151

Stress-Related Psychopathology

as a Vulnerability Factor in

Drug-Taking: The Role of Sex

D. Caroline Blanchard, Ph.D.

STRESS, STRESS-RELATED

PSYCHOPATHOLOGY, AND SUBSTANCE USE

There is a strong empirical relationship between stress or stressrelated psychopathology and substance use, abuse, and addiction.

Lindenberg and colleagues (1993) reviewed nine relatively large-scale

studies of the relationship between magnitude or intensity of social stress

and one or more types of substance use and abuse. Of these nine studies,

conducted between 1984 and 1991, six showed a significant positive

relationship, two showed no significant correlation, and one reported

mixed findings—unemployment and part-time employment predicted

chronicity of substance use, but stressful life events did not. Examination of studies that failed to find a relationship (e.g., Tennant et al.

1986) between stress and substance use suggests that certain factors may

obscure this relationship, including wide variations in the timespan between the stressful experience and the measurement of substance use,

possible increased attrition within the sample of individuals showing

greater medical or psychiatric psychopathology as a result of the stressful

experience, and the use of a control group that also had experienced

stress. The term “timespan” refers to the time between the occurrence of

the stressful experience and the time when the study measures sequelae.

One study (Tennant et al. 1986) examined World War II prisoners of

war and other combat veterans with a stress experience-to-measurement

interval of more than 40 years. Attrition within this group of veterans

included those who had died or become unavailable for evaluation because of negative medical consequences or other reasons. Some studies

have noted high rates of substance use or abuse in subgroups that experience unusually high stress levels, such as firefighters (Boxer and Wild

1993), homeless women (Smith et al. 1993), and HIV-positive homosexual men (Atkinson et al. 1988). These groups’ extremely divergent

characteristics (e.g., social and employment status), other than high
152

stress levels, suggest that stress is a major common factor in their elevated substance use.

Comorbidity of affective disorders and substance abuse also has been

well documented in several studies. A review by Ries (1993) reports

comorbid rates of 40 to 80 percent for addictive and psychiatric disorders

when patients only in psychiatric settings are considered. In a group of

more than 500 patients at an addiction research and treatment facility,

78 percent had a lifetime psychiatric disorder, and 65 percent had a current mental disorder, in addition to substance abuse (Ross et al. 1988).

Patients with psychiatric disorders had more severe abuse and addiction

problems. Although these psychiatric disorders included some for which

a strong link to stress was not apparent, such as antisocial personality

disorder, stress- and emotion-linked disorders were well represented.

Hesselbrock and associates (1985) reported that major depression was

the most common associated disorder among alcoholic women. Primm

(1992) reported a substance abuse rate of more than 60 percent in individuals with bipolar I disorders. In a group of veterans referred to an outpatient clinic for posttraumatic stress disorder (PTSD), Behar (1987)

found that 54 percent reported cannabis abuse, 49 percent reported alcohol abuse, and 35 percent reported opiate abuse. Keane and coworkers

(1988) reviewed studies of Vietnam combat veterans seeking treatment

for PTSD and found that 60 to 80 percent had concurrent diagnoses of

substance abuse or dependence.

Although these data suggest a strong connection between substance

abuse and stress- or emotion-linked psychopathologies, the dynamics of

this relationship are difficult to determine in clinical or field studies.

One possible indication concerns the onset of behavioral symptoms. In

a study of more than 1,000 young adults who abused alcohol and nonprescription drugs, Christie and colleagues (1988) reported rates of depression 2.7 times higher and rates of anxiety disorders 1.7 times higher than

that of a cohort group. Anxiety was reported to have preceded substance

abuse by about 5 years; the depressive or anxiety disorder preceded the

abuse in three-quarters of the cases; and, when depression was a preexisting condition, probability of abuse was doubled. Among those who

experience frequent or chronic stress, substance use or abuse is more

common for individuals who believe that substance-taking will alleviate

distress (Cooper et al. 1992; McKirnan and Peterson 1989), and there is

evidence that drug treatment for psychiatric disorders closely associated
153

with substance abuse also may reduce substance intake (Weiss and Mirin

1989). Thus, although the relationship between substance use and psychiatric disorders is likely to be bidirectional, these reports emphasize the

importance of one component of this relationship: Stress-related changes

in brain and behavior may be an important factor in the development of

substance abuse and addiction.

OVERREPRESENTATION OF WOMEN IN

STRESS-RELATED PSYCHOPATHOLOGY

The importance of stress-related psychopathologies in vulnerability

to substance use, abuse, and addiction may be particularly important

for women because women show much higher rates of these psychopathologies than do men. It has long been acknowledged that women

are overrepresented among patients with depression (Silverman 1968;

Nolen-Hoeksema 1987). The Diagnostic and Statistical Manual of Mental

Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association

1994) indicates that depressive episodes occur twice as frequently in

women as in men. Studies of possible mechanisms of gender discrepancy

in depression strongly suggest that the difference is not an epiphenomenon and that it remains after factors such as gender-specific diagnostic

bias, differential experience with aversive events, income and education

level, occupation, and particular response bias have been considered and

controlled for (see Nolen-Hoeksema 1987 for a review).

DSM-IV also acknowledges that women are diagnosed with particular

anxiety disorders far more frequently than men. Panic disorder (PD)

without agoraphobia is diagnosed twice as often, and PD with agoraphobia three times as often, in women as in men, whereas agoraphobia

without a history of PD “is diagnosed far more often in females than in

males” (American Psychiatric Association 1994, p. 403). Women receive

from 55 to 90 percent of the diagnoses for specific phobias, including

the animal and natural environment, the situational, and the bloodinjection-injury types. Generalized anxiety disorder is diagnosed slightly

more often in women (55 to 60 percent of diagnoses), but epidemiological studies show about twice as many women as men. The only codable

anxiety disorders for which approximately equal ratios of men and women

are noted are obsessive-compulsive disorder and social phobia, although

epidemiological and community-based studies of social phobia suggest

that it is more common in women. Although DSM-IV (American
154

Psychiatric Association 1994) does not provide information on sex

factors in PTSD, one study (Helzer et al. 1987) using data from the

National Institute of Mental Health-sponsored Epidemiologic Catchment Area Study (Robins and Regier 1991) found that more than

70 percent of those with PTSD in its large sample were women.

These findings for anxiety and depression suggest a striking gender

difference in reactivity to stressful or threatening situations. Because

the gender discrepancy for anxiety disorders has only recently been

recognized (see Cameron and Hill [1989, pp. 175-186] for a review of

previous findings), there have been comparatively few studies analyzing

the mechanisms involved. However, Thyer and associates (1985)

reported that clinical severity of phobic symptoms were not different

for phobic men and women, suggesting that the gender difference for

phobic disorder cannot be attributed to a lower threshold for reporting

a phobic response, or presenting at a clinic, by women.

STRESS AND SUBSTANCE SELFADMINISTRATION: NONHUMAN MAMMALS

A nexus of relationships among stress, psychopathology, and substance-taking—with gender as a potential factor because women show

higher rates of stress-related psychopathology—is well documented in

human research but difficult to analyze in human populations. Animal

studies, in which a wider range of analytic techniques is clearly possible,

are complicated by the lack of unequivocal and well-accepted animal

models of stress-related psychopathology. However, a body of evidence

suggests that stress enhances self-administration of several abusable

substances. Stressful rearing conditions have been shown to increase

self-administration of cocaine (Schenk et al. 1987), amphetamine, and

barbital (Zimmerberg and Brett 1992) by rats, with the latter study also

finding a sex difference in the effects of early social isolation on the

choice of drug preferred. Offspring of rat mothers stressed by periods of

forced immobility in a restraint tube during gestation days 14 to 21 also

showed enhanced amphetamine self-administration (Deminiere et al.

1992), suggesting that maternal hypersecretion of corticosterone may

have lasting effects on the rat fetus. Consonant with this view, the

restraint stress-based enhancement of the locomotor response to amphetamine and morphine was not obtained in adrenalectomized animals

with corticosterone implants (Deroche et al. 1992).
155

Rats vulnerable to amphetamine self-administration, either because

of individual differences (Deminiere et al. 1989) or prenatal stress

(Deminiere et al. 1992), also showed enhanced locomotor response to

amphetamine in a novel but not a familiar environment (Piazza et al.

1990). These animals had stress-induced increases in nucleus accumbens

concentrations of dopamine that were longer lasting and of higher magnitude than those of animals not showing the enhanced locomotor response

to amphetamine, according to Rouge-Pont and colleagues (1993), who

suggest that changes in these brain systems may constitute an important

neurobiological substrate of the predisposition to acquire amphetamine

self-administration as well as other addictive behaviors. Rats that developed self-administration also tended to be those that showed an enhanced locomotor response in a novel environment and also acquired

schedule-induced polydipsia (SIP) (drinking in the context of an intermediate schedule of food delivery). However, when tested for SIP first

(an experience that is interpreted as having a coping function), the polydipsic rats subsequently failed to acquire self-administration and had a

reduced locomotor response to novelty (Piazza et al. 1993).

Pohorecky and coworkers (1989) presented a somewhat similar picture for caffeine effects: Doses of 10 mg/kg caffeine increased crossover

frequency and duration, and rearing frequency and duration in an open

field, for 60-day-old rats. Prenatal stress (during gestation days 14 to 21)

increased sensitivity to caffeine on measures of locomotor activity in the

corners of the apparatus and rearing. Again, individual difference factors

may be important, in addition to the effects of prenatal stress: Taylor and

colleagues (1990) reported that rats that showed a high plasma catecholamine response to stress showed higher intake of a cocaine solution than

did low-catecholamine stress responders.

Stress effects on substance self-administration are not limited to

psychostimulants. Although stress enhancement of voluntary alcohol

consumption has been demonstrated in rhesus monkeys (Orloff and

Masserman 1975), most of the considerable literature in this area has involved laboratory rodents (see reviews by Pohorecky [1981, 1990] and

Blanchard and associates [1993b]). Briefly, a range of stressors, including

shock (Bond 1978; Caplan and Puglisi 1986), grouping (Ellison 1981;

Ellison et al. 1983), and subordination (Blanchard et al. 1987, 1992),

increase voluntary alcohol consumption in rats and in mice (HilakiviClarke and Lister 1992). Because the literature on human subjects
156

suggests that psychopathology may be a mediator of stress enhancement

of substance-taking, it is interesting to note findings of individual differences’ effects on the stress-induced enhancement of voluntary alcohol

consumption. High-plasma-catecholamine, stress-responding rats showed

more voluntary alcohol consumption than did low-catecholamine, stressresponding rats (Taylor et al. 1990). When male rats were evaluated on

a variety of defense measures prior to grouping, pregrouping defense

scores were highly (and significantly) correlated with pregrouping to

postgrouping increases in voluntary alcohol consumption for subordinates (Blanchard et al. 1992).

Although there are no well-accepted animal models of psychopathology that are homologous to clinical disorders in humans, there is an

emerging trend to examine the relationship between specific changes in

defensive behaviors in laboratory animals and the target symptoms of

emotion-linked psychopathologies in humans. Highly stressed subordinate male rats and tree shrews show a variety of consistent behavior

changes, many of which are isomorphic to major symptoms of clinical

depression. These include reductions in nondefensive behaviors (eating,

drinking, social, sexual, and exploratory), weight loss, changes in resting/

activity cycles and circadian rhythm, decreased movement celerity, and

longer periods of attention to potential threat stimuli (Von Holst 1986;

Blanchard and Blanchard 1990; Blanchard et al. 1993a, 1995a; Tornatzky

and Miczek 1993).

Although female rats generally do not participate in the dominance

hierarchies established by males (making it more difficult to study

chronic social stress in these animals), analysis of the defensive behaviors

of both male and female rats to a natural stressor (a cat predator) provides a foundation for evaluating sex differences in the rat’s response to

acute stress. Moreover, particular defensive behaviors measured in these

studies have been shown to respond selectively to anxiolytic (Blanchard

et al. 1993c) or antipanic (Griebel et al. 1996) drugs, suggesting that

these defensive behaviors to stressful stimuli may provide animal models

for some behavioral psychopathologies. Notably, among control animals

used in a variety of drug studies, female rats showed consistently different, and often higher, levels of certain defensive behaviors than did

males, particularly in situations involving cued or anticipatory (as opposed to present) threat (see Blanchard et al. 1991 for a review). When

serotonergic compounds were tested in this defense test battery, female
157

rats frequently showed patterns of drug response different from males

(Blanchard et al. 1993d; Shepherd et al. 1992, 1993). In addition,

Fernandez-Guasti and Picazo (1990) noted that the anxiolytic action of

several serotonergic compounds and ligands appears to be different for

male and female rats and for different phases of the estrous cycle. However, sex differences in defense are by no means confined to laboratory

rodents. On the basis of a review of sex-specific reactivity profiles to

threatening stimuli in a variety of primate species under natural conditions, Crepeau and Newman (1991) suggest that these differences may be

related to variations in adaptive outcomes of specific defensive behaviors

for males and females, given their different social and reproductive roles.

These findings suggest gender modulation of the biological mechanisms of responsivity to stress and threat, and an emerging literature (see

Blanchard et al. 1995b for review) attests to a variety of sex-linked differences in neurotransmitter and neuromodulatory systems in both laboratory rodents and humans. Sex differences appear to be particularly notable for the serotonin (5-HT) systems (e.g., Biegon and Israeli 1987;

Carlsson and Carlsson 1988; Haleem 1992; Haleem et al. 1990; Simerly

et al. 1984, 1985), which are influenced by the estrous cycle in female

rats (Biegon et al. 1980; Uphouse et al. 1986) and the menstrual cycle in

women (Halbreich 1990). Sex differences in 5-HT systems have been

demonstrated to result in physiological (e.g., Uphouse et al. 1991), behavioral (e.g., Uphouse et al. 1991; Cutler 1991), and stress response

(Heinsbroek et al. 1988; Albonetti et al. 1994) effects of manipulation of

5-HT systems.

These studies consistently indicate the importance of analyzing gender differences in studies of the biology of defense-related psychopathologies, both for their intrinsic interest and because such studies may provide information crucial in understanding substance abuse and addiction

among women. However, such studies are rare and show no sign of becoming more common. An examination (Blanchard et al. 1995b) of a

database on essentially all preclinical studies of serotonergic compounds

in conjunction with tests designed to provide a model of anxiety included about 1,600 studies published between 1960 and early 1994.

Although the number of such studies has increased in recent years, the

proportion in which only males were used as subjects has remained relatively consistent. Male-only studies constituted about 95 percent of

preclinical research on how serotonin affects anxiety, which is much
158

more common among women than men. In addition, of those studies

using females, only a few involved both females and males, as required

for meaningful comparisons within each study. Although this review

specifically involved serotonin and anxiety, there appears to be little

reason to believe that the situation of virtually exclusive use of male

subjects for preclinical research on models of psychopathology is different when other biological variables and other models are used.

SUMMARY: RELATIONSHIPS

AND RESEARCH STRATEGIES

Stress appears to enhance substance-taking in both humans and

laboratory animals. Moreover, recent work on the defensive behaviors

of lower mammals suggests that alterations of these systems, like human

emotional psychopathologies, may be mediators of the stress/substancetaking relationship. Because women show consistently higher rates of

emotional psychopathologies such as anxiety and depression, whereas

female laboratory animals also show a greater defensive response to

potential threat, this may be a particularly important vulnerability

factor in substance abuse by women.

This view suggests that research into the mechanisms of this vulnerability may be important in the development of improved treatment for

drug abuse and addiction, for both men and women, but especially for

women. Specifically, it suggests that research leading to improved interventions, either pharmacological or experiential, for stress, anxiety, and

depression, might be effective in reducing women’s vulnerability to substance use and abuse. However, like the effects of stress on drug vulnerability generally, research on gender effects on the biology of the stress

response has been neglected. This continuing omission is a substantial

barrier to understanding gender modulation of the relationship between

stress and drug-taking and to creating more effective treatments for these

disorders among women.

Finally, these detailed similarities between animal and human findings provide support for the view that a wide range of human phenomena can be well modeled in laboratory settings incorporating attention

to the natural behaviors shown by the subject species, with results that

are, in turn, sensitive to the same array of factors that are important on

the human level. For all mammals, the relationship between the organism and experience is bidirectional, with the interplay of biological and
159

experiential factors reflected in a range of important behaviors. For

optimum progress in understanding behavioral phenomena common to

all mammals, the results of research using human and animal subjects

should be used to provide reciprocal enlightenment.

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AUTHOR

D. Caroline Blanchard, Ph.D.

Professor

Department of Anatomy

Bekesy Laboratory of Neurobiology

John A. Burns School of Medicine

Pacific Biomedical Research Center

University of Hawaii at Manoa

1993 East-West Road

Honolulu, HI 96822-2359

(808) 956-8067 (Tel)

(808) 956-9612 (Fax)

blanchar@hawaii.edu (E-mail)