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Stress-that is, any type of stimulus that challenges the organism's normal internal balance-induces a physiologic response involving a variety of hormones and other signaling molecules that act on, among other organs, the brain. This stress response also can influence the progression of alcohol and other drug (AOD) addiction through various stages. For example, AODs can directly activate the stress response. In turn, certain stress hormones (i.e., glucocorticoids and corticotrophin-releasing factor) also act on the brain system that mediates the rewarding experiences associated with AOD use (i.e., the mesocorticolimbic dopamine system). Moreover, elevated glucocorticoid levels and stress increase AOD self-administration in certain animal models. During a later stage of the addiction process, in contrast, excessive and/or prolonged stress may impair the reward system, inducing heavier AOD use to maintain the rewarding experience. During the final stage of addiction, when the addicted person experiences withdrawal symptoms if no drug is consumed, chronic AOD use results in gross impairment of the normal stress response and other signaling mechanisms in the brain, resulting in a state of anxiety and internal stress. At this stage, people continue to use AODs mainly to relieve this negative-affect state.
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The Influence of Stress
on the Transition From
Drug Use to Addiction
Gary Wand, M.D.
G
ARY WAND, M.D., is a professor of
medicine and psychiatry at the Johns
Hopkins University School of Medicine,
Baltimore, Maryland.
Stress—that is, any type of stimulus that challenges the organism’s normal internal balance—induces a
physiologic response involving a variety of hormones and other signaling molecules that act on, among
other organs, the brain. This stress response also can influence the progression of alcohol and other
drug (AOD) addiction through various stages. For example, AODs can directly activate the stress
response. In turn, certain stress hormones (i.e., glucocorticoids and corticotrophin-releasing factor) also
act on the brain system that mediates the rewarding experiences associated with AOD use (i.e., the
mesocorticolimbic dopamine system). Moreover, elevated glucocorticoid levels and stress increase
AOD self-administration in certain animal models. During a later stage of the addiction process, in
contrast, excessive and/or prolonged stress may impair the reward system, inducing heavier AOD use to
maintain the rewarding experience. During the final stage of addiction, when the addicted person
experiences withdrawal symptoms if no drug is consumed, chronic AOD use results in gross impairment
of the normal stress response and other signaling mechanisms in the brain, resulting in a state of anxiety
and internal stress. At this stage, people continue to use AODs mainly to relieve this negative-affect
state. K
EY WORDS: Addiction; alcohol and other drug (AOD) dependence; stress; stress as an AOD cause (AODC);
stress response; brain; brain reward pathway; glucocorticoid; dopamine; animal studies; human studies
A
ddiction to alcohol and other
drugs (AODs) is a complex
phenomenon influenced by
genetic and environmental determi-
nants. For example, in both animals
(i.e., rodents and nonhuman primates)
and humans, various forms of stress
play a role in escalating AOD use as
the individual progresses from episodic
exposure to addiction. Studies in spe-
cific rodent models have shown that
stress and certain hormones released in
response to stress (i.e., glucocorticoids
1
)
increase AOD self-administration dur-
ing the earliest stage of addiction devel-
opment (i.e., the acquisition phase).
(The stages of AOD addiction devel-
opment are discussed in more detail in
the section “Theories of Addiction.”)
Once rodents are addicted to AODs,
high levels of glucocorticoids and other
stress-related molecules (i.e., stress pep-
tides) produced by the addicted animal
create an internal form of stress that is
characterized by anxiety-like behaviors
and dysfunction of the brains reward
system. This negative-affect state fur-
ther escalates AOD consumption.
I
n humans, numerous stressors
increase the risk of alcohol use disor-
ders (Richman et al. 1996; Rospenda
et al. 2000; Vasse et al. 1998). In
AOD-dependent people, internal and
external forms of stress increase drug
craving (Sinha et al. 2003) and may
trigger relapse (Sinha et al. 2006).
This article explores how various forms
of stress may contribute to AOD use
as the individual transitions from
occasional AOD use to dependence.
After providing some general infor-
mation on stress and on theories of
addiction, the article summarizes the
findings of animal and human models
examining the detrimental effects of
stress and stress hormones on the
brains reward pathways that mediate
the pleasurable or rewarding effects of
drinking. These effects ultimately
result in a dysfunction of the reward
system and contribute to escalation of
AOD use.
What Is Stress?
Stress generally is defined as any stimulus
that challenges physiological homeosta-
sis—that is, which alters the balance or
equilibrium of the normal physiological
state of the organism. It is important to
realize, however, that the term “stress
is rather nonspecific and should always
be qualified. Although all forms of
stress alter homeostasis, they do not
all do so in the same manner (i.e.,
they have different physiological conse-
quences). D
ifferent kinds of stress can
1
For a definition of this and other technical terms, see
the glossary on pp. 177–179
Vol. 31, No. 2, 2008 119
stimulate different combinations of sig-
naling molecules (i.e., molecules that
aid in cell-to-cell communication, such
as neurohormones), thereby producing
unique effects on physiological pro-
cesses. Accordingly, it is imperative to
specify the type and duration of stress
to which an organism is subjected.
Moreover, reactions to a given type of
stress vary between individuals, and
physiological and behavioral responses
tend to be associated with distinct cop-
ing styles (Øverli et al. 2007).
Like the susceptibility to AOD use
disorders, peoples responses to stress
are regulated by the interaction of
environmental and genetic factors. In
fact, prenatal and early-life stress can
have lifelong effects on the body sys-
tems involved in the stress response,
and these effects may predispose an
individual to certain diseases (Maccari
et al. 2003). This early programming
effect in part is influenced by mecha-
nisms (i.e., epigenetic mechanisms)
that alter heritable traits without
manifesting as changes in the DNA
sequence and which also can aid in the
development of AOD use disorders.
The Stress Response
Mammals respond to the various forms
of stress with a response comprising at
least three components:
The glucocorticoid response medi-
ated through a hormone system
known as the hypothalamic–
pituitary–adrenal (HPA) axis;
Activation of the peptide cortico-
trophin-releasing factor (CRF)
outside the hypothalamus; and
Activation of one branch of the ner-
vous system (i.e., the sympathetic
nervous system) that results in the
release of signaling molecules called
epinephrine (or adrenaline) and
norepinephrine (or noradrenaline).
The glucocorticoid response
mediated by the HPA axis involves,
as the name implies, three distinct
organs (see figure 1):
The hypothalamus, a brain region
located deep within the brain;
The pituitary gland, a small,
hormone-secreting gland located
directly below the hypothalamus;
and
The adrenal glands, hormone-
producing structures located on
top of the kidneys.
When an individual is in a stress-
ful situation, the hypothalamus
releases CRF. This hormone then is
transported to a certain region of the
pituitary gland (i.e., the anterior pitu-
itary), where it interacts with specific
proteins on the surface of the pituitary
cells (i.e., CRH-1 receptors).
2
This
interaction stimulates the anterior
pituitary to produce a molecule called
proopiomelanocortin (POMC), which
then is processed further into smaller,
biologically active peptides, including
β-endorphin and adrenocorticotropic
hormone (ACTH). The ACTH sub-
sequently is carried via the blood to
the adrenal glands, where it induces
secretion of glucocorticoids. The
main glucocorticoid in humans and
other primates is cortisol; the main
glucocorticoid in rodents is called
corticosterone. The glucorticoids are
transported by the blood to the brain,
where they act on numerous signaling
systems and also on the AOD reward
system, as well as to numerous other
organs throughout the body, where
they induce some of the physiological
stress responses (e.g., increases in blood
glucose levels and blood pressure).
The activity of the HPA axis
is regulated by a sensitive negative-
feedback loop. This means that the
glucocorticoids secreted by the adrenal
glands are transported through the
bloodstream back to the pituitary
gland, hypothalamus, and hippocam-
pus, where they interact with specific
receptors to shut off the HPA axis
and thereby limit the stress response.
There are different types of glucocor-
ticoid receptors:
Type I mineralocorticoid receptors
tightly bind to cortisol even at low
cortisol concentrations (i.e., have a
high affinity for cortisol); as a result,
these receptors usually interact with
cortisol at the low levels normally
found in the body, thereby helping
to regulate HPA axis activity in the
normal, resting state.
Type II glucocorticoid receptors
have a lower affinity for cortisol and
only interact with it when cortisol
levels in the blood are elevated dur-
ing stressful situations. Accordingly,
these receptors primarily help regu-
late the stress response.
The interaction of glucocorticoids
with both types of receptors leads to
the activation of certain signaling
molecules in the cells (i.e., transcription
factors) that, in turn, activate certain
genes; however, the two types of recep-
tors activate different sets of genes.
CRF is produced not only in the
hypothalamus but also in other brain
regions, and stress also stimulates the
production of this CRF. This extrahy-
pothalamic CRF has three effects:
First, it stimulates the HPA axis, just
like the CRF produced by the hypotha-
lamus. Second, it activates the sympa-
thetic nervous system, the branch of
the nervous system that is primarily
responsible for regulating many home-
ostatic mechanisms in living organisms.
For example, the sympathetic nervous
system coordinates the neuronal and
hormonal response to stress (the “fight-
or-flight” response). In a stressful situa-
tion, the sympathetic nervous system
causes the release of epinephrine and
norepinephrine from the adrenal
glands. These hormones help prepare
the body for an emergency situation.
For example, both epinephrine and
norepinephrine increase the supply of
oxygen and nutrients to the brain and
muscles (e.g., by increasing heart rate
and widening blood vessels in the
muscle). Moreover, these hormones
suppress nonessential bodily processes
(e.g., digestion). Finally, norepinephrine
also acts on the brain to increase
2
CRF sometimes also is called corticotrophin-releasing
hormone (CRH).
Alcohol Research & Health 120
Hypothalamus
Neurons regulating
CRH release
CRH-producing
neuron
CRH
Cortisol
Cortisol-producing cell
ACTH
POMC-producing cell
Adrenal gland (on kidney)
Pituitary Gland
+
+
+
+
5-HT
NE
GABA
Opioids
Figure 1 The major components of the stress response mediated by the hypothalimic-pituitary-adrenal (HPA) axis. Both alcohol
and stress can induce nerve cells in one brain region (i.e., the hypothalamus) to produce and release corticotropin-
releasing hormone (CRH). Within the hypothalamus, CRH stimulates the release of a hormone that produces mor-
phine-like effects (i.e., β-endorphin). CRH also is transported to a key endocrine gland, the anterior pituitary gland.
There, CRH stimulates production of a protein called proopiomelanocortin (POMC). POMC serves as the basis for a
number of stress-related hormones, including adrenocorticotropic hormone (ACTH), β-lipotropin (β-LPH), and β-endor-
phin. ACTH stimulates cells of the adrenal glands to produce and release the stress hormone cortisol. When cortisol
levels reach a certain level, CRH and ACTH release diminishes. Other neurons releasing serotonin (5-HT), norepin-
ephrine (NE), γ-aminobutyric acid (GABA), or endogenous opioids also regulate CRH release.
NOTE: = excites; = inhibits.
The Influence of Stress on Addiction
Vol. 31, No. 2, 2008 121
attention and promote responding
actions.
Third, increased CRF production
outside the hypothalamus stimulates
a brain system known as the meso-
corticolimbic dopamine system. This
brain pathway includes several inter-
connected brain areas whose activity
involves the signaling molecule (i.e.,
neurotransmitter) dopamine. The
components of this system are the ven-
tral tegmental area (VTA), the nucleus
accumbens, and the constituents of
the limbic system (particularly the hip-
pocampus and amygdala), all of which
are located deep inside the brain, as
well as some areas of the outer layer of
the brain (i.e., the prefrontal cortex)
(see figure 2). (The mesocorticolimbic
system will be described in more detail
later in this article.) The mesocorti-
colimbic dopamine system represents
the brains reward pathway—that is,
it mediates the rewarding effects asso-
ciated with AOD use and other expe-
riences and thereby is a central factor
in the development of addiction. In
addition, the hypothalamus and limbic
system, particularly the hippocampus
and amygdala, are intimately involved
in the stress response (e.g., anxiety and
other stress behaviors) that is initiated
by the stimulation of CRF activity.
VTA
Amygdale
Nucleus
accumbens
Prefrontal
cortex
Figure 2 Location of the components of the mesocorticolimbic dopamine system
and other brain regions affected by the stress response and its interac-
tions with alcohol and other drugs.
Allostasis
Allostasis is the process utilized by mam-
mals to maintain homeostasis through
a variety of physiological or behavioral
changes when the organism is threat-
ened by various forms of stress. It involves
a series of dynamic actions through
which the hormones of the HPA axis,
immune factors (i.e., cytokines), and
signaling molecules used by the auto-
nomic nervous system are triggered
(McEwen 2007). When an organism
is exposed to extended periods of stress,
it is said to be accumulating an allostatic
load. If the stressful situation persists,
the allostatic load increases, resulting
in wear and tear on the organism from
excessive exposure to glucocorticoids,
stress peptides, and inflammation-
promoting (i.e., pr
oinflammatory)
cytokines. For example, chronic activa-
tion of the HPA axis is associated with
the development of mood and anxiety
disorders, such as depression (Gillespi
and Nemeroff 2005). Likewise, excess
cortisol exposure can contribute to
various medical problems, including
obesity, insulin resistance, bone dem-
ineralization, cognitive impairment,
and impaired immunity (Kyrou et al.
2006; Lee et al. 2007).
As described in more detail in the
following section, the concept of
allostasis also is used in addiction
research. In this context, the term
allostatic load” refers to a state of
reward dysregulation—that is, a state
in which the individual’s drug-seeking
behavior is driven by a need to recap-
ture the initial rewarding effects of
the drug (i.e., “chasing the high”).
With increasing allostatic load, envi-
ronmental events or cues that previ-
ously have been associated with drug
use become increasingly important
(i.e., have increased salience) to the
addicted individual.
Theories of Addiction
Many theories of addiction have been
proposed to explain mechanisms
involved in this complicated disorder.
This review focuses on two of these
models—incentive sensitization and
hedonic allostasis—that can be com-
bined to conceptualize the impact that
various forms of stress have on the
development of drug dependence
(Vanderschuren and Everitt 2005).
According to the incentive sensitization
model, in some people the effects of
casual AOD use sensitize the mesocor-
ticolimbic reward system so that the
drug user wants to repeat these reward-
ing effects. This results in an extremely
high motivation to use AODs again.
This model helps explain how initial
experimentation with AODs by an
occasional user can escalate to repeated
drug administration. The motivational
force at this stage is primarily hedonic
pleasure. With chronic AOD use, how-
Alcohol Research & Health 122
The Influence of Stress on Addiction
ever, the motivation for drug seeking
can change as a result of hedonic allosta-
sis. According to the hedonic allostasis
model, chronic AOD exposure results
in reduced activity (i.e., downregula-
tion) of positive reward circuits, which
generates a chronic stress situation. As
a result, the body produces stress fac-
tors that create a negative emotional
state (i.e., negative affect) characterized
by withdrawal symptoms, sadness (i.e.,
dysphoria), and anxiety. This negative
affect then becomes the dominant
force driving drug craving. Thus, the
individual no longer seeks to use AODs
to achieve a pleasurable experience but
to avoid a negative-affect state. Various
forms of stress can impact this transi-
tion from incentive sensitization to
hedonic allostasis.
Koob and Le Moal (1997) have
proposed that drug addiction pro-
gresses through three stages:
The preoccupation/anticipation
stage, which is characterized by exag-
gerated motivation for drug use
associated with a sensitized mesocor-
ticolimbic dopamine system. This
phase is modeled by the incentive
sensitization theory. In animal mod-
els used to study the development of
AOD dependence, this stage is
referred to as the acquisition phase.
The binge/intoxication stage, dur-
ing which a downregulation of posi-
tive reward pathways occurs—that
is, the drug levels needed to trigger
the brain reward system increase
(Koob and Kreek 2007). This corre-
sponds to the maintenance phase in
animal models.
The withdrawal/negative-affect
stage, during which the drug user
transitions to drug addiction. During
this stage, negative affect becomes
dominant, further escalating craving
and use of the addictive drug. The
analogous state in animal models
can be created by experimental
designs in which the drug is with-
held from the animals (i.e., using
drug deprivation protocols).
There is a harmful interaction
between AODs and the stress response
that influences the transition through
these three stages of addiction. AODs
can “hijack” the stress and reward sys-
tems in three ways. First, AODs
directly activate the stress response,
and the glucocorticoids released dur-
ing this process can, at least initially,
sensitize the reward pathways, leading
to further AOD use. This may con-
tribute to reward sensitization during
the preoccupation stage. Second, as
the AOD user transitions to addic-
tion, negative affect and withdrawal
symptoms become a dominant force
that also stimulates the release of anx-
iety-inducing (i.e., anxiogenic) stress
peptides such as CRF. At this stage, AOD
use escalates as the addict administers
the AODs more for stress-dampening
purposes than for pleasure. Third,
environmental stress (which often is
caused or exacerbated by the chaotic
lifestyle and negative consequences of
AOD abuse) interacts with the nega-
tive-affect state created by withdrawal
or abstinence to amplify the anxiety
and dysphoria induced by the stress
peptides. At each of these steps, allo-
static mechanisms are initiated by the
organism to try and maintain home-
ostasis in the presence of the AODs
and the resulting stress.
The following sections review the
evidence supporting the relationship
between various forms of stress and
AOD use disorders as it fits into this
model of allostatic transition from
reward sensitization to negative-affect
development (Koob and Kreek 2007).
Where appropriate, these processes
will be discussed in the context of
the proposed three stages of addiction
(Koob and Le Moal 1997). The dis-
cussion primarily focuses on alcohol
and cocaine, whose relationship with
stress has been studied best.
Stage One: AOD Use Based
on Positive Reward
The Mesocorticolimbic Dopamine
System and Reward Pathways
As mentioned earlier, the mesocortico-
limbic dopamine system functions as
a reward and reinforcement pathway,
providing salience to internal and exter-
nal stimuli (Berridge 2007). In other
words, this system governs our atten-
tion and intentions related to a particular
stimulus, and its integrity is crucial for
maintaining a healthy response to stimuli.
The central components of the
mesocorticolimbic dopamine system
are nerve cells (i.e., neurons) whose
cell bodies are located in a region
called the ventral tegmental area
(VTA) (see figure 2). From these cell
bodies, long extensions (i.e., axons)
reach out to various other brain
regions, most prominently the nucle-
us accumbens (NAc), which is locat-
ed in a brain region called the ventral
striatum and is part of the limbic sys-
tem, and the prefrontal cortex. The
NAc is thought to assign importance
(i.e., salience) to the drug experience.
In the NAc and prefrontal cortex, the
VTA neurons release the neurotrans-
mitter dopamine from the ends of
their axons into the space separating
the axon from the neighboring cell
(i.e., into the synapse). The released
dopamine then interacts with specific
receptors on the neighboring neurons
in those brain regions, thereby alter-
ing their activity in a specific manner.
Cells of the mesocorticolimbic
dopamine system have several proper-
ties that allow them to mediate the
rewarding experience associated with
AOD use and other events. For
example, the dopaminergic neurons
can transmit signals either by emit-
ting short bursts of several signals,
which is known as phasic firing, or
by emitting low signals over longer
periods of time, which is known as
tonic firing (Grace 2000). The partic-
ular patterns of tonic and phasic fir-
ing may determine the salience of the
reward signal (Grace 2000). Another
characteristic property of the meso-
corticolimbic dopamine system is its
ability to generate signals that repre-
sent the relationship between the
rewarding experience a drinker has
come to expect after consuming a
certain amount of alcohol (i.e., the
predicted reward) and the actual
reward associated with a particular
experience (Schultz et al. 1997)—
Vol. 31, No. 2, 2008 123
a reward that is greater than predicted
results in increased firing of the
dopamine-releasing (i.e., dopaminer-
gic) neurons and, conversely, a reward
that is less than predicted results in
decreased firing of these neurons.
Rewards that are as predicted do not
alter firing rates. Some researchers
have proposed that during the transi-
tion from recreational AOD use to
addiction, the reward signal associated
with drug use shifts from “better than
predicted” to “worse than predicted”
(Schultz et al. 1997).
AODs have both positive and neg-
ative reinforcing properties. During
the first stage of the progression from
AOD use to addiction, the positive
reinforcing properties, which are
linked to the hedonic aspects of drug
intoxication, prevail. Considerable
evidence shows that these positive
reinforcing effects are mediated by
signal transduction systems that stim-
ulate the mesocorticolimbic dopamine
neurons. Thus, casual use of alcohol,
psychostimulants, and opioids increases
dopamine accumulation in the synaps-
es within the NAc and other affected
regions and thereby provides salience
to their signal (Spanagel and Heilig
2005).
Animal Studies on Stress,
Glucocorticoids, and Meso-
corticolimbic System Function
As mentioned earlier, the ultimate
result of the bodys stress response via
the HPA axis is the release of glucocor-
ticoids from the adrenal glands.
Therefore, to investigate if and how
stress can influence the perceived
effects of AODs, one approach is to
study, in laboratory animals, how glu-
cocorticoids alter mesocorticolimbic
signaling and thereby modulate (e.g.,
amplify) the positive reinforcing effects
of AODs. For example, researchers
lowered animals’ glucocorticoid con-
centrations in the blood by removing
the animals’ adrenal glands (i.e., per-
forming an adrenalectomy). This
manipulation led to reduced dopamine
levels in the NAc, both when the VTA
neurons were in a resting state and
when they were stimulated (Barrot et
al. 2000; Piazza et al. 1996) (see figure
3). When the animals were injected
with corticosterone to replace adrenal
glucocorticoid production, normal
dopamine levels were restored. Additional
analyses demonstrated that the effects
of adrenalectomy on dopamine levels
were limited only to certain regions of
the NAc (i.e., the shell of the NAc)
(Barrot et al. 2000). Furthermore, cor-
ticosterones effects on dopamine con-
centrations in the shell of the NAc
involve activation of the glucocorticoid
(type II) receptors, which only are acti-
vated at higher corticosterone concen-
trations but not the mineralocorticoid
(type I) receptors, which also are acti-
vated at lower corticosterone concen-
trations (Marinelli and Piazza 2002).
Many studies have demonstrated
that not only glucocorticoid manipu-
lation but also stress will increase
dopamine levels in the NAc. For
example, using microdialysis techniques,
investigators have shown that diverse
experiments involving different types
of stress can increase mesocorticolim-
bic dopamine activity (Marinelli and
Piazza 2002). Other studies, however,
do not support these findings (Imperato
et al. 1989, 1991; Reid et al. 1998).
Additionally, one study (Pacak et al.
2002) showed that chronic exposure
to elevated corticosterone levels inhibits
dopamine synthesis and turnover,
suggesting that the effects of gluco-
cortiocoids on the mesocorticolimbic
dopamine system depend on the
duration of glucocorticoid exposure.
Thus, short-term exposure to gluco-
corticoids increases dopamine levels,
whereas chronic exposure results in
decreased dopamine levels.
3
Interest-
ingly, elevated glucocorticoid levels
resulting from exposure to stressors
or injections of corticosterone also
can sensitize animals to the behav-
ioral and neurochemical responses
(e.g., dopamine release in the NAc)
to cocaine (Prasad et al. 1998; Rouge-
Pont et al. 1995). Conversely, these
effects are attenuated in rats that no
longer produce corticosterone (Prasad
et al. 1998; Przegalinski et al. 2000;
Rouge-Pont et al. 1995). Thus, it
appears that glucocorticoid concen-
trations in the normal range are nec-
essary for optimal transmission of
dopamine-mediated signals in the
mesocorticolimbic system.
Another important region of the
mesocorticolimbic system is the VTA,
where the bodies of the dopaminergic
axons ending in the NAc originate.
To trigger dopamine release by these
neurons in the NAc, nerve signals
emitted by other neurons must acti-
vate (i.e., excite) the bodies of the
dopaminergic neurons in the VTA.
Various drugs (e.g., cocaine, ampheta-
mine, morphine, nicotine, and alco-
hol) as well as CRF administration
increase excitatory synaptic strength
in the VTA (Kauer 2003) (see figure
3). This means that after a drug or
CRF is administered, neurons that
act on the cell bodies of the dopamin-
ergic neurons in the VTA send out
more and/or stronger signals, thereby
leading to increased excitement of the
dopaminergic neurons. In addition,
the dopaminergic neurons in the VTA
can be activated by corticosterone
(e.g., after exposure to a stressful situ-
ation). For this activation to occur,
other neurons must emit a signal by
releasing the neurotransmitter gluta-
mate, which then can interact with
receptors on the dopaminergic cells
(Overton et al. 1996). Administration
of an agent that inhibits these recep-
tors (i.e., the
N-methyl-
D-aspartic
acid [NMDA] receptor antagonist
MK-801) blocks stress-induced changes
in glutamate-mediated signal trans-
mission (Morrow et al. 1993). More-
over, administration of a glucocorticoid
receptor antagonist before stress also
prevents the synaptic changes. Finally,
when laboratory animals were exposed
to a stressful situation, the resulting
stress activated CRF in the VTA and
thereby stimulated glutamate-mediated
signal transmission to dopaminergic
neurons (Wang et al. 2005). Taken
together, these findings suggest that
CRF and glucocorticoids released
during stress are responsible for
enhancing glutamate-mediated signal-
ing, ultimately resulting in increased
dopamine release in the NAc.
3
This is called a biphasic effect.
Alcohol Research & Health 124
The Influence of Stress on Addiction
In summary, stress and stress-induced
glucocorticoids appear to influence the
mesocorticolimbic dopamine system
through two separate actions: First,
they lead to the activation of the cell
bodies of the dopaminergic neurons in
the VTA, primarily through stimula-
tion of glutamate-mediated signaling.
This indirectly leads to increased
dopamine release in the NAc. Second,
they directly impact the axons of the
dopaminergic neurons in the NAc,
thereby further enhancing dopamine
release in that brain region.
Dopaminergic neurons
in the VTA
Activation of neurons
in the NAc
Rewarding, reinforcing
experience
Dopamine
release in
the NAc
+
Adrenalectomy
Short-term
stress and
exposure to
glucocorticoids
Chronic stress
and exposure to
glucocorticoids
+
++
CRF
++
++
++
Alcohol
Cocaine
Amphetamine
Morphine
Nicotine
Glutamate-
releasing
neurons
Figure 3 Regulation of the mesocorticolimbic dopamine system. Cell bodies of dopamine-releasing (i.e., dopaminergic) neurons
located in the ventral tegmental area (VTA) are activated by glutamate-releasing neurons. This activation leads to the
release of dopamine in the nucleus accumbens (NAc), resulting in the activation of other neurons whose cell bodies
are located in the NAc and in the generation of rewarding and reinforcing experiences. Alcohol and other drugs
(AODs), corticotrophin-releasing factor (CRF), and stress and stress-induced hormones (i.e., glucocorticoids) all can
influence this chain of events by acting on the glutamate-releasing neurons, dopaminergic neurons in the VTA, or
dopamine release in the NAc.
Vol. 31, No. 2, 2008 125
Animal Studies on the Effects of
Glucocorticoids and Stress on AOD
Self-Administration
Psychostimulants. Animal studies
demonstrated that the acquisition stage—
the first time that an animal comes
into contact with a drug and its
rewarding properties—is modulated by
glucocorticoids. For example, when
investigators reduced glucocorticoid
levels in the blood through both sur-
gical and pharmacologic manipula-
tion, the animals stopped cocaine
self-administration during acquisition
(Goeders 2002). This reduction in
self-administration could be reversed
in a dose-dependent manner by
administering different amounts of
external corticosterone.
Acquisition also is a time when the
mesocorticolimbic system can be sen-
sitized. The contribution of corticos-
teroids to this sensitization has been
demonstrated in several ways. For
example, during the acquisition stage,
cocaine self-administration activates
the HPA axis, leading to increased
corticosterone levels in the blood in
rodents (Goeders 2002). Other studies
demonstrated that repeated adminis-
tration of glucocorticoids at doses
typically found during stressful situa-
tions increases drug self-administration
(Goeders 2002). Moreover, glucocor-
ticoid administration can facilitate the
psychomotor stimulant effects of cocaine
(Marinelli et al. 1994), amphetamine
(Cador et al. 1993), and morphine
(Marinelli et al. 1994).
Another strategy to investigate how
increased glucocorticoid levels affect
AOD self-administration is to expose
the animals to stressful situations that
activate the HPA axis. Multiple studies
have shown that various experimental
procedures to induce different types
of both short-term (i.e., acute) and
long-term (i.e., chronic) stress increase
psychostimulant or opiate self-admin-
istration in rats (Marinelli and Piazza
2002). Exposure to electric footshock
also increases the subsequent reinforc-
ing effects of heroin in rats (Shaham
and Stewart 1994).
In another series of studies, researchers
further explored the role of glucocor-
ticoids in cocaine self-administration
during the acquisition, maintenance,
and reinstatement periods in order
to better understand the conditions
required for glucocorticoids and stress
to increase cocaine self-administration
(Goeders 2003). During the acquisi-
tion phase, rats exposed to stressors
(e.g., electric shocks) they could not
control exhibited increased rates of
low-dose (but not high-dose) cocaine
self-administration compared with
rats exposed to no stressors or to
stressors they could control through
their behavior. Moreover, self-admin-
istration did not occur unless corti-
costerone levels in the blood were
increased above a specific threshold,
and greater stress-induced increases in
corticosterone levels were associated
with greater increases in self-adminis-
tration (Goeders 2002). The same
effects could be achieved if corticos-
terone levels were increased directly
by administering the hormone rather
than indirectly by exposing the ani-
mals to a stressor. Importantly, this
effect occurred only during the acqui-
sition phase, not during the mainte-
nance phase or during cue-induced
reinstatement of cocaine self-adminis-
tration. These findings were confirmed
by other investigators who demon-
strated that blood corticosterone levels
predicted how much cocaine the ani-
mals would self-administer (Koob and
Kreek 2007; Mantsch et al. 2001) and
that this relationship was only observed
at low doses of cocaine (Mantsch et al.
2000). Together, these findings indicate
that individual differences in stress-
related cocaine self-administration are
relevant only with low doses of cocaine
and only during the acquisition period.
As mentioned earlier, corticosterone
binds to both mineralocorticoid
receptors (which bind to corticos-
terone at normal, low concentrations)
and glucocorticoid receptors (which
bind to corticosterone only at high,
stress-induced concentrations). The
relationship between stress and cocaine
self-administration appears to involve
only the glucocorticoid receptors. For
example, administration of an agent
that specifically inactivates the gluco-
corticoid receptor (i.e., the glucocor-
ticoid receptor antagonist RU486)
reduces cocaine self-administration in
rats (Deroche-Gamonet et al. 2003).
Moreover, when the investigators
used genetic engineering techniques
to create mice that produced no glu-
cocorticoid receptors, these animals
self-administered less cocaine than
did normal mice (Deroche-Gamonet
et al. 2003). Sensitization to cocaines
psychomotor effects also was sup-
pressed in the modified animals. This
observation was confirmed by other
researchers using a different set of
genetically modified animals in whom
the activity of the genes encoding the
glucocorticoid receptor (i.e., the levels
of glucocorticoid receptor mRNA)
was reduced by 50 percent (St. Hilaire
et al. 2003). Other studies, in con-
trast, found that reduction of gluco-
corticoid receptor mRNA actually
stimulated the mesocorticolimbic
dopamine system (Cyr et al. 2001;
Steckler and Holsboer 2001). Never-
theless, the prevailing evidence sug-
gests that stress modulates low-dose
cocaine self-administration through
actions at the glucocorticoid receptor.
Alcohol. In rodents, acute alcohol
administration, like psychostimulant
administration, activates the HPA axis
by inducing CRF release from the
hypothalamus (Lee et al. 2004). How-
ever, the effects of glucocorticoids and
stress during the acquisition phase of
alcohol exposure have not been studied
as systematically as during the acquisi-
tion phase for psychostimulants.
Moreover, studies designed to examine
the effects of various forms of stress on
alcohol consumption in nondependent
rodents have produced less consistent
results than models using alcohol
deprivation of dependent animals (see
below), with nondependent animals
showing highly variable stress-induced
increases in alcohol consumption.
Finally, it appears that in rodents,
the effect of stress on voluntary alco-
hol consumption is influenced both
by the type of stress and by the genetic
background of the animal. For
example, stress caused by electric
shocks increased alcohol consumption
in several different lines and strains of
non–alcohol-dependent rodents (i.e.,
unselected Wistar rats, alcohol-prefer-
ring [P] rats, high-alcohol–drinking
[HAD] rats, and Alko alcohol [AA]
rats) (Vengeliene et al. 2003).
Another type of stress (i.e., swim
stress), however, increased alcohol
consumption only in the unselected
Wistar rats, not in other strains or
lines. Similar differences in the
response to stressful situations were
observed in different strains of mice.
Finally, chronic, unpredictable
restraint stress actually reduced vol-
untary alcohol drinking during the
application of stress in P rats and
HAD1 rats (Chester et al. 2004).
4
4
These differences are not related to the duration of the
stressful situations (i.e., whether acute, repeated, or
chronic stress was studied).
Alcohol Research & Health 126
The Influence of Stress on Addiction
The Relationship of Stress,
Glucocorticoids, and AOD Use
in Humans
Effects of Acute Alcohol and Cocaine
on the HPA Axis and
Mesocorticolimbic Dopamine. Like
various forms of stress, alcohol and
psychostimulant consumption can lead
to increased glucocorticoid levels in
humans. Alcohol drinking in humans
stimulates the HPA axis as it does in
rodents. However, the response is not
clearly dose dependent and most likely
is observed when blood alcohol con-
centrations are greater than 0.1 percent
(Wand 1993). Psychostimulants such
as intravenous, intranasal, and smoked
cocaine also activate the HPA axis,
increasing the secretion of cortisol
(Mello and Mendelson 1997).
If the findings obtained in rodents
also reflect the conditions in humans,
then increased glucocorticoid levels
associated with initial stress and/or
alcohol or psychostimulant use may
also sensitize mesocorticolimbic reward
pathways in humans. This also would
mean that changes in glucocorticoid
levels can alter the rewarding experi-
ences associated with AOD use dur-
ing the early stage of use. The next
section reviews the evidence that a
relationship between cortisol, meso-
corticolimbic dopamine, and positive
subjective feelings about or responses
to the drug (i.e., drug liking) exists in
social (i.e., nonaddicted) drinkers.
Relationship Between Cortisol,
Mesocorticolimbic Dopamine,
and Drug Liking
Imaging methods that can show
receptor activity in the brain, such as
positron emission tomography (PET)
imaging, allow researchers to translate
observations originally made in rodent
models to humans and to study the
effect of AODs on mesocorticolimbic
dopaminergic activity. For example,
PET imaging studies on the effects of
alcohol, amphetamine, methylphenidate,
and cocaine found that mesocortico-
limbic dopamine responses are corre-
lated with positive subjective effects
of the drug that originally triggered
dopamine release (Boileau et al. 2003;
Oswald et al. 2005; Volkow et al. 1999).
These and other studies corroborate
the results of animal studies demon-
strating that AODs activate mesocorti-
colimbic dopamine.
Researchers also have used PET
technology to study the relationship
among stress hormones, mesocorti-
colimbic dopamine activity, and drug
liking. For example, Pruessner and
colleagues (2004) showed that in
people who reported receiving insuf-
ficient maternal care during their
early lives, dopamine release in the
ventral striatum, which also contains
the NAc, was increased in response to
a psychosocial stressor—an effect that
could increase drug liking. In another
series of studies, researchers examined
the relationship among cortisol,
dopamine responses to amphetamine,
and drug liking in a group of healthy
college-age students without a history
of alcohol use disorders, drug use, or
psychiatric illness. The first of these
studies (Oswald et al. 2005) demon-
strated that amphetamine-induced
dopamine release
5
correlated with
amphetamine-induced cortisol secre-
tion as well as with positive subjective
drug responses, such as drug “liking,”
desire,” “good effect,” “high,” and
rush.” The study did not determine,
however, whether cortisol responses
to a psychological stressor also would
be associated with dopamine responses
to amphetamine administrated dur-
ing a separate session. In a second
study, the same group of investigators
extended these findings by stimulat-
ing cortisol secretion through psycho-
logical mechanisms (Wand et al. 2007).
The researchers employed a test called
the Trier Social Stress Test (TSST)—
a well-validated procedure that has
been widely used to evoke the stress
response in human laboratory experi-
ments—to examine whether cortisol
responses to psychological stress were
5
Dopamine release was defined as amphetamine-
induced changes in the ability of the dopamine antagonist
raclopride to bind to dopamine receptors. If high levels of
dopamine are released, all receptors are occupied by the
dopamine and raclopride cannot bind. If dopamine
release declines, however, more receptors become unoc-
cupied and the ability of raclopride to bind to these recep-
tors increases.
associated with enhanced dopamine
release and/or subjective responses to
amphetamine. The study yielded sev-
eral important observations:
Both baseline and stress-induced
cortisol levels were positively
correlated with dopamine release
throughout the ventral striatum,
which contains the NAc.
Cortisol levels were measured for up
to 1 month before or after the PET
procedures, and the results suggest
that the observed relationships
between cortisol and dopamine
release are not based solely on short-
term mechanisms.
Stress-induced cortisol levels
were positively associated with
the subjective pleasant effects of
amphetamine.
These results suggest that in
healthy, young adults without signifi-
cant prior exposure to AODs, those
who secrete high levels of cortisol also
release high levels of dopamine and
experience greater subjective effects
from psychostimulants than those
who release only low levels of cortisol
and dopamine. The fact that both
baseline and stress-induced cortisol
levels correlated with dopamine
release suggests that ambient cortisol
concentrations over time may influ-
ence or sensitize mesocorticolimbic
dopaminergic signal transmission.
Altered HPA Axis Dynamics
Predates Alcohol Use Disorders
The contention that high and low cor-
tisol states produce clinically meaning-
ful alterations in positive reinforcement
of AODs could be supported if altered
cortisol dynamics—that is, alterations
in the extent and rate at which cortisol
levels change after exposure to a stres-
sor—already were found in people who
are at increased risk for AOD use dis-
orders (e.g., children of AOD abusers)
but have not yet developed these disor-
ders. If aberrant cortisol dynamics pre-
dated the development of alcohol
dependence and were determined by
Vol. 31, No. 2, 2008 127
genetic factors, it should be possible to
detect abnormal cortisol responses in
the offspring of AOD abusers. Several
studies have compared people at
increased risk for alcohol use disorders
(e.g., children of alcoholics) with peo-
ple at low risk for these disorders with
respect to various characteristics. Using
this approach, Schuckit and Smith
(1996) found that HPA axis responses
study participants exhibited when they
were exposed to alcohol predicted future
development of alcoholism. Other inves-
tigators stimulated the HPA axis using
different approaches (King et al. 2002;
Oswald and Wand 2004; Waltman et al.
1994) and found a correlation between
HPA axis dynamics and risk for alco-
holism.
6
More recently, several studies
(Uhart et al. 2006; Zimmermann et al.
2004) demonstrated that when the HPA
axis was activated by psychological stres-
sors, people at high risk for alcoholism
showed greater cortisol responses than
people at low risk.
These findings are not unequivocal,
however, because a similar study
(Sorocco et al. 2006) of young adult
offspring of AOD abusers showed
reduced cortisol responses to mental
stress. Similarly, an earlier study
(Moss et al. 1999) found that cortisol
levels measured in the saliva after
anticipation stress were lower in high-
risk adolescent boys than in control
subjects. Indeed, a blunted cortisol
response indicates a lack of resilience
to stress and may be a form of desen-
sitization resulting from the influence
of genes and/or chronic stress on the
HPA axis. Moreover, blunted cortisol
responses to an acute stressor can sig-
nify symptoms of neuroticism and
introversion (Oswald et al. 2006)—
states in which daily cortisol produc-
tion can be elevated (Mangold and
Wand 2006). Therefore, people with
both high and low cortisol responses
6
Waltman and colleagues (1994) used CRF administra-
tion to stimulate the HPA axis. Oswald and Wand (2004)
and King and colleagues (2002) used opioid receptor
antagonists to stimulate the HPA axis. Opioids are brain-
signaling molecules that modulate nerve signal transmis-
sion, thereby affecting numerous processes in the brain.
Among others, opioid-mediated nerve signals inhibit CRF-
releasing neurons, thereby preventing CRF from acting
on the HPA axis. Opioid receptor antagonists will block
this inhibition and thus activate the HPA axis.
to acute stress may produce more
cortisol per day than people with
normal cortisol responses to stress.
Stage Two: The End of
Drug Salience
As described earlier, a reward after drug
use that is “greater than predicted
results in increased firing of mesocorti-
colimbic dopaminergic neurons,
whereas a reward that is “less than pre-
dicted” results in decreased firing of
these neurons (Schultz et al. 1997).
During casual use, alcohol and psycho-
stimulants stimulate mesocorticolimbic
dopamine activity, thereby enhancing
drug reward. During the transition from
casual use to drug dependence, however,
there may be a parallel transition in the
reward signal from “better than pre-
dicted” to “worse than predicted
(Schultz et al. 1997). As described in
this section, glucocorticoids and stress
may be involved in this process.
Multiple animal studies have
shown that, whereas acute adminis-
tration of alcohol and psychostimu-
lants increases mesocorticolimbic
dopamine (Di Chiara et al. 2004),
repeated drug administration fol-
lowed by abstinence can lower the
baseline and stimulated dopamine
signal (e.g., Mateo et al. 2005; Zhang
et al. 2003).
7
Additional studies found
that the brain reward threshold increases
during the transition from the acqui-
sition to the maintenance stage and
that this increase correlates with the
waning dopamine signal (Koob and
Kreek 2007). However, reduced levels
of mesocorticolimbic dopamine can
be induced not only by repeated drug
administration but also by adminis-
tration of high levels of glucocorti-
coids (Pacak et al. 2002). This obser-
vation suggests a biphasic effect of
glucocorticoids on mesocorticolimbic
dopamine accumulation, with low
levels of glucocorticoids increasing
and high levels of glucocorticoids
7
Several PET analyses identified an analogous situation
in humans, because the mesocorticolimbic dopamine sys-
tem was downregulated in alcohol-dependent people as
well as in chronic users of cocaine and metham-
phetamine (Volkow et al. 2003).
decreasing dopamine accumulation.
This conclusion is corroborated by
findings that chronic stress can reduce
the dopamine signal generated in
response to cocaine administration
(Gambarana et al. 1999).
In humans, actively drinking, alcohol-
dependent people as well as people in
acute withdrawal usually generate high
levels of cortisol and on occasion
actually develop features of hypercor-
tisolism known as the pseudo-Cushing
syndrome. Similar activation of the
HPA axis also has been observed in
psychostimulant users. As in rodents,
these elevated cortisol levels may be
associated with reduced mesocorticol-
imbic dopamine activity. This hypoth-
esis is supported by a PET study
demonstrating that non–substance
abusers who report high levels of life
stress have blunted dopamine respons-
es and subjective responses to a single
dose of intravenous amphetamine
compared with people reporting low
levels of life stress (Oswald et al. 2007).
Together, the findings of these ani-
mal and human studies show that
glucocorticoid levels within a certain
range are necessary to generate a nor-
mal dopamine signal. It is possible
that during the acquisition/preoccu-
pation phase of addiction, glucocorti-
coids amplify mesocorticolimbic
dopamine accumulation in response
to AOD administration, thereby
enhancing the rewarding experiences
associated with drug use. Over time,
however, excessive levels of glucocor-
ticoids, along with AOD-induced
alterations in glutamate and CRF
activity, reduce the dopamine signal,
resulting in a decrease in the reward
experienced after drug use. This area
certainly requires further study.
In summary, sensitization of the
reward pathway appears to be funda-
mental to the transition from AOD
use to abuse (Robinson and Berridge
2001). Furthermore, it is plausible
that stress and the associated gluco-
corticoids act as “sensitizers” of the
mesocorticolimbic reward pathway
during the acquisition/preoccupation
stage of AOD use. The amplified
dopamine signal, in turn, may boost
the reinforcing properties of the drug
Alcohol Research & Health 128
The Influence of Stress on Addiction
experience, thereby contributing to
vulnerability for transitioning from
casual use to abuse. Excessive and/or
prolonged stress, however, can pro-
duce the opposite result—that is,
reward dysfunction. This difference
may, in part, be caused by the bipha-
sic properties of glucocorticoids that
have a sensitizing effect during early
stages of drug exposure but have a
lesser effect, or actually impair positive
reward, when chronic stress begins to
dampen the dopamine signal and
induces enhanced expression of CRF.
Thus, the animal and human data
described here suggest a “Goldilocks
phenomenon, in which cortisol and
dopamine levels must not be too high
or too low but need to be “just right.”
Stage Three: Drug Use
Based on Negative Affect
and Stress
As described above, the positive rein-
forcing effects of AODs are important
in the early stages of drug use but
begin to wane as the individual pro-
gresses toward addiction. This transi-
tion is accompanied by the attenuation
or loss of AOD-induced pleasure as
well as the development of withdrawal
symptoms when AOD use is discon-
tinued (i.e., physical dependence).
Both processes lead to a state of nega-
tive affect. Negative affect is, in part, a
state of internal stress characterized by
anxiety, dysphoria, and intense drug
craving. Consequently, AOD-dependent
people are subjected to both internal
stress in the form of negative affect and
anxiety and the external types of stress
that everybody experiences daily. At
this stage, AOD use begins to be moti-
vated primarily by the desire to avoid
these negative experiences (i.e., by neg-
ative reinforcement).
One brain region implicated in the
negative reinforcing effects of both
AODs and stress is the extended
amygdala, which is located in the
medial temporal lobes of the brain
and is considered part of the limbic
system (see figure 2). The extended
amygdala consists of several nuclei
with distinct functions. It receives
nerve signals from the limbic system
and the olfactory system and projects
fibers to the hypothalamus and mid-
brain. The emergence of negative
affect during the transition from AOD
use to dependence, which is discussed
in the following sections, is thought to
be driven primarily by neural circuits
within the extended amygdala.
Models of Withdrawal,
Negative Affect, and AOD
Self-Administration
Studies of Rodents. As discussed
previously, CRF is a stress-related and
anxiety- inducing peptide that is pro-
duced in the hypothalamus as well as
in other brain regions (e.g., the amyg-
dala). CRF released from the hypotha-
lamus stimulates ACTH secretion and,
subsequently, glucocorticoid produc-
tion. CRF activation in the amygdala,
however, stimulates stress and anxiety-
like behaviors in rodents and primates,
and CRF levels in the amygdala are ele-
vated in these states (Arzt and Holsboer
2006). Consistent with this finding, sub-
stances that block the CRF-1 receptor
(i.e., CRF-1 receptor antagonists) have
been shown to inhibit fear conditioning
(Deak et al. 1999) and CRF-induced
anxiety-like behaviors (Zorilla et al.
2002).
The contribution of CRF produced
outside the hypothalamus to the rein-
statement of alcohol drinking after
withdrawal (which serves as an indi-
cator of alcohol dependence) has been
examined in animal models. Repeated
cycles of alcohol exposure and with-
drawal can lead to increased alcohol
intake at least in certain strains of
rodents (e.g., in C57BL/6J mice)
(Becker and Lopez 2004; Lopez and
Becker 2005). Several studies have
implicated the extrahypothalamic
CRF system in inducing increased
alcohol intake during the withdrawal
period in these rodents. For example,
Finn and colleagues (2007) found
that treatment with a CRF-1 receptor
antagonist decreased alcohol drinking
in C57BL/6J mice during withdrawal
from intermittent alcohol exposure.
Other investigators reported that
administration of the same CRF-1
receptor antagonist directly into the
fluid-filled cavities (i.e., ventricles) of
the brain of alcohol-dependent rats
reduced the reinstatement of alcohol
self-administration following alcohol
withdrawal and protracted abstinence
(Valdez et al. 2002). This effect was
not observed in nondependent rats.
Additional studies (Funk et al. 2007;
Hansson et al. 2006) using different
rodent models and different experi-
mental designs have confirmed these
observations. These results suggest
that increased CRF activity during
alcohol dependence induces motivated
alcohol-seeking behaviors that persist
into protracted abstinence.
Whether extrahypothalamic CRF
affects reinstatement of cocaine self-
administration has not been studied
as systematically. However, there is
substantial evidence that CRF influ-
ences psychostimulant as well as opiate
self-administration and withdrawal.
Several studies (Erb et al. 2005; Maj
et al. 2003; Zorrilla et al. 2001) have
shown that the levels of CRF mRNA
and of some CRF-like protein in
the amygdala are altered during self-
administration and withdrawal from
cocaine and morphine. One study
(Richter and Weiss 1999) of cocaine–
self-administering rats reported
increased CRF in the animals’ amyg-
dala during cocaine withdrawal.
Other investigators found that CRF
injection into the brains of rats led to
reinstatement of cocaine seeking,
whereas injection of a CRF-1 recep-
tor antagonist into an area of the
amygdala
8
prevented stress-induced
reinstatement of cocaine seeking (Erb
et al. 2006). Finally, treatment of
rodents with another CRF-1 receptor
antagonist significantly attenuated
cocaine self-administration, as well as
reinstatement of methamphetamine-
and morphine-seeking behaviors
(Moffett and Goeders 2007; Wang et
al. 2006).
Human Studies. AOD use disorders
have been associated with exposure to
both internal and external stressors
Vol. 31, No. 2, 2008 129
8
The CRF-1 receptor antagonist was injected into the
bed nucleus of the stria terminalis.
(Sinha 2007). External stress, such as an
unhappy marriage or job dissatisfaction,
has been associated with increased alco-
hol use. Harassment on the job and
other work-related stressors also increase
the risk of alcohol use disorders. More-
over, in alcohol-dependent people,
external stress is an important precipi-
tant of relapse (Sinha et al. 2006). Thus,
alcoholics experiencing highly threaten-
ing or chronic psychosocial stress follow-
ing treatment are more likely to relapse
than alcoholics not experiencing such
stress (Noone et al. 1999).
Other studies have shown that inter-
nal stress states (e.g., anxiety) also can
be associated with AOD use. A recent
study (Marquenie et al. 2007) of more
than 7,000 Europeans retrospectively
and prospectively analyzed the nature
of the relationship between co-mor-
bid alcohol dependence and anxiety
disorders, which can be considered
a form of chronic stress. Alcohol
dependence was associated with high
rates of lifetime anxiety; moreover,
anxiety generally preceded the devel-
opment of alcohol use disorders.
Another large-scale, international
study investigating patterns of comor-
bidity between substance use and psy-
chiatric disorders in six nations in the
Americas, Europe, and Japan also
suggested that the presence of an anx-
iety disorder may predispose to the
development of AOD use disorders
(Merikangas et al. 1998). In that
study, across all sites, 45 percent of
participants with drug dependence
also met the criteria for an anxiety
disorder. Importantly, in contrast to
the affective disorders (e.g., depres-
sion), which typically developed fol-
lowing the onset of AOD problems,
the onset of anxiety disorders preced-
ed AOD use disorders at nearly all
levels of severity of substance use dis-
orders. This finding raises the possi-
bility of a causal link between anxiety
and vulnerability to the development
of AOD use disorders. Finally, Terra
and colleagues (2006) examined the
relationship between social phobia
and alcohol use in 300 hospitalized
alcoholic patients. The study con-
firmed the high prevalence of anxiety
disorders, particularly social phobia,
among alcoholics; moreover, the
results demonstrated that in most
cases social phobia preceded alcohol
dependence.
Several studies have focused on
people with a dual diagnosis of combat-
related posttraumatic stress disorder
(PTSD) and AOD abuse (Donovan
et al. 2001). Although a causal rela-
tionship between exposure to com-
bat-related stress and AOD abuse has
not been clearly established, veterans
with PTSD typically report a higher
lifetime use of alcohol, cocaine, and
heroin than veterans screening nega-
tive for PTSD (Saxon et al. 2001).
Human laboratory studies have
corroborated these findings. For
example, Fox and colleagues (2007)
demonstrated that in treatment-seek-
ing alcohol-dependent people, expo-
sure to stress imagery significantly
increased alcohol craving, anxiety, and
negative emotions. Similar observations
were made in cocaine-dependent
patients undergoing treatment (Fox et
al. 2007). The same group of investi-
gators also reported that higher levels
of stress-induced cocaine craving were
associated with a shorter time to
relapse and that stress-induced levels
of ACTH and cortisol predicted
higher amounts of cocaine used per
occasion over a 90-day followup
(Sinha et al. 2006). Brain imaging
studies have begun to identify the
brain structures involved in stress-
and drug cue–induced craving states.
Findings indicate considerable over-
lap between the neural circuits that
process cues signaling stress and drug
use, with activity in the corticostriatal
limbic circuitry underlying both
affective and reward processing
(Sinha and Li 2007).
Researchers have long sought to
explain why various forms of external
stress may precede the development
of AOD use disorders and precipitate
relapse. Even before it was studied
systematically, this association was
first explained by the tension reduc-
tion hypothesis proposed by Conger
and colleagues (1956). According to
this hypothesis, the reduction of neg-
ative feelings by drinking alcohol may
represent an important reinforcing
effect. In fact, many studies using a
variety of experimental strategies have
demonstrated that alcohol can damp-
en the stress response (Sayette 1999).
In general, these studies have demon-
strated that people considered at risk
for developing alcohol-related prob-
lems exhibit attenuation of stress
reactions in psychologically challenging
experimental sessions after receiving
alcohol (Sinha et al. 1998). Indeed,
this may be one possible mechanism
by which a positive family history
increases the risk for alcoholism.
However, numerous other individual
differences and situational factors
affect the extent to which a person
experiences stress-response dampen-
ing after consuming alcohol. These
factors include, for example, personal-
ity traits, extent of self-consciousness,
cognitive functioning, and gender
(Sher et al. 2007).
Mechanism Underlying the
Development of Negative Affect
HPA Axis. Drug-induced activation
of the HPA axis may sensitize reward
pathways early on in the addiction pro-
cess. Chronic drug use, however, results
in gross impairments of the HPA axis
that may injure reward pathways and
activate CRF and other stress factors
during heavy AOD use (i.e., bingeing)
and withdrawal.
For more than two decades, numer-
ous studies have shown that cortisol
dynamics are impaired in alcohol-
dependent people compared with
nonalcoholics (Wand 1993). In
rodents, long-term daily administra-
tion of alcohol in a liquid diet decreased
HPA axis activity, and this reduction
persisted up to 3 weeks postabsti-
nence (Rasmussen et al. 2000). In
humans, the characteristics of the
abnormalities in the HPA axis depend
on whether the alcohol-dependent
person is studied during intoxication,
when experiencing various stages of
withdrawal, or after being abstinent for
several days or months. As mentioned
earlier, actively drinking, alcohol-
dependent people as well as people
in acute withdrawal usually generate
high levels of cortisol or even exhibit
Alcohol Research & Health 130
The Influence of Stress on Addiction
clinically relevant hypercortisolism.
Once withdrawal symptoms have
resolved, however, most alcoholics enter
a phase characterized by an impaired
ability to generate normal amounts of
cortisol in response to pharmacological
and psychological challenges (Adinoff
et al. 2005; Wand 1993). Thus, vari-
ous stages of AOD use are associated
with both high and low cortisol states.
Moreover, high cortisol levels during
early drug exposure may increase
drug taking, whereas low cortisol lev-
els during abstinence may help pre-
cipitate relapse.
A similar pattern of HPA axis activa-
tion and then injury has been observed
in both rodents and humans exposed
to cocaine. In rodents, acute and
repeated cocaine administration initially
activates the HPA axis, resulting in
elevated corticosterone release. With
repeated high-dose cocaine administra-
tion over time, however, corticosterone
levels progressively decline (Koob and
Kreek 2007). Similar findings have
been obtained in human long-term
cocaine addicts in a clinical laboratory
setting (Aouizerate et al. 2006).
Extended Amygdala. As mentioned
earlier, the extended amygdala con-
sists of several nuclei with distinct
functions. These include the basolat-
eral amygdala, the central and medial
amygdala, and the cortical nucleus.
Several stress peptides and neuro-
transmitters associated with the extend-
ed amygdala appear to influence the
development of negative affect and
anxiety. As described above, CRF is
an anxiety-inducing neuropeptide.
Studies in rats identified increased
extracellular levels of CRF in the cen-
tral amygdala during acute alcohol
withdrawal and during exposure to
various other forms of stress (Merlo-
Pich et al. 1995). Administration of
CRF antagonists reversed anxiety-like
behaviors as well as excessive alcohol
drinking associated with alcohol
withdrawal (Valdez et al. 2003).
Other studies have implicated nerve
signal transmission mediated by the
neurotransmitter
γ-aminobutyric acid
(GABA) in the central amygdala in
regulating alcohol intake (Hyytia and
Koob 1995). Chronic alcohol admin-
istration is associated with increased
GABA release in the central amyg-
dala, in part in response to CRF.
Another signaling molecule that can
modulate anxiety and alcohol abuse
through its actions on the amygdala is
called neuropeptide Y (NPY) (Valdez
and Koob 2004). Various measures
to disrupt normal NPY function all
result in anxiety-like behaviors and
increased alcohol consumption (Thiele
et al. 1998; Thiele and Badia-Elder
2003). NPY production is in part con-
trolled by a regulatory factor known as
cAMP-responsive element–binding
protein (CREB). Mice in which the
CREB protein has been inactivated
have a higher preference for alcohol
than do normal mice (Pandey et al.
2004). Similarly, the levels of both
NPY and the activated form of CREB
are reduced in the amygdala of alco-
hol-preferring (P) rats compared with
nonpreferring (NP) rats (Suzuki et al.
2004). Interestingly, the selectively
bred P rats not only consume greater
amounts of alcohol but also have
higher baseline levels of anxiety-like
behaviors compared with NP rats
(Kampov-Polevoy et al. 2000). One
hypothesis is that the P rats drink
excessive amounts of alcohol in order
to reduce anxiety levels. This hypoth-
esis is supported by findings that
alcohol stimulated a signaling mecha-
nism called the cAMP/protein kinase
A (PKA) pathway in the central and
medial amygdala (but not the baso-
lateral amygdala) that led to increased
levels of several regulatory molecules,
including NPY and CREB function
(Pandey et al. 2005). These changes
were accompanied by a reduction in
anxiety-like behavior in the P rats.
Moreover, infusion of a molecule that
can activate these signaling mecha-
nisms or of NPY directly into the
central amygdala reproduced the neu-
rochemical and anxiety-reducing
effects of alcohol. These effects were
observed only in P rats, not in NP
rats. These findings show that decreased
CREB function in the central amyg-
dala is associated with maintaining
high anxiety levels and alcohol-drink-
ing behaviors of P rats.
Another group of potential amyg-
dala modulators are small molecules
called cocaine- and amphetamine-
regulated transcript (CART) pep-
tides, which attenuate the behavioral
effects of cocaine (Jaworski and Jones
2006). These peptides are thought
to modulate neural activity in the
amygdala and other CRF-rich brain
regions. CART peptides stimulate
CRF and glucocorticoid release, while
at the same time CRF and glucocor-
ticoids increase the production of the
CART peptides. Stress and psycho-
stimulant exposure modulate CART
expression in the hypothalamus and
amygdala through cAMP/PKA and
CREB signaling. However, the role
of CART in drug-induced negative
affect states needs further investigation.
Thus, an extensive regulatory net-
work in the amygdala, comprising
NPY, CRF, GABA, CREB, the
cAMP/PKA signaling pathway, and
possibly CART peptides, may influ-
ence stress-induced anxiety and drug
intake. To date, it is unclear, however,
if and how glucocorticoids alter these
systems. Additionally, this currently
known network may just be the “tip
of the iceberg,” and other regulatory
mechanisms may have an impact as well.
Conclusion
The relationships between stress and
AOD use disorders are complex.
Prevailing evidence suggests that causal-
ity exists in both directions: Internal
and external stress can enhance AOD
use and AOD addiction creates an
internal state of stress as part of the
negative-affect state. The generaliza-
tions described in this review oversim-
plify a field that requires further inten-
sive investigation. However, several
salient points can be made.
Both stress and AODs activate the
HPA axis and extended amygdala in
a time- and dose-dependent manner.
Animal and human studies have gen-
erally shown that specific forms of
stress are associated with increased
AOD use and can precipitate relapse.
The effects of stress on AOD use
depend in part on the type, context,
Vol. 31, No. 2, 2008 131
Alcohol Research & Health 132
Addiction
Process
Stages
Reward
Process
Stage 1
• Social drinking or occasional drug use
• Glucocorticoid levels positively correlate with dopamine and reward
signal
• Reward system responds appropriately to stimuli
• Drug-induced HPA activation sensitizes mesolimbic dopamine sys-
tem, provides salience to the drug signal
• CRF and stress factors generally quiescent
• Drugs provide maximal pleasure, may be used for stress dampening
by anxious or externally stressed people
Stage 2
• Drug use escalates
• Cyclical episodes of excess cortisol levels associated with binge
and withdrawal begin to injure mesolimbic system
• Dopamine reward threshold increases; hedonic pleasure decreases
• CRF and other stress factors become activated; internal state of
chronic stress begins
• Use of higher doses because pleasure is waning (“chasing the
high”)
• All forms of external stress are additive to internal state of stress, can
escalate drug craving, drug seeking, and drug use
Stage 3
Active alcohol and other drug use
• Psychological and physiological withdrawal symptoms
• Maximal cycling of HPA axis
• Dysfunctional HPA axis and mesolimbic system
• Dopamine reward threshold high–little hedonic pleasure from drug
• CRF and other stress factors create a chronic internal stress state,
motivating drug use for stress dampening
• All forms of external stress are additive to internal state of stress,
escalate drug craving
Abstinence
• Low cortisol and dopamine state
• Dysfunctional HPA axis and mesolimbic system
• High expression of CRF and other stress factors persist, maintaining
chronic internal stress state and high craving (prolonged withdrawal
symptoms)
• All forms of external stress are additive to internal state of stress,
escalate drug craving and risk for relapse
Preoccupation/
anticipation
Acquisition
Reward
sensitization
Binge use/
intoxication
Maintenance
Dampened
reward
Withdrawal/
negative affect
Reinstatement
Negative affect
Figure 4 Changes in the body’s response to stress and the reward system over the three stages of the drug addiction process.
The stages of the addiction process are shown on the left, the state of the body’s reward system is indicated on the right.
NOTES: CRF = corticotropin-releasing factor; HPA = hypothalamic–pituitary–adrenal axis.
The Influence of Stress on Addiction
and severity of the stressor; the
genetic background of the AOD
user; and the interplay between the
positive and negative reinforcing
influences of the drug and the stres-
sor. Early in the development of
AOD use, both stress- and drug-
induced activation of the HPA axis
allow glucocorticoids to sensitize the
reward pathways, although the exact
effects on the mesocorticolimbic
dopamine system still are unknown.
As a person transitions from casual
AOD use (e.g., social drinking) to
AOD dependence, the balance
between the positive and negative
reinforcing effects of the drug shifts
(see figure 4). Although multiple
brain regions are involved in this
transition, the mesocorticolimbic
dopamine system (which is modulat-
ed by various forms of stress, gluco-
corticoids, and neuroactive steroids)
and the extended amygdala (through
alterations in CRF, NPY, CREB, and
GABA) likely alter the reinforcing
properties of both AODs and stress.
With the appearance of drug depen-
dence and episodes of withdrawal,
the neurochemical environment in
the amygdala shifts to produce anxiety-
inducing states by increasing expres-
sion of CRF and further activating
the HPA axis. This neurochemical
milieu creates craving and drug-seeking
behaviors.
The hypothesis that the stress
response and the risk of AOD abuse
and dependence are interrelated is
supported by the observation that the
offspring of alcohol-dependent people,
who are at increased risk for alcohol
use disorders, have an altered cortisol
response to various stressors that pre-
cedes the onset of heavy drinking.
Thus, a dangerous interaction between
stress and drug-seeking behaviors
likely exists throughout the different
stages of addiction, aided by the allo-
static adaptive mechanisms described
in this review.
Understanding the allostatic adap-
tive process and its interaction with
stress and the risk of AOD abuse and
dependence will someday enable
researchers and clinicians to target
specific treatment interventions to
patients at a specific stage of addic-
tion. For example, ongoing pharma-
cological research is aimed at devel-
oping medications that modulate the
activity of glucocortioids, CRF, NPY,
and the other stress-regulated factors
that are involved in the transition
from AOD use to AOD dependence.
Most of these studies still are in a
preclinical stage but will soon advance
to human trials. But although these
exciting interventions still are many
years away, important information
already can be shared with high-risk
populations. For example, children
of alcoholics, with their high cortisol
responses to stress, are at increased
risk for alcohol abuse and depen-
dence. These people should be made
aware of the biological reasons that
place them at higher risk for addic-
tion and should be counseled to limit
or avoid alcohol. Patients with PTSD
and other anxiety disorders constitute
another high-risk population and
should be educated accordingly about
the dangers of using AODs to self-
medicate prior to social interactions.
Finally, any treatment plan for
addicted patients must be fluid and
periodically reevaluated to take into
account the emergence of internal
and external stressors that could pre-
cipitate relapse.
Acknowledgments
The author’s cited studies were sup-
ported by grants from NIAAA and the
Kenneth Lattman Foundation.
Financial Disclosure
The author declares that he has no
competing financial interests.
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... However, most importantly, stress exposure and drug abuse result in the progressive up-regulation or excess of the brain stress system (till now referred to as the "anti-reward" brain system), which is the key to understanding the stress-like state of the negative emotion/withdrawal stage, driving drug-seeking and taking through negative reinforcement. This up-regulation results from the increase in the reactivity of the HPA axis and amygdala, also increasing hypersensitivity to stress (Belujon, & Grace, 2011;Koob, 2013Koob, , 2015Koob, & Le Moal, 2008;Koob et al., 2014;Lammel, Lim, & Malenka, 2014;Wand, 2008). It is, therefore, involved in the relief-craving (Preston, Kowalczyk, Phillips, Jobes, Vahabzadeh, Lin, Mezghanni, & Epstein, 2018;Sinha, 2008;Wand, 2008). ...
... This up-regulation results from the increase in the reactivity of the HPA axis and amygdala, also increasing hypersensitivity to stress (Belujon, & Grace, 2011;Koob, 2013Koob, , 2015Koob, & Le Moal, 2008;Koob et al., 2014;Lammel, Lim, & Malenka, 2014;Wand, 2008). It is, therefore, involved in the relief-craving (Preston, Kowalczyk, Phillips, Jobes, Vahabzadeh, Lin, Mezghanni, & Epstein, 2018;Sinha, 2008;Wand, 2008). Furthermore, repeated exposure to drugs and withdrawal from drugs can be considered, in themselves, as stressors, inducing the same brain (Mather, & Lighthall, 2012;Chandler, & Gass, 2013). ...
... A growing body of evidence emphasises the central role of stress in the transition from drug abuse to addiction(Al´Absi, 2018; Duffing, Greiner, Mathias, & Dougherty, 2014; Hassanbeigi, Askari, Hassanbeigi, & Pourmovahed, 2013; Hildebrandt, & Greif, 2013; Koob, 2017; Koob, & LeMoal, 2017; Koob, & Schulkin, 2018; Koob, & Volkow, 2016;Sinha, 2008;Wand, 2008). The progression towards drug addiction is currently best described as the result of an accumulation of allostatic changes, similar to other chronic conditions such as hypertension, diabetes or obesity. ...
Article
Background: The high prevalence and burden to society of drug abuse and addiction is undisputed. However, its conceptualisation as a brain disease is controversial, and available interventions insufficient. Research on the role of stress in drug addiction may bridge positions and develop more effective interventions. Aim: The aim of this paper is to integrate the most influential literature to date on the role of stress in drug addiction. Methods: A literature search was conducted of the core collections of Web of Science and Semantic Scholar on the topic of stress and addiction from a neurobiological perspective in humans. The most frequently cited articles and related references published in the last decade were finally redrafted into a narrative review based on 130 full-text articles. Results and discussion: First, a brief overview of the neurobiology of stress and drug addiction is provided. Then, the role of stress in drug addiction is described. Stress is conceptualised as a major source of allostatic load, which result in progressive long-term changes in the brain, leading to a drug-prone state characterized by craving and increased risk of relapse. The effects of stress on drug addiction are mainly mediated by the action of corticotropin-releasing factor and other stress hormones, which weaken the hippocampus and prefrontal cortex and strengthen the amygdala, leading to a negative emotional state, craving and lack of executive control, increasing the risk of relapse. Both, drugs and stress result in an allostatic overload responsible for neuroadaptations involved in most of the key features of addiction: reward anticipation/craving, negative affect, and impaired executive functions, involved in three stages of addiction and relapse. Conclusion: This review elucidates the crucial role of stress in drug addiction and highlights the need to incorporate the social context where brain-behaviour relationships unfold into the current model of addition.
... With continued substance use, adaptations in these neurocircuits occur that alter the rewarding effects of drugs, and thus, the motivation to use them. As another consequence maladaptive stress responses are enhanced which contributes to compulsive drug use and continued relapse vulnerability even after substance use has ceased for a long time 3,5,6 . ...
... It was concluded that HPA-axis activity heightens the sensitivity for cocaine reward and therefore influences an individuals' susceptibility to develop CUD 10 . Animal studies further indicated that chronic cocaine administration augments the physiological stress load, thereby changing HPA-axis reactivity over time 5,12 . Accordingly, hospitalized CU showed elevated plasma 13,14 and salivary cortisol levels 15 and more frequent cocaine use before hospitalization was associated to greater basal plasma cortisol 13 . ...
... Furthermore, chronic CU exhibit lower glucocorticoid receptor gene (NR3C1) expression in blood 16 and a longitudinal analysis of this sample has shown that NR3C1 expression of CU normalized when cocaine consumption was reduced 17 . Specifically, a dysregulated HPA-axis response has been suggested to increase the probability of relapse due to the negative reinforcement properties of substance use 2,3,5,18 . Accordingly, a blunted salivary cortisol response has been observed in CU and methamphetamine users in response to the Trier Social Stress Test (TSST) and personalized stress imagery 19 , whereas another study only observed a blunted plasma cortisol response to the TSST in female but not in male CU 20 . ...
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There is evidence that stress and craving contribute to the development, maintenance, and relapse in cocaine use disorder. Previous research has shown altered physiological responses to psychosocial stress as well as increased vegetative responding to substance-related cues in chronic cocaine users (CU). However, how psychosocial stress and cue-induced craving interact in relation to the physiological response of CU is largely unknown. Therefore, we investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. Participants were randomly exposed first to a video-based cocaine-cue paradigm and second to the Trier Social Stress Test (TSST) or vice versa in a crossed and balanced design to investigate possible mutually augmenting effects of both stressors on the physiological stress response. Plasma cortisol, ACTH, and noradrenaline as well as subjective stress and craving were assessed repeatedly over the course of the experimental procedure. Growth models and discontinuous growth models were used to estimate the responses during the cocaine-cue paradigm and TSST. Overall, both groups did not differ in their endocrinological responses to the TSST but CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU. However, if the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. Cocaine-cues robustly evoked craving in CU but no stress response, while cue-induced craving was intensified after the TSST. Taken together, CU did not show an altered acute stress response during the TSST but stress and craving together seem to have mutually augmenting effects on their stress response.
... Among women experiencing IPV, hypothalamic-pituitaryadrenal (HPA)-axis functioning may be particularly important to assess in relation to AUD. Production of cortisol, which is triggered by stress-induced activation of the HPA-axis, has been studied extensively in relation to AUD (Stephens & Wand, 2012;Wand, 2008). Notably, studies report a correlation between cortisol responsivity and activity within the mesolimbic dopaminergic pathway, which underlies AUD development, maintenance, and exacerbation (Oswald et al., 2005;Stephens & Wand, 2012;Wand et al., 2007). ...
... This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. PTSD-AUD AND HPA-AXIS FUNCTIONING 7 Oswald et al., 2005;Stephens & Wand, 2012;Wand, 2008;Wand et al., 2007) and PTSD (Speer et al., 2019;Szabo et al., 2020) separately, underscoring the moderating role of PTSD symptom severity in the relationships between both baseline HPA-axis functioning and HPA-axis recovery and AUD. Specifically, our findings suggest that severity of PTSD symptoms exacerbates the link between HPA-axis functioning and AUD among women experiencing IPV. ...
Article
Women experiencing intimate partner violence (IPV) experience a heightened prevalence of alcohol use disorder (AUD). Hypothalamic-pituitary-adrenal (HPA)-axis functioning has been associated with increased risk for AUD in other populations, including individuals with posttraumatic stress disorder (PTSD) symptoms. The goal of the present study was to determine whether PTSD symptom severity exacerbates the relationship between HPA-axis functioning and AUD. Participants were 151 community women who had experienced physical or sexual IPV in the past 30 days by their current male partners and used any amount of alcohol or drugs. A two-phase emotion induction protocol was utilized: Neutral mood induction followed by randomly assigned negative, positive, or neutral emotion induction. Saliva cortisol samples were obtained immediately following the neutral mood induction (baseline HPA-axis functioning), 20 min following the individualized emotion induction script (HPA-axis reactivity), and 40 min post the emotionally evocative cue (HPA-axis recovery). Findings revealed that PTSD symptom severity moderated the relations between baseline HPA-axis functioning and HPA-axis recovery and log odds of meeting criteria for AUD. Specifically, baseline HPA-axis functioning was positively associated with log odds of meeting criteria for AUD at high (but not low) PTSD symptom severity, whereas HPA-axis recovery was negatively associated with log odds of meeting criteria for AUD at high (but not low) PTSD symptom severity. Results contribute to our understanding of the biological processes involved in the etiology and maintenance of AUD among women experiencing IPV-specifically the prominent role of PTSD symptom severity. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
... Repeated exposures to addictive stimuli and withdrawal from those stimuli can be stressors to the brain and potentially induce brain changes and possibilities of relapse (George et al., 2014). Therefore, stress has been known as the single most powerful and reliable trigger for cravings and relapse (Sinha, 2008;Wand, 2008;Preston et al., 2018). In contrast, resilience-the ability to be healthy and adaptable and to cope positively with changes (Southwick et al., 2014) is considered a protective factor against the development of addictive disorders (Nam et al., 2018;Shin et al., 2019;Ersche et al., 2020). ...
Article
Full-text available
Stress plays an important role in the pathophysiology of addictive disorders. The kynurenine (KYN) pathway involved in neuroimmune and cognitive functions is activated under stress. However, the neuroimmunological–neurocognitive mechanisms in the role of stress in addictive disorders are unclear still now. Ninety-nine young adults aged 18–35 years [alcohol use disorder (AUD), N = 30; Internet gaming disorder (IGD), N = 34; healthy controls (HCs), N = 35] participated in this study. Stress levels, resilience, addiction severity, and neurocognitive functions were evaluated, and serum levels of tryptophan (TRP), 5-hydroxytryptamine (5-HT), KYN, and kynurenine acid (KYNA) were determined using liquid chromatography coupled with tandem mass spectrometry through blood samples. Both addictive disorder groups showed higher levels of stress, lower resilience, and impaired executive functions compared to the HC group. Importantly, the AUD group revealed significantly increased KYN levels and KYN/TRP ratios, as well as decreased KYNA levels and KYNA/KYN ratios compared to HCs (p < 0.001, p < 0.001, p = 0.033, and p < 0.001, respectively). The IGD group showed KYN levels and KYNA/KYN ratios intermediate between those of the AUD group and HCs. Furthermore, in the AUD group, the mediating effect of AUD on KYN through stress level was moderated by resilience [index of moderated mediation = −0.557, boot S.E = 0.331, BCa CI (−1.349, −0.081)]. Stress may induce an imbalance in downstream of KYN pathway metabolites, and the KYN/TRP ratio may play as a neuromediator between stress and behavioral changes in both addictive disorders. This study suggests that regulation of the KYN pathway is critical in the pathophysiology of addictive disorders and it may serve as an important target for future treatment modalities.
... This, in turn, can lead to sensitization of extrahypothalamic stress systems, e.g., amygdaloid CRH activity (Makino et al., 2002). The role of HPA activity has been extensively studied in excessive drug, including ethanol, taking behavior [for review see (Wand, 2008)]. For instance, ethanol dependence and withdrawal are associated with the dysregulation of HPA activity, including elevated serum GC concentrations and inhibition of the HPA response to subsequent stressors (Wand and Dobs, 1991;Lee et al., 2000). ...
Article
Full-text available
Evidence suggests the hypothalamic-pituitary-adrenal (HPA) axis is involved in Alcohol Use Disorders (AUDs), which might be mediated by an imbalance of glucocorticoid receptor (GR), GRα and GRβ, activity. GRβ antagonizes the GRα isoform to cause glucocorticoid (GC) resistance. In the present study, we aimed to investigate the effects of chronic continuous free-choice access to ethanol on GR isoform expression in subregions of the mesocorticolimbic reward circuit. Adult male alcohol-preferring (P) rats had concurrent access to 15% and 30% ethanol solutions, with ad lib access to lab chow and water, for six weeks. Quantitative Real-time PCR (RT-PCR) analysis showed that chronic ethanol consumption reduced GRα expression in the nucleus accumbens shell (NAcsh) and hippocampus, whereas ethanol drinking reduced GRβ in the nucleus accumbens core (NAcc), prefrontal cortex (PFC), and hippocampus. An inhibitor of GRα, microRNA-124-3p (miR124-3p) was significantly higher in the NAcsh, and GC-induced gene, GILZ, as a measure of GC-responsiveness, was significantly lower. These were not changed in the NAcc. Likewise, genes associated with HPA axis activity were not significantly changed by ethanol drinking [i.e., corticotrophin-releasing hormone (Crh), adrenocorticotrophic hormone (Acth), and proopiomelanocortin (Pomc)] in these brain regions. Serum corticosterone levels were not changed by ethanol drinking. These data indicate that the expression of GRα and GRβ isoforms are differentially affected by ethanol drinking despite HPA-associated peptides remaining unchanged, at least at the time of tissue harvesting. Moreover, the results suggest that GR changes may stem from ethanol-induced GC-resistance in the NAcsh. These findings confirm a role for stress in high ethanol drinking, with GRα and GRβ implicated as targets for the treatment of AUDs.
... Stress is known as an important factor for both mental and physical health of humans [1][2][3] . Chronic stress causes dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to an increased level of glucocorticoids that contribute to the development of neuropsychiatric disorders such as anxiety and depression, and metabolic disturbances such as obesity and insulin resistance 4,5 . Stress that occurs during adolescence, a crucial period of brain development and maturation, could potentially increases one's susceptibility to development of neuropsychiatric disorders during adulthood and has immediate consequences on an individual's psychological health 6 . ...
Article
Full-text available
The human gut microbiome plays a central role in human health, and has been implicated in the development of a number of chronic gastrointestinal and systemic diseases. For example, microorganisms can serve as microbial endocrine mediators and can respond to stimuli and produce neurochemicals, ultimately influencing the brain-gut-microbiome axis of their host, a bidirectional communication system between the central nervous system and the gastrointestinal tract, especially during developmental stages. To begin to explore potential dynamic changes of the gut microbiome, we characterized gut microbiota in adolescent rats that underwent a fixed period of restraint stress, examined whether the gut microbial population and their metabolic functions were changed by stress, and if such changes during adolescence persist or recover in young adulthood. Integrated 16S ribosomal DNA sequencing and liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) based metabolic profiling were utilized to discover any significant differences in gut microbial genus and microbial metabolites immediately at the end of the chronic restraint stress and three weeks after the stress treatment, compared to control rats that did not receive stress treatment. Interestingly, while adolescent chronic stress-induced differences in relative microbial abundance (i.e., microbial species and distribution) disappeared three weeks after the stress treatment ended, the differences in microbial metabolic profiles persisted into adulthood. In addition, a number of significantly altered metabolites and their correlated gut microbes detected in our study facilitated a possible connection between gut microbiota and host stress response, which can be further investigated in the future to study the causal relationship between gut microbial metabolites and their impact on human health.
... This physically tedious work drives them to consume alcohol, tobacco, and various illicit drugs relieving their stress and deteriorating their oral health. [13][14][15] The outcome of the current study reveals that the subjects practicing oral hygiene were more in number as compared to the addicts practicing irregular/no oral hygiene practices; this was similar to the previous studies. 8,12 This distribution could be due to easy availability of oral hygiene aids nowadays. ...
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... [85] Elevated cortisol can upsurge the secretion of dopamine in nucleus accumbens, and in turn, suppression of cortisol reduces the extracellular release of dopamine during response to stress and addictive substances. [86] Hence, the cortisol induced by noise stressor may play a major role in dopamine alteration resulting in addiction and behavior. The differences in gender psychopathic traits personality could be due to alteration in cortisol production [87] and women's whom are psychologically sensitive and also execute similar tendency like men to definite noise. ...
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