, a luxury to the individual (Lazarus 1993). mitter norepinephrine (NE) to uncon- that may not be affordable. Thus, sys- Broadly speaking, coping can be subdi- trollable stressors is more profound than tems designed for immediate response vided into several subtypes, including that provoked by controllable stressors. (e.g., activation of the HPA axis or the emotion-focused coping (e.g., emo- Likewise, the controllability of stressors immune system) ought to react compar- tional expression, emotional contain- may differentially influence the functions ably to both controllable and uncon- ment, blame, avoidance, denial, and of the neurotransmitters serotonin trollable stressors. Conversely, systems passivity); problem-focused coping; (5-HT) and dopamine (DA) in specific that are uniquely involved in the appraisal social support; cognitive restructuring; brain regions. In addition, some behav- of processive stressors might react dif- and problem-solving. ioral disturbances evoked by uncontrol- ferently to controllable than to uncon- Researchers often assume that lable stressors can be mimicked by drugs trollable stressors. emotion-focused coping is a relatively that disrupt the functioning of these Studies in humans support the view ineffective strategy, whereas social neurotransmitters. Conversely, treat- that stressor controllability may be fun- buffering, problem-solving, and cogni- ments that attenuate the neurochemical damental in determining the stress tive restructuring may be more effica- alterations elicited by stressors limit response, despite the fact that in a great cious. To some extent, this conclusion such behavioral disturbances (Anisman number of instances, control is actually is based on findings that depressed et al. 1991). In effect, an individual’s patients, relative to control subjects, response to a stressor may be dictated by tend to favor emotion-focused coping the availability of appropriate coping NERVE CELL and revert to a more problem-focused strategies, and certain behavioral distur- strategy with successful treatment bances may be most pronounced under COMMUNICATION AND (Ravindran et al. 1997). Although conditions where stressor controllability THE STRESS RESPONSE emotion-focused coping can be ineffec- is not possible or where coping responses tive and even counterproductive, the Nerve cells communicate with are ineffective. effectiveness of a strategy may depend one another through chemical Although researchers may be tempted on the specific stressor regimen. A messengers called neurotransmit- to conclude that the ability to neutral- given strategy may be ineffective under ters. The neurotransmitters dis- ize a stressor is the fundamental feature one set of conditions but be highly cussed in this article interact in predicting neurochemical and behav- effective under another. Ultimately, the extensively to perform a variety ioral change, this conclusion may be abilities to maintain flexibility and be of regulatory activities. Serotonin premature. For instance, when stressed prepared to use different strategies may affects a wide range of physiolog- animals are permitted to fight with a be the hallmark of effective coping. ical functions, including appetite, member of their species, the effects ordi- sleep, and body temperature. narily elicited by uncontrollable stressors Serotonin also influences emo- Chronicity and Predictability may be mitigated, a phenomenon tional states, and its dysfunction known as displacement (Anisman et al. Intuitively, one would suspect that the has been implicated in both psy- 1991). Nevertheless, displacement behavioral and neurochemical impact chiatric and addictive disorders. aggression may not eliminate the stres- of an acute stressor would be exacerbated Dopamine helps regulate goal- sor and may in fact create additional by repeated exposure to the stressor. directed behaviors (including the stress. An important aspect of displace- However, some stressor-induced behav- reinforcing effects of alcohol and ment behaviors, such as aggression, is ioral, neurochemical, and immunologi- other drugs) as well as certain that by offsetting the impact of stressors, cal disturbances in rats and mice may motor functions. Within the the displacement behaviors may become be mitigated by prolonged stressor brain, norepinephrine plays a role reinforced. AOD use may serve, in exposure. For example, the decline of in arousal and in the modulation part, as such a displacement behavior. brain NE concentrations associated of other neurotransmitter sys- Whether or not the displacement behav- with acute stressor exposure may reverse tems. When released into the iors related to stressful events actually following protracted or repeated expo- bloodstream by the adrenal support both the initiation and mainte- sure (Weiss and Simson 1985). Such glands, norepinephrine functions nance of AOD abuse remains to be adaptation appears to represent an active as a stress-related hormone, determined. process, because NE levels in chroni- preparing the body for “fight or Not all neurochemical or physiolog- cally stressed animals do not simply flight” in response to threatening ical processes are differentially influenced return to prestress levels but, instead, situations. by stressor controllability. The ability exceed basal values. Chronic stressors to respond rapidly to a stressful chal- appear to promote a compensatory

244 Alcohol Research & Health Understanding Stress: Characteristics and Caveats

increase in the production of NE (or, in pathological outcomes (Schulkin et may determine why a stressor increases in the case of DA, moderation of exces- al. 1998). Evaluating the contribution the vulnerability to a particular pathol- sive utilization), leading to increased of stressors to behavioral disturbances ogy in one individual but a different neurotransmitter concentrations. (e.g., alcoholism) in humans requires pathology in another individual. In Factors that prevent or limit neuro- large-scale prospective studies assessing addition, if the organism is endowed chemical adaptation may be associated the impact of acute and chronic insults, with increased vulnerability to stressor with behavioral or physiological disorders. the contribution of coping factors, and effects on neurochemical processes as For example, some of the behavioral allostatic load associated with certain well as increased genetic vulnerability and neurochemical changes associated stressor regimens. to a particular pathology, then the stressor with chronic predictable stressors are less would be expected to increase the risk apt to appear following chronic unpre- for this particular pathology. In the case dictable stressors (Anisman et al. 1991). Effects of Genetics, of alcoholism, genetic factors favoring Interestingly, a regimen of chronic mild Gender, Age, and Previous increased alcohol intake, coupled with stressors may result in an inability to Stressor Exposure an inherited disposition toward exces- experience pleasure (i.e., anhedonia) sive stressor reactivity or inappropriate similar to that elicited by relatively intense coping styles, could potentially con- stressors. Thus, even stressors that have Genetic Differences tribute to alcohol abuse. modest effects when applied acutely may have pronounced behavioral repercus- Both the psychological and physiological Gender sions when experienced on a chronic, responses to a given stressor may vary unpredictable basis (Willner 1997). greatly between individuals, thereby influ- Data concerning gender-dependent In humans, stressors are typically of encing the type of pathology to which a effects of stressors are relatively limited, a varied nature, are encountered on an person is vulnerable. Such vulnerability although researchers have found that intermittent and unpredictable basis, may be influenced by genetic factors. the HPA response to stressors is greater and may be experienced over protracted In mice and rats, behavioral, hor- in female rats than in male rats. This periods. As indicated earlier, many stres- monal, immunological, and neurochem- effect appears to occur at almost every sors have secondary effects (e.g., rumi- ical effects of a given environmental level of HPA functioning, and the nation, financial loss, or loss of social stressor may differ significantly between responses, to some extent, are regulated support), which are themselves stressful different genetic strains. For example, by interaction among the hypothala- or limit coping abilities. A chronic, some rodent strains exposed to a stressor mus, pituitary gland, and gonadal intermittent stressor regimen is less may display marked HPA alterations organs (Ferrini et al. 1997; Viau and likely to lead to neurochemical adapta- or variations of brain neurotransmitter Meaney 1991). Such factors may con- tion and, hence, favor the development levels, whereas other strains may display tribute to the gender differences often of pathology. When the chronic stres- fewer or less profound effects. Similarly, seen with respect to some behavioral sor regimen is not only unpredictable, the same stressful event may induce disturbances (e.g., mood disorders), but but is also uncontrollable and associated opposite effects on certain aspects of the contribution of these factors to with secondary stressors, the occurrence immune functioning in different rodent AOD consumption is not yet clear. of behavioral disturbances might, per- strains. Rather than regarding such haps, increase (Anisman et al. 1991). interindividual or interstrain variations Age Two important caveats must be as a “noise factor,” the experimenter stressed with respect to the impact of can use them to help identify both the In humans, the age-dependent effects chronic stressors. First, the compensatory factors that predict the response to a stres- of stressors intertwine with numerous neurotransmitter changes associated sor and the occurrence of a pathological psychosocial factors (e.g., reduced with repeated stressor exposure vary state related to the stressor (Anisman et physical abilities; financial constraints; widely and occur in several brain regions. al. 1991, 1998). and loss of coping resources, social sup- Not all of these variations necessarily Individual or genetic differences in port, and psychological flexibility). progress at comparable rates or in all the stress response may indicate either Animal studies further suggest that cer- species of laboratory animals. Thus, the an overall increase of reactivity or a highly tain neurochemical systems that are nature of the pathology associated with specific increase in the reactivity of a sensitive to stressors react differently in a chronic stressor regimen may depend particular biological system. Similarly, aged compared with young individuals. on the specific neurochemical disturb- alterations of transmitter function in In aged rats, stressor-provoked neuro- ances incurred. Second, the process of one brain region, or alterations of one chemical alterations are induced more coping with chronic stressor exposure aspect of immune functioning, do not readily than in young rats, and the creates prolonged and intense demands suggest similar alterations in other brain return to basal levels of neuronal func- on neurochemical systems, a condition regions or in other aspects of immu- tioning requires a relatively sustained termed “allostatic load.” Sustained and nity. Interindividual differences in the period of time. Theoretically, stressors excessive allostatic load may culminate fragility of different biological systems should generate rapid neurochemical

Vol. 23, No. 4, 1999 245 responses that readily normalize upon Stewart 1991). Interestingly, these effects adaptation with respect to stressor stressor termination. Thus, the sustained have not only been observed when the appraisal or some aspects of neuronal neuronal activation of aged animals may reexposure session involves the same functioning (e.g., the stressor is appraised reflect a lack of adaptability of func- stressor, but also when it involves an as being less aversive, or variations occur tioning. Aged animals might therefore entirely different stressor (Nisenbaum with respect to either the receptor sen- be more vulnerable to stressor-provoked et al. 1991). Furthermore, such cross- sitivity and/or number present at presy- pathology (Anisman et al. 1991; Sapolsky sensitization effects have been witnessed naptic or postsynaptic sites, or with et al. 1986). In humans, where aging is between processive stressors and drug respect to transmitter release), these frequently associated with reduced cop- treatments. Thus, treatment with amphet- processes may be affected in a different ing abilities or opportunities (owing, amine or cocaine may enhance the fashion when a novel stressor is intro- for example, to diminished social sup- response introduced by subsequent duced, culminating in augmented neu- ports following loss of friends and loved exposure to a stressor (Kalivas and ronal functioning. ones, reduced physical abilities, and Stewart 1991). Studies by Tilders and colleagues possibly financial concerns), the effects The sensitization appears to depend (Tilders and Schmidt 1998; Tilders et of stressors on pathological processes on the characteristics of the stressors to al. 1993) have revealed important pro- may be particularly marked. Given that which the animal had previously been cesses concerning the sensitization of developmental, social, and cultural fac- exposed. As indicated earlier, young neuroendocrine functioning that occur tors influence not only stressor percep- animals that have been exposed to an in response to both processive and sys- tion but also individual coping styles acute stressor demonstrate increased temic stressors. These investigators (Aldwin 1994). Ultimately, such vari- activity of NE and DA when they are have found that stressors may induce ables probably contribute to pathologi- later exposed to a stressor. As a result, prolonged changes of neuroendocrine cal states and should be considered in reexposure may result in declining neu- functioning within certain neurons of relating stress to alcoholism. rotransmitter levels. However, in animals the hypothalamus that communicate Similar to an aged animal, however, that have been exposed to a chronic with the pituitary gland. As discussed in a very young organism may lack or stressor regimen, subsequent reexpo- the sidebar, both corticotropin-releasing may not have developed the behavioral sure to the stressor induces a sensitiza- hormone (CRH) and arginine vasopressin and neurochemical repertoire to cope tion with respect to both synthesis and (AVP) can stimulate the release of adreno- with stressors effectively and thus may utilization of NE and DA. As a result, corticotropic hormone (ACTH) and, be at increased risk for pathology. As the level of the neurotransmitter does hence, corticosterone release from the discussed shortly, stressors in young not decline readily. In effect, the nature adrenal glands. Furthermore, AVP may animals may act to program (or repro- of the previous stressor experiences potentiate the effects ordinarily elicited gram) neuronal functioning to increase (and the neurochemical changes engen- by CRH. With the passage of time vulnerability to neurochemical disturb- dered) determine an animal’s response following stressor exposure, the CRH ances encountered later in life. to stressor reexposure and thus might neurons may co-produce AVP, thus also influence behavioral responses rendering the HPA axis more sensitive Effects of Prior Life Events engendered by subsequent challenges to stressors. Essential features of these or Stressor Exposure (Anisman et al. 1991). findings include the following: (1) When animals are repeatedly exposed changes of AVP and CRH co-production Sensitization. Stressful events not only to a particular stressor, adaptation may may be long lasting and thus account have marked immediate effects but also occur and, consequently, neurotrans- for some of the protracted effects of may influence one’s response to later mitter alterations may become progres- stressors that have been reported, and stressor experiences. Such a sensitization sively less pronounced. However, when (2) the long-term effects of stressors effect may be responsible for the high animals are subsequently introduced to also could be provoked by the adminis- rates of relapse associated with psychi- a stressor not previously encountered, tration of cytokines (i.e., substances atric disorders, such as depression (Post then the adaptation is not evident, and that act as signaling molecules within 1992). Studies in animals have indi- a marked neurochemical change is again the immune system), suggesting that cated that exposure to stressors typically elicited. Thus, the adaptation that occurs immune activation also may proactively induces physiological changes that per- with sustained exposure to a stressor influence the response to subsequently sist for a relatively brief duration. How- may be unique to that particular stressful encountered adverse experiences. ever, if animals are reexposed to the same stimulus, and diminished responsivity stressor at a later time, then the neuro- may not occur in response to a new Early Life Stimulation. The stimula- chemical changes in the brain occur more stimulus. Conversely, a chronic stressor tion or handling of laboratory animals readily. Such effects have been noted regimen may result in an increased during their first few weeks after birth with respect to several neurotransmitters, response following exposure to a differ- (which also entailed a brief separation but particular attention has been devoted ent type of stressor. In effect, it seems from their mothers) was found to to the analysis of norepinephrine and that although repeated exposure to a decrease age-related learning disturbances dopamine (see reviews in Kalivas and particular stressor may promote either and increased resistance to the effects

246 Alcohol Research & Health Understanding Stress: Characteristics and Caveats

of later stressors (Meaney et al. 1996). tory processes associated with HPA exhibited increased licking, grooming, Animals that had experienced stimula- functioning (Meaney et al. 1996) but and nursing of their offspring. Moreover, tion during the first 21 days of life also in variations with respect to the because the high levels of these mater- showed basal concentrations of ACTH propensity to consume alcohol during nal responses were correlated with altered and corticosterone comparable to that later adulthood (Lancaster 1998; Jones hormonal responses to stressors, the of nonstimulated animals. However, as et al. 1985). researchers suggested that maternal adults, when exposed to a stressor, the Liu and colleagues (1997) conducted behavioral style acted to “program” stimulated animals displayed blunted studies to determine why brief handling HPA responses to later environmental ACTH and corticosterone responses and involving separation from the mother stressors. Whether such factors also a faster return to basal hormone levels. (i.e., for as little as 15 minutes per day) contribute to alcohol intake remains to These long-lasting variations may have had such pronounced and persistent be established. involved a cascade of neuronal changes, effects. After reuniting with their young Anisman and colleagues (1998) culminating not only in altered regula- following the brief separation, mothers studied two mouse strains that exhibit

Regulating the Stress Response

The maintenance of a relatively stable balance of physio- stimuli, the hypothalamus, which is located near the base of logical functions (i.e., homeostasis) is constantly chal- the brain, secretes two hormones that travel directly to the lenged by illness; injury; hostile environmental condi- adjacent pituitary gland. These two hormones, corticotropin- tions; unpleasant emotional states; and even certain nor- releasing hormone (CRH) and arginine vasopressin (AVP),1 mal functions, such as sexual activity and exposure to new promote the secretion of adrenocorticotropic hormone environments. The body’s response to such stressors is reg- (ACTH) from the pituitary gland. Traveling through the ulated largely by interactions among the hypothalamus, bloodstream, ACTH reaches the adrenal glands, which pituitary gland, and adrenal glands, together termed the are located on top of the kidneys. In humans, the adrenal HPA axis (see figure). In response to potentially harmful glands respond to ACTH by releasing the steroid hormone cortisol into the bloodstream.2 Cortisol exerts widespread physiological effects throughout the body, acting in con- cert with other chemical messengers to help direct oxy- gen and nutrients to the stressed body site and suppress (+) Hypothalamus Stress the immune response, while influencing certain func- tions, such as appetite and satiety; arousal, vigilance, and CRH (+) attention; and mood. Under normal circumstances, the presence of cortisol Pituitary gland in the bloodstream signals the hypothalamus to termi- nate CRH secretion, thereby preventing overactivity of (-) (-) (-) the stress response. The regulation of a physiological ACTH (+) response through inhibition mediated by the end-product of the response is called negative feedback. When nega- Cortisol tive feedback control of the HPA axis does not operate Adrenal gland adequately, as may occur following chronic stress or as a consequence of certain psychiatric disorders (possibly Kidney including severe depression), persistent activation of the HPA axis may occur. Damage resulting from HPA over- activity may include suppression of growth, immune sys- tem dysfunction, and localized brain cell damage that Regulation of the stress response by the hypothalamus- might result in impairment of learning and memory. pituitary-adrenal (HPA) axis. —Hymie Anisman and Zul Merali

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing 1 hormone; + = stimulates; - = inhibits. AVP also serves a key function in maintaining the body’s water balance. 2The corresponding hormone in rodents is corticosterone.

Vol. 23, No. 4, 1999 247 very different behavioral and neurochem- also induce such long-term effects. In differences. International Journal of Developmental ical profiles in response to stressors. The any case, early life trauma, which includes Neuroscience 16:149–164, 1998. more stress-reactive strain displayed rel- not only separation from the mother BROWN, G.W. Life events and affective disorder: atively poor maternal behavior, spent but also bacterial infection, appears to Replications and limitations. Psychosomatic Medicine less time within the nest, and took longer have potentially far-reaching implica- 55:248–259, 1993. to retrieve young offspring, which had tions. Thus, various early life experiences FERRINI, M.G.; GRILLO, C.A.; PIROLI, G., DE KLOET, been placed in different portions of the in newborn humans might significantly E.R.; AND DE NICOLA, A.F. Sex difference in glu- cage, compared with the less stress- affect reactivity to stressors encountered cocorticoid regulation of vasopressin mRNA in the reactive strain (Anisman et al. 1998). paraventricular hypothalamic nucleus. Cellular and during adulthood. Molecular Neurobiology 17:671–686, 1997. Thus, the exaggerated response to stres- sors in the more reactive mice may be FINLAY-JONES, R., AND BROWN, G.W. Types of related in part to maternal factors. When stressful life events and the onset of anxiety and Summary depressive disorders. Psychological Medicine 11:803– young mice of the stress-reactive strain 816, 1981. were raised by mothers from the less In response to stressors, a series of behav- reactive strain (cross-fostered on the HAMMEN, C. Generation of stress in the course of ioral, neurochemical, and immunologi- unipolar depression. Journal of Abnormal Psychology day of birth), some behavioral disturb- cal changes occur that ought to serve in 100:555–561, 1991. ances and the exaggerated HPA alter- an adaptive capacity. However, if these HERBERT, T.B., AND COHEN, S. Stress and immunity ations of the more reactive mice were systems become overly taxed, the organ- decreased. However, maternal behavior in humans: A meta-analytic review. Psychosomatic ism may become vulnerable to pathol- Medicine 55:364–379, 1993. alone is not sufficient for this outcome ogy. Likewise, the biological changes, if HERMAN, J.P., AND CULLINAN, W.E. Neurocircuitry to emerge. In particular, being raised sufficiently sustained, may themselves by a mother from the more reactive of stress: Central control of hypothalamo-pituitary- adversely affect the organism’s well-being. adrenocortical axis. Trends in Neuroscience 20:78– strain did not engender behavioral or Several factors may dictate an individ- 84, 1997. hormonal disturbances in young mice ual’s response to environmental stressors, of the more resilient strain. This finding JONES, B.; GOLSTINE, R.; GURLEY, M.; AND REYES, implies that heightened stress reactivity including characteristics of the stressor E. Appetite for alcohol: Influence of genetics and (i.e., type of stressor and its controlla- early experience. Neurobehavioral Toxicology and in these mice results from a combina- Teratology 2:125–127, 1985. tion of genetic factors and inadequate bility, predictability, and chronicity); maternal care (Zaharia et al. 1996). biological factors (i.e., age, gender, and KALIVAS, P.W., AND STEWART, J. Dopamine trans- genetics); and the subject’s previous mission in the initiation and expression of drug- stressor history and early life experiences. and stress-induced sensitization of motor activity. Early Life Deprivation. In contrast to Brain Research Reviews 16:223–244, 1991. early life stimulation, early life stressors Ultimately, these factors interact to determine the organism’s biological LANCASTER, F.E. Sex differences in voluntary (e.g., separation from the mother for drinking by Long Evans rats following early stress. relatively long periods, such as 3 hours responses to environmental stressors; Alcoholism: Clinical and Experimental Research per day) may increase the potential for thus, not surprisingly, much interindi- 4:830–836, 1998. later stressor-promoted HPA activation. vidual variability exists with respect to LAZARUS, R.S. Theory-based stress measurement and Indeed, protracted separation provokes the impact of stressors. Of course, the commentaries. Psychological Inquiry 1:3–51, 1990. an increase of plasma ACTH and corti- retinue of biological changes and the costerone and increased behavioral and broad range of variables that influence LAZARUS, R.S. Coping theory and research: Past, present, and future. Psychosomatic Medicine 55:234– neuroendocrine reactivity to stressors these outcomes often make it difficult 247, 1993. encountered during adulthood (Meaney to identify the mechanisms associated et al. 1996). Paralleling the effects of with stressor-provoked pathology. LIU, D.; DIORIO, J.; TANNENBAUM, B.; CALDJI, C.; FRANCIS, D.; FREEDMAN, A.; SHARMA, S.; PEARSON, early life deprivation—in which young D.; PLOTSKY, P.; AND MEANEY, M.J. Maternal care animals were made ill by the adminis- during infancy: Hippocampal glucocorticoid receptor tration of a bacterial toxin—several References gene expression and hypothalamic-pituitary-adrenal aspects of the HPA response to stressors responses to stress. Science 277:1659–1662, 1997. ALDWIN, C.M. Stress, Coping, and Development: An during adulthood were increased (Shanks Integrated Perspective. New York: Guilford Press, 1994. MEANEY M.J.; DIORIO, J.; FRANCIS, D.; WIDDOWSON, et al. 1995). Of course, bacterial toxins J.; LAPLANTE, P.; CALDJI, C.; SHARMA, S.; SECKL, may induce fever, possibly altering the ANISMAN, H.; ZALCMAN, S.; SHANKS, N.; AND J.R.; AND PLOTSKY, P.M. Early environmental reg- mother’s behavior toward the young ZACHARKO, R.M. Multisystem regulation of perfor- ulation of forebrain glucocorticoid receptor gene mance deficits induced by stressors: An animal model expression: Implications for adrenocortical responses (e.g., elevations of body temperature of depression. In: Boulton, A.; Baker, G.; and Martin- to stress. Developmental Neuroscience 18:49–72, 1996. may serve as a cue for termination of Iverson, M., eds. Neuromethods. Volume 19: Animal nursing), which, in turn, precipitates Models of Psychiatry, II. Totowa, NJ: Humana Press, MERALI, Z.; MCINTOSH, J.; KENT, P.; MICHAUD, the altered response to subsequently 1991. pp. 1–59. D.; AND ANISMAN, H. Aversive as well as appetitive events evoke the release of corticotropin releasing encountered stressors. It remains to be ANISMAN, H.; ZAHARIA, M.D.; MEANEY, M.J.; AND hormone and bombesin-like peptides at the central determined whether metabolic stressors MERALI, Z. Proactive hormonal, neurochemical and nucleus of the amygdala. Journal of Neuroscience that do not elevate body temperature behavioral effects of early life stimulation: Genetic 18:4758–4766, 1998.

248 Alcohol Research & Health Understanding Stress: Characteristics and Caveats

MONROE, S.M., AND SIMONS, A.D. Diathesis- SAPOLSKY, R.M.; KREY, L.C.; AND MCEWEN, B.S. TILDERS, F.J.H.; SCHMIDT, E.D.; AND DE GOEIJ, stress theories in the context of life stress research: The neuroendocrinology of stress and aging: The D.C.E. Phenotypic plasticity of CRF neurons dur- Implications for the depressive disorders. Psychological glucocorticoid cascade hypothesis. Endocrinology ing stress. Annals of the New York Academy of Bulletin 110:406–425, 1991. Review 7:284–301, 1986. Sciences 697:39–52, 1993.

MUNCK, A.; GUYRE, P.M.; AND HOLBROOK, N.J. SCHULKIN, J.; GOLD, P.W.; AND MCEWEN, B.S. VIAU, V., AND MEANEY M.J. Variations in the Physiological functions of glucocorticoids in stress Induction of corticotropin-releasing hormone gene hypothalamic-pituitary-adrenal response to stress and their relation to pharmacological actions. Endocrine expression by glucocorticoids: Implication for under- during the estrous-cycle in the rat. Endocrinology Review 5:25–44, 1984. standing the states of fear and anxiety and allostatic 129:2503–2511, 1991. load. Psychoneuroendocrinology 23:219–243, 1998. NISENBAUM, L.K.; ZIGMOND, M.J.; SVED, A.F.; WEISS, J.M., AND SIMSON, P.G. Neurochemical AND ABERCROMBIE, E.D. Prior exposure to chronic SELIGMAN, M.E.P. Helplessness: On Depression, mechanisms underlying stress-induced depression. stress results in enhanced synthesis and release of Development and Death. San Francisco: Freeman In: Field, T.; McCabe, P.; and Schneiderman, N., hippocampal norepinephrine in response to a novel Press, 1975. eds. Stress and Coping. Hillsdale, NJ: Lawrence stressor. Journal of Neuroscience 11:1478–1484, SHANKS, N.; LAROCQUE, S.; AND MEANEY, N. Erlbaum, 1985. pp. 93–116. 1991. Neonatal endotoxin exposure alters the develop- WILLNER, P. Validity, reliability and utility of the ment of the hypothalamic-pituitary-adrenal axis: POST, R.M. Transduction of psychosocial stress chronic mild stress model of depression: A 10-year Early illness and later responsivity to stress. Journal into the neurobiology of recurrent affective dis- review and evaluation. Psychopharmacology 134: of Neuroscience 15:376–384, 1995. order. American Journal of Psychiatry 149:999– 319–329, 1997. 1010, 1992. SKLAR, L.S., AND ANISMAN, H. Stress and cancer. ZAHARIA, M.; KULCZYCKI, J.; SHANKS, N.; Psychological Bulletin 89:369–406, 1981. RAVINDRAN, A.V.; MERALI, Z.; AND ANISMAN, H. MEANEY, M.J.; AND ANISMAN, H. The effects Dysthymia: A biological perspective. In: Licinio, J.; TILDERS, F.J.H., AND SCHMIDT, E.D. Interleukin- of early postnatal stimulation on Morris water- Bolis, C.L.; and Gold, P., eds. Dysthymia: From 1-induced plasticity of hypothalamic CRH neurons maze acquisition in adult mice: Genetic and mater- Clinical Neuroscience to Treatment. Washington, DC: and long-term stress hyperresponsiveness. Annals of nal factors. Psychopharmacology 128:227–239, World Health Organization, 1997. pp. 21–44. the New York Academy of Sciences 840:65–73, 1998. 1996.

Erratum We regret that an error occurred in the reproduction of the figure included in the article “Approaching Avoidance: A Step Essential to the Understanding of Craving,” by Mary Jo Breiner, Werner G. K. Stritzke, and Alan R. Lang, in Alcohol Research & Health volume 23, number 3, page 197. The corrected figure and the full figure legend appear below.

Historical Factors Expectancies Evaluative Space Decision

¥ Biochemical reactivity ¥ Personality characteristics Negative expectancies Avoidance Ambivalence Not drink ¥ Sociocultural environment ¥ Past reinforcement drink not

Inclination to Indifference Approach Drink Current Factors

Positive ¥ Quantity and quality of expectancies positive and negative Inclination to drink incentives Yes ¥ Access to alternative valued activities No

A multidimensional model of inclinations to drink or not drink. Dashed lines represent factors that promote alcohol avoidance, whereas solid lines represent factors that promote the desire to approach alcohol. This table depicts only the most essential connections with regard to historical factors, expectancies, motivations, and decisions in alcohol use, although other connections may exist.

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