Chronic Stress, Drug Use, and Vulnerability

to Addiction
Rajita Sinha
Department of Psychiatry, Yale University School of Medicine,
New Haven, Connecticut, USA

Stress is a well-known risk factor in the development of addiction and in addiction

relapse vulnerability. A series of population-based and epidemiological studies have
identified specific stressors and individual-level variables that are predictive of sub-
stance use and abuse. Preclinical research also shows that stress exposure enhances
drug self-administration and reinstates drug seeking in drug-experienced animals. The
deleterious effects of early life stress, child maltreatment, and accumulated adver-
sity on alterations in the corticotropin releasing factor and hypothalamic-pituitary-
adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the
central noradrenergic systems are also presented. The effects of these alterations on
the corticostriatal-limbic motivational, learning, and adaptation systems that include
mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways
are discussed as the underlying pathophysiology associated with stress-related risk of
addiction. The effects of regular and chronic drug use on alterations in these stress and
motivational systems are also reviewed, with specific attention to the impact of these
adaptations on stress regulation, impulse control, and perpetuation of compulsive drug
seeking and relapse susceptibility. Finally, research gaps in furthering our understand-
ing of the association between stress and addiction are presented, with the hope that
addressing these unanswered questions will significantly influence new prevention and
treatment strategies to address vulnerability to addiction.

Key words: chronic stress; early life stress; addiction risk; relapse; craving; mesolimbic
dopamine

Introduction the cross examination of laboratory-induced

methods of stress and craving and their asso-
Stress has long been known to increase vul- ciation to specific brain regions associated with
nerability to addiction. The last decade has reward and addiction risk. This paper focuses
led to a dramatic increase in understanding primarily on the association between stress and
the underlying mechanisms for this associa- addiction in humans but also draws from the
tion. Behavioral and neurobiological correlates broader animal literature to support the pro-
are being identified, and some evidence of posed hypotheses. A definition of stress and its
molecular and cellular changes associated with neural underpinnings is presented with specific
chronic stress and addiction has been identified. emphasis on its effects on motivation and be-
Human studies have benefited from the emer- havior. In the context of strong epidemiologi-
gence of sophisticated brain-imaging tools and cal evidence linking early-childhood and adult
adversity and risk of addiction, results from
basic and human research that point to pu-
Address for correspondence: Rajita Sinha, Ph.D., Professor, Depart- tative mechanisms underlying this association
ment of Psychiatry, Director, Yale Interdisciplinary Stress Center, Yale are presented. A critical role is seen for pre-
University School of Medicine, 2 Church Stress South, Suite 209,
New Haven, CT 06515. Voice: +203-974-9608; fax: +203-974-7076.
frontal circuits involved in adaptive learning
rajita.sinha@yale.edu and executive function, including controlling
Ann. N.Y. Acad. Sci. 1141: 105–130 (2008). 
C 2008 New York Academy of Sciences.
doi: 10.1196/annals.1441.030 105
106 Annals of the New York Academy of Sciences

distress and desires/impulses, in the associa- that are mild/moderately challenging but lim-
tion between stress and addiction risk. How- ited in duration and results in cognitive and be-
ever, several questions remain unanswered in havioral responses that generate a sense of mas-
understanding stress-related addiction risk, and tery and accomplishment, and can be perceived
these are reviewed in order to inform future re- as pleasant and exciting.1,3,6,7 Such situations
search. Finally, the effects of chronic drug use rely on adequate motivational and executive
on stress and reward pathways particularly with functioning to achieve goal-directed outcomes
respect to relapse risk are examined. Future di- and homeostasis.3,6,8 However, the more pro-
rections in addressing stress-related relapse risk longed, repeated, or chronic the stress—for
in clinical settings are also discussed. example, states associated with increased in-
tensity or persistence of distress—the greater
the uncontrollability and unpredictability of the
Stress, Emotions, stressful situation, lower the sense of mastery or
and Adaptive Behavior adaptability, and greater the magnitude of the
stress response and risk for persistent home-
The term “stress” refers to processes in- ostatic dysregulation.1,6,9–11 Thus, the dimen-
volving perception, appraisal, and response to sions of intensity, controllability, predictability,
harmful, threatening, or challenging events or mastery, and adaptability are important in un-
stimuli.1–3 Stress experiences can be emotion- derstanding the role of stress in increasing risk
ally or physiologically challenging and acti- of maladaptive behaviors such as addiction.
vate stress responses and adaptive processes The perception and appraisal of stress relies
to regain homeostasis.2,4–6 Examples of emo- on specific aspects of the presenting external or
tional stressors include interpersonal conflict, internal stimuli, personality traits, availability
loss of relationship, death of a close family of internal resources (including physiological
member, and loss of a child. Common phys- condition of the individual), prior emotional
iological stressors are hunger or food depriva- state (including beliefs and expectancies), and
tion, sleep deprivation or insomnia, extreme specific brain regions mediating the appraisal
hyper- or hypothermia, and drug withdrawal of stimuli as distressing, and the resulting phys-
states. In addition, regular and binge use of iological, behavioral, and emotional experi-
many psychoactive drugs serve as pharmaco- ences and adaptive responses. Brain regions
logical stressors. This kind of conceptualization such as the amygdala, hippocampus, insula,
allows the separate consideration of (1) internal and orbitofrontal, medial prefrontal, and cin-
and external events or stimuli that exert de- gulate cortices are involved in the perception
mands or load on the organism; (2) the neural and appraisal of emotional and stressful stimuli,
processes that evaluate the demands and assess and the brain stem (locus ceruleus and related
availability of adaptive resources to cope with arousal regions), hypothalamus, thalamus, stri-
the demands (appraisal); (3) the subjective, be- atal, and limbic regions are involved in phys-
havioral, and physiological activity that signal iological and emotional responses. Together
stress to the organism; (4) neuroadaptations in these regions contribute to the experience of
emotional and motivational brain systems as- distress. Physiological responses are manifested
sociated with chronic stress; and (5) behavioral, through the two major stress pathways, namely
cognitive, and physiological adaptation in re- corticotropin releasing factor (CRF) released
sponse to stressors. from the paraventricular nucleus (PVN) of the
While stress is often associated with negative hypothalamus, which stimulates adrenocorti-
affect and distress, it can include “good stress” cotrophin hormone from the anterior pituitary,
which is based on external and internal stimuli which subsequently stimulates the secretion
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 107

of cortisol/corticosterone from the adrenal Stress and the Development

glands, and the autonomic nervous system, of Addictive Behaviors
which is coordinated via the sympathoadrenal
medulary (SAM) systems.4,12 There is a substantial literature on the sig-
In addition, CRF has extensive influ- nificant association between acute and chronic
ence in extrahypothalamic regions across the stress and the motivation to abuse addictive
corticostriatal-limbic regions and plays a crit- substances (see30 for review). Many of the ma-
ical role in modulating subjective and be- jor theories of addiction also identify an im-
havioral stress responses.13 Furthermore, cen- portant role of stress in addiction processes.
tral catecholamines, particularly noradrenaline These range from psychological models of ad-
and dopamine, are involved in modulating diction that view drug use and abuse as a coping
brain motivational pathways (including the strategy to deal with stress, to reduce tension,
ventral tegmental area or VTA, nucleus ac- to self medicate, and to decrease withdrawal-
cumbens [NAc], and the medial prefrontal related distress,31–37 to neurobiological models
[mPFC] regions) that are important in regu- that propose incentive sensitization and stress
lating distress, exerting cognitive and behav- allostasis concepts to explain how neuroadap-
ioral control, and negotiating behavioral and tations in reward, learning, and stress pathways
cognitive responses critical for adaptation and may enhance craving, loss of control, and com-
homeostasis.8,14,15 The hypothalamic and ex- pulsion, the key components in the transition
trahypothalamic CRF pathways and central from casual use of substances to the inability to
catechoamines target brain motivational path- stop chronic use despite adverse consequences,
ways to critically affect adaptive and home- a key feature of addiction.38–40 In this section,
ostatic processes. For example, different parts we review the converging lines of evidence that
of the medial prefrontal cortex are involved in point to the critical role that stress plays in in-
higher cognitive or executive control functions, creasing addiction vulnerability.
such as controlling and inhibiting impulses,
regulating distress, focusing and shifting atten- Chronic Adversity and Increased
tion, monitoring behavior, linking behaviors Vulnerability to Drug Use
and consequences over time, considering al-
ternatives before acting, and decision-making There is considerable evidence from
responses.16,17 Psychosocial and behavioral sci- population-based and clinical studies support-
entists have elegantly shown that with increas- ing a positive association between psychosocial
ing levels of emotional and physiological stress adversity, negative affect, and chronic distress
or negative affect, there is a decrease in be- and addiction vulnerability. The evidence in
havioral control and increases in impulsiv- this area can be categorized into three broad
ity, and with increasing levels of distress, and types. The first includes prospective studies
chronicity of stress, greater the risk of mal- demonstrating that adolescents facing high re-
adaptive behaviors.18–27 Neurobiological ev- cent negative life events show increased levels
idence shows that with increasing levels of of drug use and abuse.41–55 Negative life events
stress, there is a decrease in prefrontal function- such as loss of parent, parental divorce and con-
ing and increased limbic-striatal level respond- flict, low parental support, physical violence
ing, which perpetuates low behavioral and and abuse, emotional abuse and neglect, iso-
cognitive control.28,29 Thus, the motivational lation and deviant affiliation, and single-parent
brain pathways are key targets of brain stress family structure have all been associated with
chemicals and provide an important potential increased risk of substance abuse.
mechanism by which stress affects addiction The second type of evidence is the as-
vulnerability. sociation between trauma and maltreatment,
108 Annals of the New York Academy of Sciences

negative affect, chronic distress, and risk of sub- pendence in a dose-dependent manner, even
stance abuse. Overwhelming evidence exists after accounting for control factors. Both distal
for an increased association between childhood and proximal events significantly and indepen-
sexual and physical abuse and victimization dently affected addiction vulnerability. Further-
and increased drug use and abuse.56–60 There more, the dose-dependent effects of cumulative
is also some evidence that recent negative life stressors on risk for addiction existed for both
events and physical and sexual abuse each ex- genders and for Caucasian, African-American,
ert somewhat independent risk on addiction and Hispanic race/ethnic groups. The types
vulnerability.58 In addition to sexual and phys- of adverse events significantly associated with
ical abuse, negative affect and chronic distress addiction vulnerability were parental divorce
states are predictive of addiction vulnerability. or conflict, abandonment, forced to live apart
Findings indicate that negative affect, including from parents, loss of child by death or re-
temperamental negative emotionality, is asso- moval, unfaithfulness of significant other, loss
ciated with substance abuse risk.61–67 Several of home to natural disaster, death of a close
studies have also shown a significant associ- one, emotional abuse or neglect, sexual abuse,
ation between prevalence of mood and anx- rape, physical abuse by parent, caretaker, fam-
iety disorders, including post-traumatic stress ily member, spouse, or significant other, vic-
disorder (PTSD), behavioral conduct prob- tim of gun shooting or other violent acts, and
lems and increased risk of substance use dis- observing violent victimization. These repre-
orders.68–78 As stress is significantly associated sent highly stressful and emotionally distressing
with prevalence of mood and anxiety disorders events, which are typically uncontrollable and
and chronic psychiatric distress,79,80 these asso- unpredictable in nature. Table 1 summarizes
ciations raise the issue of whether psychiatric the types of life events, chronic stressors, mal-
disorders conceptualized as chronic distress treatment, and individual level variables asso-
states may largely account for the significant ciated with addiction risk.
association between stress and substance use
disorders. Stress Exposure Increases Initiation and
In the third type of evidence from population Escalation of Drug Self-Administration
studies, recent research has examined lifetime
exposure to stressors and the impact of cumu- There is some evidence from animal stud-
lative adversity on addiction vulnerability af- ies to support the notion that acute exposure
ter accounting for a number of control factors to stress increases initiation and escalation
such as race/ethnicity, gender, socioeconomic of drug use and abuse (see30,83 for reviews).
status, prior drug abuse, prevalence of psychi- For example, in animal models, social de-
atric disorders, family history of substance use, feat stress, social isolation, tailpinch and foot-
and behavioral and conduct problems.81,82 Cu- shock, restraint stress, and novelty stress are
mulative adversity or stress was assessed using a known to enhance acquisition of opiates, alco-
checklist method and by counting the number hol, and psychostimulant self-administration,
of different events that were experienced in a with caveats relating to stressor type, genetic
given period during the lifespan. The effects of background of animals, and variations by drug
distal (events occurring more than 1 year prior) type (see84–87 for reviews). Also, although there
and proximal stress experiences (events during are some negative findings, other evidence
the most recent 1-year period), and their effects indicates that early life stress, using proce-
on meeting criteria for substance use disorders dures such as neonatal isolation or mater-
were also assessed. The findings indicate that nal separation, and prolonged and repeated
the cumulative number of stressful events was stressors representing chronic stress experi-
significantly predictive of alcohol and drug de- ences, enhances self-administration of nicotine,
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 109

TABLE 1. Types of Adverse Life Events, Trauma, Chronic Stressors, and Individual-Level Variables
Predictive of Addiction Risk
Loss of parent Physical neglect Negative emotionality
Parental divorce and conflict Physical abuse by parent/caretaker/family Poor behavioral control
Isolation & abandonment member/spouse/significant other Poor emotional control
Single-parent family structure Emotional abuse and neglect
Forced to live apart from parents Sexual abuse
Loss of child by death or removal Rape
Unfaithfulness of significant other
Loss of home to natural disaster
Death of significant other/close
family member
Victim of gun shooting or other
violent acts
Observing violent victimization

psychostimulants, and alcohol and/or their their activation of the mesolimbic dopaminer-
acute behavioral effects.88–93 Notably, sex plays gic (DA) pathways, which include dopamine
an important role in stress-related sensitivity neurons originating in the ventral tegmental
to the reinforcing effects of drugs and in stress area and extending to the ventral striatum and
enhancement of drug self-administration.93–97 the prefrontal cortex (PFC).115–117 This path-
In humans, there is substantial evidence from way is also involved in assigning salience to
prospective and longitudinal studies to sup- stimuli, in reward processing, and in learning
port the effects of stress on drug use initia- and adaptation.14,118 Human brain imaging
tion and escalation in adolescents and young studies also support the role of these systems
adults.24,98–109 Furthermore, there are sex dif- in drug reward, as psychostimulants, alcohol,
ferences in the effects of early trauma and opioids, and nicotine all activate the mesolim-
maltreatment on the increased risk of addic- bic DA systems, in particular, the ventral and
tion.74,110–114 Laboratory studies examining ef- dorsal striatum, and such activity has been asso-
fects of stress exposure on drug use are lim- ciated with the drug ratings of high or euphoria
ited to legal drugs such as alcohol and nicotine, and craving.119–126
for ethical reasons. Nonetheless, there is evi- However, stress exposure and increased
dence that stress increases drinking and nico- levels of glucocorticoids (GC) also enhance
tine smoking (see83 for review), but the effects dopamine release in the NAc.127–132 Suppres-
of drinking history, history of adversity, social sion of GC by adrenalectomy reduces extracel-
stress, and expectancies are known to play a lular levels of dopamine under basal conditions
role in these experimental studies. and in responses to stress and psychostim-
ulants.131,133 However, chronic GC inhibits
Possible Mechanisms Underlying Stress DA synthesis and turnover in the NAc,134
Effects on Addiction Vulnerability suggesting that alterations in the hypothalamic-
pituitary-adrenal (HPA) axis and glucocorti-
As evidence using diverse approaches has coids can significantly affect DA transmis-
accumulated in support of a significant effect sion. There is also evidence that, like drugs
of stress on risk of addiction, this section ex- of abuse, stress and concomitant increases
amines research on neurobiological links be- in CRF and glucocorticoids enhance gluta-
tween stress and reward pathways activated by mate activity in the VTA, which in turn en-
abusive drugs. It is well known that the re- hances activity of dopaminergic neurons.135–138
inforcing properties of drugs of abuse involve Human brain imaging studies have further
110 Annals of the New York Academy of Sciences

shown that stress-related increases in cortisol ulant effects of cocaine and morphine.156 Fur-
are associated with dopamine accumulation thermore, GC receptor antagonists injected
in the ventral striatum,125,139 and some evi- into the VTA decrease morphine-induced loco-
dence also reveals that amphetamine-induced motor activity,157 suggesting that activity of GC
increases in cortisol are associated with both receptors in the VTA could mediate dopamine-
dopamine binding in the ventral striatum and dependent behavioral effects. Mice with dele-
with ratings of amphetamine-induced eupho- tion of the GR gene show a dose-dependent
ria.140 Given that both stress and drugs of abuse decrease in motivation to self-administer co-
activate the mesolimbic pathways, it is not sur- caine.158 These data suggest that HPA-related
prising that each results in synaptic adapta- corticosterone release could at least partially
tions in VTA dopamine neurons and in mor- mediate the dopamine increases seen after drug
phological changes in the medial prefrontal administration.
cortex.87,136,141,142 Although in nonhuman primates the
In addition to a role in reward, a growing link between cortisol, dopamine, and drug
body of human imaging studies and preclinical self-administration has not been reported,
data indicate that the ventral striatum is also in- there is evidence that stress related to so-
volved in aversive conditioning, in experience cial subordination is associated with lower
of aversive, pain stimuli, and in anticipation levels of D2 receptors and higher cocaine
of aversive stimuli.143–146 Such evidence points self-administration.159 In humans, positive
to a role for the mesolimbic dopamine path- emission tomography (PET) studies using
ways beyond reward processing, and one that [11 C]raclopride indicate that acute stress expo-
more broadly involves motivation and attention sure increases dopamine release in the ventral
to behavioral response during salient (aversive striatum (VS). For example, in a small-sample
or appetitive) events.147–150 Furthermore, ad- study, Pruessner and colleagues (2004)139 found
ditional regions connected to the mesolimbic that healthy individuals with low early-life ma-
DA pathways and involved in reward, learn- ternal care showed greater dopamine release
ing, and adaptive and goal-directed behaviors in the ventral striatum during an acute psycho-
are the amygdala, hippocampus, insula, and logical stress task as compared to those with a
related corticolimbic regions.118,151 These re- history of high early-life maternal care. Fur-
gions, along with the mesolimbic DA pathways, thermore, cortisol response during the stress
play an important role in interoception, emo- task was correlated significantly (r = .78) to
tions and stress processing, impulse control and VS dopamine release. Oswald and colleagues
decision making, and in the addictive proper- (2005)125 also demonstrated that acute
ties of drugs of abuse.29,152 amphetamine challenge-related subjective
“high” responses and concomitant increase in
Stress Mechanisms Involved in dopamine in the VS were each significantly
Acquisition of Drug Self-Administration associated with amphetamine-induced cortisol
responses. More recently, the same group has
Research has also examined whether also shown a similar significant relationship
stress-related increases in acquisition of between cortisol levels and dopamine release
drug self-administration are mediated by in the VS using a psychological stress task.140
corticosterone (cortisol in humans). Findings Although these data support the link between
indicate that HPA-activated corticosterone stress/cortisol and dopamine transmission,
release is important for acquisition of drug self- human research linking stress-induced changes
administration.131,153–155 Corticosterone ad- in VS activity or dopamine binding and risk
ministration also facilitates psychomotor stim- of addictive behavior is needed to directly
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 111

establish the association between stress, dent on environmental experiences for matu-
mesolimbic dopamine, and addiction risk. ration.171 The PFC, and particularly the right
PFC, plays an important role both in activat-
Early Life and Chronic Stress, Dopamine ing the HPA axis and autonomic responses
Systems, and Drug Self-Administration to stress and in regulating these responses.171
For example, lesions of the ventromedial PFC
There is growing evidence from basic science result in enhanced HPA and autonomic re-
studies that early-life stress and chronic stress sponses to stress. High levels of glucocorti-
significantly affect the mesolimbic dopamine coid receptors are also found in the PFC, and
pathways and play a role in drug self- chronic GC treatment results in a dramatic
administration. Repeated and prolonged ex- dendritic reorganization of PFC neurons sim-
posure to maternal separation (MS) in neona- ilar to that seen in the hippocampus.172,173
tal rats significantly alters the development of Furthermore, early postnatal MS and social
central CRF pathways.11 These animals as isolation result in abnormally high synaptic
adults show exaggerated HPA and behavioral densities in the PFC and altered densities of
responses to stress.160,161 Such physiological DA and serotonin (5-HT) terminals through-
and behavioral changes are associated with out the medial PFC.174 Social defeat stress also
altered CRF mRNA expression in the PVN, alters feedback from the PFC and contributes
increased CRF-like immunoreactivity in the lo- to drug self-administration.84 Human studies
cus ceruleus (LC), and increased CRF recep- on the neurobiological effects of child mal-
tor levels in the LC and raphe nuclei.11 The treatment document neuroendocrine changes
adult animals also show decreased negative as well as alterations in size and volume of pre-
feedback sensitivity to glucocorticoids,162 and frontal, thalamic, and cerebellar regions asso-
these changes are accompanied by decreased ciated with maltreatment and with initiation of
GC receptor expression in the hippocampus addiction.175,176 Together, the data presented
and frontal cortex.11,163 Decreased GABA re- in this section highlight the significance of stress
ceptor levels in noradrenergic cell body re- effects on mesolimbic and prefrontal regions in-
gions in the LC and decreased central ben- volved in stress related behavioral control.
zodiazepine (CBZ) receptor levels in the LC
and the amygdala have also been reported.164 Stress, Self-Control,
More importantly, MS rats show significantly and Addiction Vulnerability
elevated DA responses to acute stress along
with increased stress-induced behavioral sen- High emotional stress is associated with loss
sitization and robust behavioral sensitization to of control over impulses and an inability to
psychostimulant administration.11,143,165 This inhibit inappropriate behaviors and to delay
cross-sensitization of stress and drugs of abuse gratification.20,177,178 Neurobiological data in-
is associated with enhanced release of DA in the dicate that stress impairs catecholamine mod-
NAc, lower NAc-core, and striatal DA trans- ulation of prefrontal circuits, which in turn im-
porter sites, and reduced D3 receptor binding pairs executive functions like working memory
sites and mRNA levels in the NAc shell.166–168 and self-control.17,28,179 There is also grow-
In addition, chronic norepinephrine deficiency ing evidence that adolescents at risk for sub-
induces changes similar to sensitization that stance abuse who have experienced several
could be related to alterations in DA-signaling of the stressors listed in Table 1 are more
pathways.169,170 likely to show decreased emotional and be-
Early-life stress and prolonged and repeated havioral control, and decreased self-control
stress also adversely affect development of the is associated with risk of substance abuse
prefrontal cortex, a region that is highly depen- and other maladaptive behaviors.104,152,180,181
112 Annals of the New York Academy of Sciences

Figure 1. A schematic model of stress effects on addiction, representing the cross-sensitization of stress
and drugs on behavioral and neurochemical responses, that are mediated by the stress and reward pathways.
Column A lists three types of vulnerability factors: (1) developmental/individual-level factors such as frontal
executive function development, negative emotionality, behavioral/self control, impulsivity or risk taking, and
altered initial sensitivity to rewarding effects of drugs; (2) stress-related vulnerability factors such as early
adverse life events, trauma and child maltreatment experiences, prolonged and chronic stress experiences;
and (3) genetic influences and family history of psychopathology. Each of these factors influences each other
to significantly affect alterations in neurobiological pathways involved in stress regulation and cognitive and
behavioral control (Column B). Such changes at least partially mediate the mechanisms by which stress and
individual and genetic factors in column A interact to increase risk of maladaptive behaviors represented in
column C when an individual is faced with stress or challenge situations.

Adolescents at risk for substance abuse are but with high stress, both groups showed low
known to have decreased executive function- DA release. These findings demonstrate the
ing, low behavioral and emotional control, important effects of stress and impulsivity on
poor decision making, and greater levels of mesolimbic dopamine transmission and high-
deviant behavior and impulsivity.24,152,182–184 light the fact that both factors need to be care-
The corticostriatal-limbic dopamine pathways fully considered to fully understand the role of
have been associated with impulsivity, deci- stress and impulsivity on addiction risk.
sion making, and addiction risk,185,186 and
as discussed in previous sections, specific re-
Schematic Model of Stress Effects
gions of this pathway, such as the VTA, NAc,
on Addiction
PFC, and amygdala, are highly susceptible to
stress-related signaling and plasticity associated Figure 1 presents a schematic model of
with early-life stress and chronic stress experi- stress effects on addiction. It highlights cross-
ences. In a recent PET imaging study, Oswald sensitization of stress and drug abuse on specific
(2007)187 examined the effects of chronic stress behavioral and neurochemical responses and
and impulsivity on amphetamine-induced stri- indicates the common neurobiological path-
atal dopamine release. These findings indicated ways upon which both stress and drugs of abuse
that high trait impulsivity was associated with act. Column A lists three types of vulnerability
blunted right VS dopamine release. However, factors: (1) developmental/individual-level fac-
these effects were modified by a significant in- tors such as frontal executive function develop-
teraction with chronic life events stress. With ment, negative emotionality, behavioral/self-
low to moderate stress, dopamine release was control, impulsivity, or risk taking, and altered
greater in low than in high impulsive subjects, initial sensitivity to rewarding effects of drugs;
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 113

(2) stress-related vulnerability factors such as stress pathways (CRF-HPA axis and the au-
early adverse life events, trauma and child mal- tonomic nervous system pathways) with in-
treatment experiences, prolonged and chronic creases in plasma adrenocorticotropic hor-
stress experiences; and (3) genetic influences mone (ACTH) and corticosterone, changes in
and family history of psychopathology and ad- heart rate and blood pressure, and skin con-
diction, which have not been discussed here ductance responses.204–217 On the other hand,
but have significant interactive effects on ad- acute exposure to opiates decreases cortisol lev-
diction risk and in emotion and stress mark- els in humans.218,219 Regular and chronic use of
ers.188–194 Each of these factors may influence these drugs is also associated with adaptations
each other to significantly affect alterations in these systems that are specific by drug. For
in neurobiological pathways involved in stress example, changes in heart rate and heart rate
regulation and cognitive and behavioral con- variability (HRV) are reported with regular and
trol (column B). Specific synaptic changes in chronic alcohol use.220–222 Sustained increases
these pathways at molecular and cellular lev- in HPA axis function in the case of psychos-
els118,195 provide the basis for the mechanism timulants, and tolerance to the inactivating ef-
by which stress and individual and genetic fects of the drug in the case of morphine, nico-
factors in column A interact to increase risk tine, and alcohol has also been reported.223–226
of maladaptive behaviors represented in col- These direct effects of drugs of abuse on major
umn C. The model suggests that stress expe- components of the physiological stress response
riences in the presence of these vulnerability support their classification as pharmacological
factors result in maladaptive stress and self- stressors.
control responses that increase addiction risk. Acute withdrawal states are associated with
The specific mechanism by which the mal- increases in CRF levels in CSF, plasma ACTH,
adaptive stress responding increases this risk cortisol, norepinephrine (NE), and epinephrine
involves dysregulation in brain stress circuits, (EPI) levels.38,211,216,227–231 Early abstinence is
particularly the CRF and NE systems, and associated with high basal cortisol responses
their interactions with the mesocorticolimbics- and a blunted or suppressed ACTH and corti-
triatal dopamine pathways and its modulation sol response to pharmacological and psycho-
by glutamate and GABA.114,196,197 Further- logical challenges in alcoholics and chronic
more, recent evidence suggests that stress regu- smokers, while hyper-responsivity of HPA hor-
latory molecules, including neuropeptides such mones in response to metyrapone has been
as neuropeptide (NPY) endocannabinoids, and reported in opiate and cocaine addicts.232–236
neuroactive steroids play a role in addiction Furthermore, withdrawal and abstinence from
vulnerability.198–203 chronic alcohol is also associated with al-
tered sympathetic and parasympathetic re-
sponses,234,237–239 and altered noradrenergic
Drug Use and Abuse and Changes responses to yohimbine challenge in early absti-
in Stress and Reward Pathways nence from cocaine has also been observed.240
All of the above changes highlight the signifi-
Acute and Chronic Drug Use and cant effects of drug use and abuse on physio-
Changes in Stress Responses logical stress responses.
Although acute administration of drugs in-
Acute administration of the most commonly creases mesolimbic dopamine,241 regular and
abused drugs such as alcohol, nicotine, co- chronic use of abusive drugs and acute
caine, amphetamines, and marijuana that ac- withdrawal states down regulate mesolimbic
tivate brain reward pathways (mesocorticolim- dopamine pathways with decreases in basal
bic dopaminergic systems) also activate brain and stimulated dopamine reported in several
114 Annals of the New York Academy of Sciences

preclinical studies.242–251 Chronic use of co- behavioral alterations in stress and dopaminer-
caine has also been shown to dramatically alter gic pathways associated with chronic drug use,
central noradrenergic pathways in the ventral which in turn could affect craving and compul-
and dorsal striatum, other areas of the fore- sive seeking, maintenance of drug use, and re-
brain, and the ventromedial prefrontal cor- lapse risk. It is not entirely clear how long these
tex.252,253 Human brain imaging studies cor- changes persist or the extent to which there is
roborate these preclinical data, with reduced recovery or normalization of these pathways
D2 receptors and dopamine transmission in and responses in related functional responses.
the frontal and ventral striatum regions in
alcoholics and cocaine abusers during acute Altered Stress Responses and Craving
withdrawal and protracted withdrawal (up with Chronic Drug Abuse
to 3–4 months).254–256 Furthermore, blunted
dopamine release in the ventral striatum and Clinical symptoms of irritability, anxiety,
anterior caudate was associated with a prefer- emotional distress, sleep problems, dyspho-
ence to self-administer cocaine over receiving ria, aggressive behaviors, and drug craving
money in human cocaine abusers.257 These are common during early abstinence from al-
changes are similar to the effects of pro- cohol, cocaine, opiates, nicotine, and mari-
longed and repeated stressors on mesolim- juana.30,266–269 A mild “negative affect” and
bic dopamine and norepinephrine deficiency craving state ensues postwithdrawal, associated
noted in the previous section134,187,258 and raise with alterations in the stress and dopamine
the question whether chronic drug effects on pathways.37,197,250,270 The severity of the these
extrahypothalamic CRF, noradrenergic, or glu- symptoms has been associated with treatment
cocorticoid systems may at least partially mod- outcomes, with greater dependence and absti-
ulate these dopamine-related changes in the nence severity predictive of worse treatment
corticostriatal limbic dopamine pathways. outcomes.271–274 Drug craving or “wanting” for
On the other hand, acute, regular, and drug is conceptually different from other anx-
chronic exposure to drugs results in “sensitiza- iety and negative affect symptoms as it comes
tion” or enhanced behavioral and neurochem- from “desire” or a wish for a hedonic stimu-
ical response to drugs and to stress. Synaptic lus. However, with chronic drug use, the term
alterations in the VTA, NAc, and medial PFC becomes associated with a physiological need,
modulated by glutamate effects on dopamine hunger, and strong intent to seek out the de-
neurons and CRF and noradrenergic effects sired object, thereby representative of the more
on DA and non-DA pathways contribute to compulsive aspects of craving and drug seeking
behavioral sensitization of stress and drugs of identified by addicted patients.274–277 In partic-
abuse.210,259–262 In addition, increased levels of ular, craving and compulsive seeking is strongly
brain derived neurotrophic factor (BDNF) in manifested in the context of stress exposure,
the mesolimbic dopamine regions has been as- drug-related cues, and drug itself and can be-
sociated with increases in drug seeking dur- come a potent trigger for relapse.30,274,278–281
ing abstinence from chronic drug use.263,264 Several recent models of addiction have pre-
Furthermore, behavioral sensitization observed sented the concept that this heightened craving
with drugs of abuse and with stress are as- or wanting of drug is the behavioral manifes-
sociated with synaptic changes in mesolimbic tation of molecular and cellular changes in the
dopamine regions, particularly the VTA, NAc, stress and dopamine pathways discussed in the
and amygdala, and such changes contribute to previous section. Indeed some support for this
compulsive drug seeking.118,265 Thus, there are idea comes from laboratory and imaging stud-
significant physiological, neurochemical, and ies summarized below.
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 115

In my laboratory, we have examined the These findings were extended to directly com-
effects of stress and drug-related cues on pare abstinent cocaine-dependent individuals
drug craving in alcoholics, cocaine-dependent to a demographically matched group of healthy
individuals, and naltrexone-treated, opiate- social drinkers, using individually calibrated
dependent individuals in recovery. Drug crav- personally emotional stress and drug/alcohol
ing and stress responses were assessed in cue-related imagery compared to neutral im-
treatment-engaged, abstinent, addicted indi- agery. Findings indicated that cocaine pa-
viduals who were exposed to stressful and tients showed an enhanced sensitivity to emo-
nonstressful drug-cue situations and neu- tional distress and physiological arousal and
tral relaxing situations, using personalized higher levels of drug craving to both stress and
guided imagery procedures as the induction drug-cue exposure compared to controls.291
method.282 Our initial findings indicated that Similarly, we also compared 4-week abstinent
in addicted individuals, stress imagery elicited alcoholics to matched social drinkers. The
multiple emotions of fear, sadness, and anger recovering alcoholics at 4 weeks abstinence
as compared to the stress of public speaking, showed greater levels of basal heart rate and
which elicited increases in fear but no anger or salivary cortisol levels compared to control
sadness. In addition, imagery of personal stres- drinkers. Upon stress and alcohol-cue expo-
sors produced significant increases in cocaine sure, they showed persistently greater subjec-
craving, while public speaking did not.283–285 tive distress, alcohol craving, and blood pres-
Significant increases in heart rate, salivary cor- sure responses, but a suppressed heart rate and
tisol, drug craving, and subjective anxiety were cortisol response compared to controls.239 In-
also observed with imagery exposure to stress terestingly, both cocaine patients and alcoholics
and nonstress drug cues as compared to neutral show increased anxiety and negative emotions
relaxing cues in cocaine-dependent individu- during drug-cue exposure, while social drinkers
als.285 More recently, we have shown that stress report lower levels of negative affect and anxi-
and alcohol/drug-related stimuli similarly in- ety with alcohol-cue exposure. These data pro-
crease craving, anxiety, negative emotions, and vide direct evidence of high drug craving and
physiological responses in abstinent alcoholics altered hedonic responses to both stress and
and in naltrexone-treated, opiate-addicted in- drug cues in addicted individuals compared to
dividuals.286,287 On the other hand, recently social drinkers (see Fig. 2). They also indicate
abstinent alcoholics and smokers show altered that alterations in physiological stress responses
basal HPA responses and a suppressed HPA are associated with high levels of stress-induced
response as measured by cortisol to stress com- and cue-induced craving and distress states.
pared to their nonaddicted counterparts.288–290 The nature of the alterations are marked by
In a more comprehensive assessment of increased emotional distress, heightened crav-
the biological stress response in recently ab- ing, altered basal responses, and blunted or sup-
stinent cocaine-addicted individuals, we re- pressed physiological responses in abstinent ad-
ported that brief exposure to stress and to dicted individuals compared to social drinkers.
drug cues as compared to neutral relaxing Many studies have also examined brain
cues activated the HPA axis (with increases regions associated with craving in ad-
in ACTH, cortisol, and prolactin levels) as dicted individuals. Exposure to drug cues
well as the sympthoadrenomedullary systems, known to increase craving increases ac-
as measured by plasma norepinephrine and tivity in the amygdala and regions of
epinephrine levels.282 Furthermore, we found the frontal cortex,292–294 with gender differ-
little evidence of recovery or return to base- ences in amygdala activity and frontal cor-
line in ACTH, NE, and EPI levels even more tex response in cocaine-dependent individu-
than 1 h after the 5-min imagery exposure. als.295,296 Cue-induced craving for nicotine,
116 Annals of the New York Academy of Sciences

healthy controls during stress, while cocaine

patients showed a striking absence of such acti-
vation.298 In contrast, cocaine patients had in-
creased activity in the caudate and dorsal stria-
tum region during stress that was significantly
associated with stress-induced cocaine craving
ratings.
Recent PET studies have also shown signif-
icant positive correlations between the dorsal
striatum and drug cue–induced cocaine crav-
ing.299,300 These findings are consistent with
imaging studies with alcoholic patients show-
ing increased association between dorsal stria-
tum regions and alcohol craving in response
to presentation of alcohol-related stimuli.301,302
Using PET imaging with alcoholics and co-
caine patients, research has shown a signifi-
cant association between dopamine D2 recep-
tor binding in the VS and drug craving as well
as motivation for self-administration.124,303,304
On the other hand, neuropsychological and
imaging studies examining prefrontal executive
functions, including impulse control, decision
making, and set shifting, have shown executive
function deficits and hypofrontal responses in
Figure 2. Mean and standard errors for peak
craving and anxiety ratings during exposure to stress, addicted individuals compared to control vol-
drug cues, and neutral imagery conditions. (A) Peak unteers.305–312 Together, these findings indicate
craving is significantly higher in abstinent alcoholics that increased stress and cue-induced craving
and cocaine patients compared to social drinkers and compulsive drug-seeking states in addicted
(P < 0.0001). (B) Peak anxiety ratings are signifi- individuals are associated with greater activity
cantly higher in abstinent alcoholics and cocaine pa-
tients compared to social drinkers (P < 0.001). (De-
in the striatum, but decreased activity in specific
tailed statistics provided in Fox et al.291 and Sinha regions of the cingulate and prefrontal cortex
et al.239 ) and related regions involved in controlling im-
pulses and emotions.
methamphetamine, or opiates also activates re-
gions of the prefrontal cortex, amygdala, hip- Stress-Induced Reinstatement of Drug
pocampus, insula, and VTA (see Ref. 297). As Seeking and Relapse
stress also increases drug craving, we examined
brain activation during stress and neutral im- While several efficacious behavioral and
agery in a functional magnetic resonance imag- pharmacological therapies in the treatment of
ing (fMRI) study. Although healthy controls and addiction exist, it is well known that relapse
cocaine-dependent individuals showed simi- rates in addiction remain high.30,313,314 Expo-
lar levels of distress and pulse changes dur- sure to stress, drug-related stimuli, and drugs
ing stress exposure, brain response to emo- themselves each reinstate drug-seeking behav-
tional stress in paralimbic regions such as ior in animals and increase relapse susceptibil-
the anterior cingulate cortex, hippocampus, ity in addicted individuals.274,315–317 Such data
and parahippocampal regions was greater in underscore the need for specific attention to
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 117

the chronic relapse susceptibility as a target in ing and in stress and drug cue–induced HPA re-
addiction treatment development. sponses. These data suggest that at least in the
In the last decade, a substantial number case of cocaine dependence, stress and drug
of preclinical studies have shown that brain cue–induced distress states produce a similar
CRF, noradrenergic, and glutamatergic path- compulsive drug-seeking state that is associ-
ways contribute to reinstatement of drug seek- ated with relapse vulnerability. In alcoholics,
ing.86,316–320 Neuroadaptations associated with negative mood, stress-induced alcohol craving,
chronic drug use include overactive brain and blunted stress and cue-induced cortisol
CRF and glutamatergic pathways, altered au- responses have been associated with alcohol
tonomic responses, and underactive dopamine relapse outcomes.236,326–329 Nicotine-deprived
and GABA systems, and these changes may smokers who were exposed to a series of stres-
accompany the high craving states and relapse sors showed blunted ACTH, cortisol, and blood
susceptibility associated with the chronic nature pressure responses to stress but increased nico-
of addiction.118,196,197,274,313,321 Furthermore, tine withdrawal and craving scores, and these
using animal models of drug self-administration responses were predictive of nicotine relapse
and relapse, preclinical studies have identified outcomes.289 Thus, for alcoholic and smoking
CRF antagonists, alpha-2-adrenergic agonists, samples, as in the cocaine group, it appears
and more recently, glutamatergic agents as im- that the drug-craving state marked by increas-
portant in reducing stress-induced seeking in ing distress and compulsive motivation for drug
addicted laboratory animals (see316,317,322–324 ). (craving) along with poor stress regulatory re-
These data are consistent with human find- sponses (altered glucocorticoid feedback or in-
ings reviewed in the previous section indicat- creased noradrenergic arousal) results in an en-
ing that alterations in stress and dopaminergic hanced susceptibility to addiction relapse.
pathways accompany high distress and crav- Findings from basic science and human lab-
ing states and blunted physiological and neural oratory and clinical outcome studies identify
responses that are important in regulation of several pharmacological treatment targets to
stress, craving, and impulse control. address stress-induced reinstatement of drug
Human research has also begun to iden- seeking and relapse susceptibility. Basic science
tify markers of the stress and craving states data suggest CRF antagonists, alpha-2 adren-
that are predictive of relapse outcomes. To ergic agonists, and glutamatergic agents could
fully understand whether the increased distress be promising in addressing stress-related re-
and drug-craving state is predictive of relapse, lapse. Human laboratory studies are needed
we followed the inpatient treatment-engaged that will screen these agents to assess their
cocaine- and alcohol-dependent individuals in promise with regard to intermediate markers of
our studies described in previous sections after stress-related relapse susceptibility. Such studies
discharge from inpatient treatment for 90 days would target stress- and cue-induced drug crav-
to assess relapse outcomes. For the cocaine ing, craving-related anxiety, HPA measures,
group, we found that stress-induced cocaine and heart rate or heart rate variability as well
craving in the laboratory significantly predicted as responses in specific brain regions.297 For
time to cocaine relapse. While stress-induced example, in a preliminary laboratory and clin-
ACTH and cortisol responses were not asso- ical outcomes study, we have shown that lofex-
ciated with time to relapse, these responses idine, an alpha-2 adrenergic agonist, signifi-
were predictive of amounts of cocaine con- cantly decreased stress-induced opiate craving
sumed during follow-up.325 While drug cue– and stress-induced anger ratings, while also im-
induced craving was not predictive of relapse proving opiate relapse outcomes in naltrexone-
in this study, there was a high correlation be- treated, opiate-dependent individuals.330 Simi-
tween stress and drug cue–induced drug crav- larly, behavioral strategies that decrease anxiety
118 Annals of the New York Academy of Sciences

and stress-related drug craving and normalize ciation with drug use is also needed. Figure 1
stress responses so as to potentiate adaptive re- presents a schematic model of associations that
sponding in high-challenge contexts would be have been supported in research, as well as re-
of benefit in decreasing the effects of stress on maining gaps.
drug seeking and relapse. For example, mind- A review of evidence indicating the effects
fulness based stress reduction (MBSR) is effica- of drug use and abuse on stress responses and
cious in decreasing relapse to major depression, dopamine transmission is presented, along with
and adaptations of these strategies could be of altered emotional and motivational responses
benefit to address relapse risk in addiction.274 associated with craving and relapse to drug
use. While substance abuse results in changes in
stress and dopaminergic pathways involved in
Summary and Future Directions motivation, self control, and adaptive processes
necessary for survival, evidence for whether
This review focuses on the accumulating ev- such changes enhance drug seeking or craving
idence from preclinical, clinical, and popula- and drug use behaviors is lacking. For exam-
tion studies that highly stressful situations and ple, studies on whether prior exposure to licit
chronic stress increase addiction vulnerability, and illicit drugs modifies the association be-
that is, both risk of developing addiction and tween stress and drug self-administration are
risk of relapse. The types of stressors that in- rare. While there are specific neuroadaptations
crease addiction risk are identified in Table 1. in reward and associated regions, it is also im-
The stressors tend to be highly emotionally, dis- portant to examine which of these changes are
tressing events that are uncontrollable and un- involved in increasing drug intake and support-
predictable for both children and adults. The ive of addictive processes such as progressive
themes range from loss, violence, and aggres- loss of control, persistence of craving, and es-
sion to poor support, interpersonal conflict, calating drug self-administration. As stress also
isolation, and trauma. There is also evidence increases risk of mood and anxiety disorders
for a dose-dependent relationship between ac- that are highly comorbid with addiction, it is
cumulated adversity and addiction risk—the important to examine whether there are spe-
greater the number of stressors an individual cific stress-related factors that contribute to risk
is exposed to, the higher the risk of devel- for mood and anxiety disorders and addiction
oping addiction. Work-related stressors have risk. That is, what are the resiliency factors that
weaker support, but individual-level variables are protective for one set of illness but are vul-
such as trait negative emotionality and poor nerabilities for the other. Exploration of gene–
self-control (possibly similar to poor executive environment interactions could be particularly
function) appear to also contribute uniquely to helpful in answering such questions.
addiction risk. Exposure to such stressors early A review of recent studies on stress-induced
in life and accumulation of stress (chronicity) reinstatement to drug seeking, drug craving,
result in neuroendocrine, physiological, behav- and relapse susceptibility is also provided. Clin-
ioral, and subjective changes that tend to be ical implications include the development of
long lasting and adversely affect development new assessment procedures and markers that
of brain systems involved in learning, motiva- will be useful in identifying those who are at
tion, and stress-related adaptive behaviors. Re- particular risk for stress-related relapse and test-
search that directly addresses stress-related neu- ing of novel pharmacological therapies that tar-
robiological changes and their association with get the link between stress and relapse risk. As
behavioral outcomes is sorely needed. Evidence shown in Figure 2, addicted individuals show
to clarify the contribution of stress to alterations enhanced sensitivity to craving and greater
in mesolimbic dopamine activity and its asso- anxiety in stress- and drug-related situations,
Sinha: Chronic Stress, Drug Use, and Vulnerability to Addiction 119

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Acknowledgments
altered corticotropin-releasing factor activation in
brian: a functionalist view of affective neuroscience.
Preparation of this review was supported
In Handbook of Stress and the Brain. Part 1: The
by grants from the National Institutes of Neurobiology of Stress. Vol. 15. T. Steckler, N.H.
Health, P50-DA165556, R01-AA13892, R01- Kalin & J.M.H.M. Reul, Eds.: 155–177. Elsevier.
DA18219, and U01-RR24925. Amsterdam.
14. Berridge, C.W. 2007. Noradrenergic modulation of
arousal. Brain Res. Rev. 58(1): 1–17.
Conflicts of Interest 15. Phan, K.L. et al. 2005. Neural substrates for vol-
untary suppression of negative affect: A functional
The author declares no conflicts of interest. magnetic resonance imaging study. Biol. Psychiatry
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16. Roberts, A., T. Robbins & L. Weiskrantz. 1998.
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