126 Vermetten et al.

DEPRESSION AND ANXIETY 15:126–147 (2002)

Review Article
CIRCUITS AND SYSTEMS IN STRESS.
I. PRECLINICAL STUDIES
Eric Vermetten, M.D.,1,4 and J. Douglas Bremner, M.D.1–4

This paper reviews the preclinical literature related to the effects of stress on
neurobiological and neuroendocrine systems. Preclinical studies of stress provide
a comprehensive model for understanding neurobiological alterations in post-
traumatic stress disorder (PTSD). The pathophysiology of stress reflects long-
standing changes in biological stress response systems and in systems involved in
stress responsivity, learning, and memory. The neural circuitry involved in-
cludes systems mediating hypothalamic-pituitary-adrenal (HPA) axis, norepi-
nephrine (locus coeruleus), and benzodiazepine, serotonergic, dopaminergic,
neuropeptide, and central amino acid systems. These systems interact with brain
structures involved in memory, including hippocampus, amygdala, and prefron-
tal cortex. Stress responses are of vital importance in living organisms; however
excessive and/or repeated stress can lead to long-lasting alterations in these cir-
cuits and systems involved in stress responsiveness. Intensity and duration of the
stressor, and timing of the stressor in life, have strong impact in this
respect. Depression and Anxiety 15:126–147, 2002. © 2002 Wiley-Liss, Inc.

Key words: stress; animals; neurobiology; circuits; neuroendocrinology;

rceptors; hippocampus; amygdala; learning; memory; brain; PTSD

INTRODUCTION response, which include the hypothalamic-pituitary-

O ver the past few years, our understanding of the
brain, neuroendocrine circuits, and involvement of trans-
mitter systems that are linked to the stress response has
increased substantially. Accumulated evidence has dem-
onstrated that stress results in long-standing changes in
biological stress response systems that underlie many of
the symptoms of post-traumatic stress disorder (PTSD)
and other stress-related disorders [see also Friedman et
al., 1995; Charney et al., 1998a,b; Bremner et al., 1999a;
Charney and Bremner, 1999; Lopez et al., 1999; New-
port and Nemeroff, 2000; McEwen, 2000; Bremner and
Vermetten, 2001; Vermetten et al., 2002].
While the blueprint for development of the brain is
most likely specified by the genome, fine details of the
central nervous system are shaped by experience and
formed in interaction with the environment. This in-
teractive process shapes an organism’s sensitivity and
responsivity to the environment and programs the
stress response system. Central aspects of the stress
response system involve perception of a stressor or
fear-producing stimulus, processing, and transduction
of this information into neurohormonal, neurobio-
logical, and behavioral responses. This review focuses
on neural circuits and systems involved in the stress
adrenal (HPA) axis and the locus coeruleus (LC). Of
key importance in these major systems are mediating
hormones and neurotransmitters, glucocorticoids,
1
Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia
2
Department of Radiology, Emory University School of Medi-
cine, Atlanta, Georgia
3
Emory Center for Positron Emission Tomography, Emory
University School of Medicine, Atlanta, Georgia
4
Atlanta VAMC, Decatur, Georgia
Eric Vermetten is now at the Department Psychiatry, University
Medical Center/Utrecht Military Hospital, Utrecht, The Netherlands.
Correspondence to: Dr. Eric Vermetten, Emory Clinical Neuro-
sciences Research Unit, Emory University School of Medicine/
Atlanta VAMC, 1256 Briarcliff Rd NE, Atlanta GA 30306.
E-mail: evermet@emory.edu
Received for publication 13 April 2001; Accepted 17 September
2001
DOI: 10.1002/da.10016
Published online in Wiley InterScience (www.interscience.wiley.
com).

© 2002 WILEY-LISS, INC.

 Review Article: Circuits and Systems in PTSD, Preclinical Data
norepinephrine, and benzodiazepine, serotonin, dopa-
minergic, neuropeptide, and central amino acid systems,
as well as brain memory systems, such as hippocampus,
amygdala, and prefrontal cortex. A knowledge of the ef-
fects of stress on neurobiology provides a basis for un-
derstanding the pathophysiology of PTSD. This can be
used to piece together a comprehensive model for how
stress can affect neurobiological systems in humans and
to formulate hypotheses for testing in patients with
PTSD. This paper will briefly summarize preclinical
findings in animals related to brain circuits and systems
affected by stress. Studies of the neurobiology of PTSD
in clinical populations, as well as future avenues for the
development of psychopharmacological agents, are re-
viewed elsewhere [Vermetten and Bremner, 2002].
MODELS OF STRESS IN
ANIMAL RESEARCH
The use of animal models is well established in the
study of biological bases in psychiatric disorders. De-
spite traditional difficulties in accepting animal models
for psychopathology that stem from the argument that
there is no evidence for concluding that what occurs in
the brain of the animal is equivalent to what occurs in
the brain of a human, these models have become an in-
valuable tool in the analysis of the multitude of causes,
genetic, environmental, or pharmacological, that can
bring about symptoms homologous to those of patients
with a specific disorder. Animal models can also allow
the study of the mechanisms of specific behaviors and
their pathophysiology, and can aid in developing and
predicting therapeutic responses to pharmacologic
agents. In these respects, animal models of stress are
useful for understanding the basic neurobiology of stress
and for generating hypotheses about the neurobiology
of PTSD, which subsequently can be tested in popula-
tions of PTSD patients [Yehuda and Antelman, 1993;
Pynoos and Ritzmann, 1996; Liberzon et al., 1997;
Rasmusson and Charney, 1997]. There is a long history
of animal models for the study of depression [see
McKinney and Bunney, 1969; Redei et al., 2001] and
anxiety [see Treit, 1985]. Many of these animal models
that were developed as indirect models of depression
(e.g., escape behavior after footshock) can well be
viewed as direct models of PTSD since exposure to ex-
treme stress (typically uncontrollable) is required for the
diagnosis of PTSD. In addition, behavior seen in ro-
dents exposed to stress in many ways parallels behaviors
seen in humans with a history with PTSD [Nijenhuis et
al., 1998]. Decreased exploration in open field can be
seen as avoidance, decreased grooming and play activity
can be seen as being cut off, and decreased responding
for rewards and self-stimulation, analgesia, and anesthe-
sia as emotional numbing.
One of the most popular models of animal research
that has been used is that of inescapable or restraint
stress. In this model, animals are exposed to single or
127
repeated stressors, such as electric (inescapable) foot-
shock or being forced to swim in cold water [e.g., van
Dijken et al., 1993; Marti et al., 2001]. Other fre-
quently used models use a social stress or social defeat
model [Henry, 1992; Koolhaas et al., 1997]. The stres-
sors used here can be predator exposure or varying
housing characteristics. The immediate and long-term
effects of defeat have been studied in a variety of re-
sponse patterns, e.g., neurobiological and behavioral
characteristics of mobilization of aggression vs. avoid-
ance, as well as environmental effects like environmen-
tal enrichment vs. poor housing [Ruis et al., 1999; de
Jong et al., 2000]. Early handling has also been used as
a model of stress (see below). In this model, pups are
deprived for varying lengths of time of maternal care
(maternal deprivation) or are placed in a situation
where there is enriched maternal care (after depriva-
tion) [Meany et al., 1988; van Oers et al., 1998; Plotsky
and Meaney, 1993; Ladd et al., 1996]. By combining
various models developmental effects of stress respon-
sivity have been studied [e.g., Oitzl et al., 2000]. In
addition, pharmacological challenges and effects of
stress-reducing agents have been tested in models that
have been well described and standardized.
The acute biobehavioral manifestations of stress in
animals are similar to symptoms of human anxiety and
PTSD, including trembling, hyperarousal, restlessness,
increased gastrointestinal motility, increased perspira-
tion, changes in food intake, increased defecation, sleep
disturbances, deficits in memory and attention, or
avoidance of novel stimuli such as an open field [Weiss
and Simson, 1985; Lechin et al., 1996]. The bio-
behavioral parameters parallel to some extent the main
symptoms of PTSD in humans and can provide a frame-
work for understanding the main features of the psycho-
biological model of PTSD (fear conditioning, failure/
inhibition of extinction of fear, and stress sensitization)
as described by Charney et al. [1993] (Table 1).
It is important to understand the limitations of the
application of animal models to PTSD. No single ani-
mal model will address the myriad facets of PTSD or
factors that lead to a PTSD-like syndrome in humans.
Animal models typically involve a single type of stres-
sor, for example, exposure to electric shock, whereas
stressors in humans are diverse and multi-factorial.
There are also multiple factors that influence the im-
pact of the stressor on the individual, including devel-
opmental epoch, coping and psychological defenses,
social support, the meaning of the event to the indi-
vidual, prior exposure to stressors, and psychiatric
comorbidity [e.g., Bremner and Narayan, 1998, Benot-
sch et al., 2000; Brady et al., 2000; Bremner and
Vermetten, 2001]. In addition, it should be noted that
most animal models are based on the rat and that the
human brain contains a much greater complexity, spe-
cifically the development. Psychological factors also
have to be taken into account [Weiss, 1972], which in-
clude factors such as controllability and predictability
of the stressor, which can account for a differentiated
128
TABLE 1. Relation between stress in different animal models of stress, their acute and long-term alterations, and the
parallels with symptom clusters in PTSD in humans*
Animal model Acute symptoms
of stress of stress
Inescapable shock Trembling
Unpredictable shock Restlessness
Social defeat Rapid heart rate
Chronic restraint Increased perspiration
Cold water swim Increased gastrointestinal
Forced swim motility
Predator exposure Urge to urinate
Shuttlebox escape Muscle tension
Maternal deprivation Arousal
Postnatal handling Shortness of breath
Elevated T-maze
*The symptom clusters are in turn reflected in the psychobiological model of PTSD in which stress sensitization, fear conditioning, and failure of extinction/
inhibition of fear are the core concepts that capture the symptomatology. Although the stressors can have different dimensional characteristics, similar pathways
may lead to the same long-term effects on stress responsivity and subsequent biobehavioral manifestations.
response that is not always reflected in animal models.
Discrete differences in neurobiological parameters
were described in an experiment that used inescapable
stress vs. escapable stress [Shors et al., 1989]. The
same differentiated response has been described for
predictability of the stressor [Shors et al., 1990].
EARLY PROGRAMMING OF
STRESS RESPONSIVITY
Stress responsivity is the result of complex interac-
tions between genetic susceptibility and environmen-
tal stress. The challenge is to identify modifiers of the
regulation and to design strategies to modify underly-
ing pathways. The availability of genomic databases
for many species is uncovering networks of conserved
stress-related genes within given physiological path-
ways. A genetic-based model of stress responsivity can
be envisaged based on the disruption of integrated ge-
nomic circuits that control morphogenesis of brain
structures, cell survival, and stress regulation. Recent
work has begun to identify the various transcription
factors that are associated with brief or intermediate
duration of a single or repeated stress. These studies
suggest that dynamic interplay is involved in convert-
ing the transient increases in the rate of transcription
into prolonged (potentially adaptive or maladaptive)
changes in gene expression [Sabban and Kvetnansky,
2001]. Recently an animal model of congenital learned
helpless (cLH) has been used to study the effects of
genetic disposition as a risk factor for the development
of PTSD-like behaviors. This showed physiologic
symptoms of analgesia, cognitive deficits, and hypo-
responsivity of the HPA axis, similar to those observed
in human subjects with PTSD [King et al., 2001].
In addition to a genetic contribution to the regula-
tion of stress responsivity, a preeminent role of early
life events in the pathogenesis of these disorders has
Vermetten et al.
Long-term biobehavioral Symptoms cluster Psychobiological
manifestation in PTSD model of PTSD
Contextual fear Increased arousal Stress sensitization
Fear to explicitly conditioned Re-experiencing Fear conditiong
aversive stimuli Numbing Failure of extinction/
Stress-induced analgesia Difficulties with attention inhibition of fear
Impairment in active avoidance and concentration
Enhanced passive avoidance Avoidance of stimuli
Freezing previously associated
Learned helplessness with the trauma
Behavioral despair
Fear potentiated startle
been postulated. Rearing effects have been well de-
scribed as important factors that influence brain and
behavior in mice [e.g., Greenough et al., 1973]. In ro-
dents, the development of behavioral and endocrine re-
sponse to stress in the offspring has been shown to be
influenced by variations in maternal care, such as ma-
ternal separation, postnatal handling, or repetitive pain
[Anand et al., 1999; Francis et al., 1999; Hennessy et al.,
1999; Liu et al., 2000]. These can be beneficial or
adversive according to the model used. They support
the notion that early stress can have an effect on the set
point of neuroendocrine responses that last until adult
life. Recent research in neonatal rat pups has shown
that rearing effects in the early postnatal period (post-
natal handling) can also attenuate the reactivity of
stress-related neuronal circuitries in the adult rat brain
[Abraham et al., 2000] and thus has important effects
on the development of behavioral and endocrine re-
sponses to stress. For example, daily handling within
the first few weeks of life (picking up rat pups and then
returning them to their mother) resulted in increased
hippocampal type II glucocorticoid receptor binding
that persisted throughout life. This was associated with
increased feedback sensitivity to glucocorticoids and re-
duced glucocorticoid-mediated hippocampal damage in
later life [Meaney et al., 1988, 1989]. As adults, the off-
spring of mothers that exhibited more licking and
grooming of pups during the first 10 days of life
showed reduced plasma ACTH and corticosterone
responses to acute stress, increased hippocampal gluco-
corticoid receptor mRNA expression, enhanced gluco-
corticoid feedback sensitivity, and decreased levels of
hypothalamic CRF mRNA [Liu et al., 1997, 2000].
These effects appear to be due to a type of “stress in-
oculation” from the mothers repeated licking of the
handled pups. Taken together, postnatal handling can
dampen HPA responsivity to stress, while if neonates
were subjected to a protracted separation from the
mother, the adult response to a stressor was exagger-
 Review Article: Circuits and Systems in PTSD, Preclinical Data
ated, e.g., showing persistently elevated cerebrospinal
fluid (CSF) concentrations of CRF [Coplan et al., 1996]
and other stress-related long-term alterations [Plotsky
and Meaney, 1993; Anisman et al., 1998; Oitzl et al.,
2000]. These and other findings in the effects of early
life stresses suggest that early in the postnatal period
there is a naturally occurring brain plasticity in key neu-
ral systems that may “program” an organism’s biologi-
cal response to stressful stimuli. In addition, recent
work on gene expression has begun to identify tran-
scription processes that are associated with the dura-
tion of a single or repeated stress. These studies
suggest that dynamic interplay is involved in convert-
ing the transient increases in the rate of transcription
into prolonged (potentially adaptive or maladaptive)
changes in gene expression [Sabban and Kvetnansky,
2001]. The effects may culminate in adult life or at
senescence in amplification of individual differences in
stress responsivity.
CIRCUITS AND SYSTEMS OF
STRESS REGULATION
IN ADULT LIFE
The corticotropin releasing factor (CRF)/HPA-axis
and the autonomic nervous system are the important
stress response systems that serve to maintain homeo-
stasis during exposure to stress. Other important
neurohormones and transmitter systems that are re-
viewed here are the dopaminergic system, serotonin,
endogenous benzodiazepine, the central amino acids
glutamate and γ-aminobutyric acid (GABA), and neu-
ropeptides like endogenous opioids, neurotensin, so-
matostatin, cholecystokinin (CCK), and neuropeptide
Y (NPY). The CRF/HPA-axis is mediated by the re-
lease of CRF (sometimes referred to as “hormone”) by
paraventricular nucleus (PVN) of the hypothalamus.
The autonomic nervous system is regulated by the LC
and its projecting noradrenergic brain neurons. Both
systems are key players in the stress responsivity and
are functionally interrelated. They both have a differ-
entiated anatomical and functional response to differ-
ent kinds of stressors, e.g., the hypothalamic PVN
neuron appears to be affected by multiple sources, in-
cluding brainstem aminergic and peptidergic afferents;
blood-borne information, indirect input from limbic
system, and associated regions, including the prefrontal
cortex, hippocampus, and amygdala; and local-circuit
interactions [Herman et al., 1996]. The neurohor-
mones and neurotransmitters involved in stress regula-
tion are summarized in Table 2.
CRF/HPA-AXIS
Hypothalamus - CRF. The PVN is the site of the
majority of CRF-containing neurons in the hypothala-
mus and is an important site in effecting cardiovascular
and neuroendocrine responses to stress. Adreno corti-
cotropin hormone (ACTH) secretion is primarily con-
129
trolled by hypothalamic secretion of CRF into pituitary
portal blood. However, arginine vasopressin (AVP),
which is co-localized in the PVN, can modulate the ac-
tions of CRF [Sawchenko et al., 1992]. Both neuropep-
tides are capable of potentiating each others’ action
and create a system in which hypothalamic control of
the pituitary-adrenocortical system has a remarkable
degree of redundancy [Makara, 1992]. Even though a
dual ACTH-secreting pathway in anterior pituitary
cells has been described, which may be controlled
separately by AVP and CRF, corticotrope cells require
CRF to maintain their capacity to secrete ACTH
[Antoni, 1993]. When CRF is released from the hypo-
thalamus, this causes release of ACTH from the ante-
rior pituitary, which stimulates release of cortisol (the
major stress hormone) from the adrenals. This axis is
turned “on” by stress and is regulated negatively by
glucocorticoids in a negative feedback loop (as well as
regulatory feedback with the noradrenergic system,
which is discussed in more detail below).
CRF is an amino acid-containing peptide that plays
a fundamental role in integrating stress-related re-
sponses throughout the neuro-immuno-endocrine axis
[reviewed in Steckler and Holsboer, 1999]. CRF has
been hypothesized to have direct behavioral effects in
the brain that lead to increased arousal, alertness, in-
creased attention, and increased readiness, which to-
gether resembles anxiety-like behavior [Behan et al.,
1996]. CRF is released from the PVN of the hypo-
thalamus; it activates anterior pituitary corticotropes,
which results in a release of ACTH in the blood-
stream. In addition to the PVN of the hypothalamus,
binding sites for CRF are located in multiple central
brain areas involved in fear and the stress response
(e.g., locus coeruleus) and also in the periphery
(spleen and direct actions on immunocytes) [De Souza
et al., 1991]. There are two CRF receptors, CRF1 and
CRF2. The latter has two splice variants, CRF2α and
CRF2β [Chalmers et al., 1996]. Both receptor types are
distinct in their localization in the brain. CRF1 recep-
tors are most abundant in neocortical, cerebellar, hy-
pothalamic, pituitary, and sensory relay structures,
hippocampus and amygdala; CRF2 receptors are gen-
erally localized to specific subcortical structures, most
notably lateral septal nuclei, choroid plexus, olfactory
bulb, amygdaloid nuclei, and various hypothalamic areas.
CRF has a higher affinity for CRF1 than CRF2. With-
in the pituitary, CRF1 expression predominates over
CRF2 expression, suggesting that CRF1 receptors may
mediate CRF-induced changes in ACTH release.
Central injection of CRF potently stimulates the re-
lease of ACTH from the pituitary [Adamec et al.,
1998], resulting in physiological and behavioral re-
sponses, which are adaptive during stress and which
are considered to be characteristic of anxiety re-
sponses. These include increased motor activity, loco-
motion and grooming in an open field environment,
and decrease in punished responding and time spent
on the open arm of an elevated T-maze. When in-
 130
TABLE 2. Overview of CNS neurotransmitter and neurohormonal systems involved in stress regulation

Brain regions Neurobiological

Agent Receptor involved CNS actions effects of stress Biobehavioral symptoms Remarks
HPA-axis
CRF (AVP) CRF1 NEOCOR, CEREB, Release of ACTH in bloodstream; ACUTE/CHRONIC: Metabolic activation, arousal, Receptor block shows
HIP, AMYG, LC, stimulates NE systems via LC increased release alertness, readiness to res- elimination of ACTH
THAL,PAG pond, increased startle, response; affinity of CRF
CRF2α SUBCOR, septal retention of inhibitory for CRF1>CRF2
CRF2β nuclei, choroid avoidance response, anxiety
plexus, olf. bulb,
AMYG, HYPO
ACTH ACTH-R ACUTE/CHRONIC:
dependent of model:
increased release,
sensitized release
Glucocorticoids/
Cortisol Type I HIP and brain Regulation of energy utilization; ACUTE: Hyperarousal; fight-flight;
inhibition of growth, and increased release coping with threat,
Type II Throughout the reproductive systems; CHRONIC: classic stress effects: hyper-

Vermetten et al.
brain containment of inflammatory dependent of model: tension, diabetes, gastric
response increase or decrease ulceration, immunosupression,
osteoporosis, muscle atrophy,
in CNS: hippocampal atrophy
Locus coeruleus
NE α adrenergic LC, COR, SUBCOR, Drives up glucose metabolism ACUTE: Anxiety, fear, hypervigilance, α2-antagonist (yohimbine)
receptor HIP, HYPO, in brain regions; stimulates CRF increased turnover; hyperarousal, irritability, blocks presynaptic
(and AMYG,THAL, systems increased responsive- attention, encoding of autoreceptor; stress
subtypes) bed n. stria ness of LC neurons memories sensitization; condi-
terminalis, NA, to repeated stress tioned fear
β adrenergic desc. proj. thor. CHRONIC:
receptor spinal cord depletion
(and
subtypes)
Dopamine
DA D1 receptor PFC, NA Control of locomotion, cog- ACUTE/CHRONIC: Vigilance, paranoia?, planning, Preferential increase in PFC
D2 receptor nition, affect and neuro- increased release, monitoring functions in stress; modulation of
endocrine secretion; turnover response by NMDA and
increase the gain of neuronal opiate receptor blockade,
information processing or preadmin with Bzs
Serotonin
Serotonin 5HT1 (and mPFC, NA, AMYG, Regulation of neuroendocrine ACUTE: Anxiety, vigilance control of Learned helplessness;
subtypes) HYPO, LC, HIP function: stimulatory at PVN, increased turnover mood; perception-learning; reversibility by SSRI;
5HT2 (and and stimulatory at adrenal CHRONIC: sleep induction; regulation preadmin of TCA Bz or
subtypes) level (?) depletion; changes in of food intake; control of SSRI is preventative against
receptor density aggression decreases in serotonin
(continued)
TABLE 2. (Continued).

Brain regions Neurobiological

Agent Receptor involved CNS actions effects of stress Biobehavioral symptoms Remarks
Endogenous Bzs
Endogenous Bz receptors Throughout the ACUTE/CHRONIC: Alterations in memory; Functional coupling with
Bzs brain, in particu- decreased Bmax anxiety and fear GABA receptor; prevention
lar HIP and COR by preadmin with Bzs, or
flumazenil
Peptides
Endogenous µ MB-PAG, medulla, Decreased firing of LC; ACUTE/CHRONIC: Analgesia; numbing; Receptor antagonist naltrexone
δ n raphe, HIP, COR inhibition of HPG axis increased release encoding of memories blocks SIA
κ decrease density of
υ-receptors
NT NT receptor HYPO, lat septum, Endogenous modulator of ACUTE/CHRONIC: NT prevents gastric ulcer
AMYG, HIPP various functions (e.g., increased release formation in chronically
attenuation of DA-induced stressed animals
inhibition)
Somatostatin SRIF receptor HYPO, AMYG, HIP, Inhibitor of HG secretion ACUTE/CHRONIC: Changes in sleep pattern,
COR, median increased release changes in food intake;
preoptic area, NA changes in locomotor
activity; changes in memory
CCK4/CCK8 CCKA COR, AMYG, HIPP, Modulates activity of opoids ACUTE/CHRONIC: Anxiogenic effects, alterations Receptor block has anxiolytic
CCKB1 PAG, s nigra, raphe and DA; stimulatory increased release in attention and memory effect, including alterations
CCKB2 nuclei (CCKB pre- effect on HIP in attention and memory
dominates in the (CCKB1 effect)
brain)
NPY NPY-1 Basal ganglia, NA, Modulation of fear, ACUTE/CHRONIC: Attenuated sensitivity to
NPY-2 Caudate Putamen, spatial memory increased release stress; impairment of
AMYG, HYPO, acquisition spatial memory acquisition
COR
Central amino acids
Glutamate MPFC, HIP, NA Regulation of emotion and ACUTE: Effect of stress-induced
mood increased release increase is blocked by
CHRONIC: adrenalectomy
attenuation of
Review Article: Circuits and Systems in PTSD, Preclinical Data

increased release
GABA GABA(A) MPFC, HIP, and Regulation of emotion and ACUTE/CHRONIC: Effect of stress-induced
GABA(B) other brain mood increased turnover increase is blocked by
regions increased level of adrenalectomy; functional
neurosteroids coupling with Bz-receptor
modulation of DA neurons
by GABA-ergic system
HIP, Hippocampus; HYPO, hypothalamus; PITU, pituitary; LC, locus coeruleus; (NEO)COR, cerebral cortex; AMYG, amygdala; PFC, prefrontal cortex; NA, nucleus accumbens; MB, midbrain; THAL,
thalamus; PAG, periaquaeductal gray. Other abbreviations are explained in the text.
131
132 Vermetten et al.
jected into the amygdala, CRF causes an increase in
the magnitude of the startle response and significantly
improved retention of the inhibitory avoidance re-
sponse, a measure of learning and memory [Dunn and
Berridge, 1990]. Blockade of CRF can eliminate the
ACTH response to various stress conditions. Mice de-
ficient for CRF2 are found to be hypersensitive for
stress and display anxiety-like behavior [Bale et al.,
2000]. These findings suggest that CRF receptor an-
tagonists may be useful for the treatment of disease
states where CRF is elevated.
Pituitary - ACTH. Corticotropin or ACTH is a
peptide that acts at the adrenal cortex to release glu-
cocorticoids (cortisol and corticosterone), the primary
peripheral stress hormones. In normal circumstances,
the rate of secretion is maintained in narrow limits;
however, conditions of physical and emotional stress
result in release of CRF as well as ACTH and
glucocorticoids. The ACTH receptor (ACTH-R) is
mainly expressed in the adrenocortical cells. Gluco-
corticoids as well as cortisol, exerting powerful in-
hibitory influences on the secretion of ACT, effect
their actions intracellularly, mainly via glucocorticoid
receptors (GRs). The mechanism responsible for
transient stress-induced hyperadrenocorticism and
feedback resistance may involve a downregulation of
glucocorticoid receptors [Sapolsky and Plotsky, 1990].
High glucocorticoid levels (such as those elicited by
chronic stress) decrease the number of hippocampal
GRs, resulting in increased corticosterone secretion
and feedback resistance. Following stress termina-
tion, when glucocorticoid levels decrease, a physi-
ological downregulation takes place where receptor
numbers are increased and feedback sensitivity is
normalized [Sapolsky et al., 1984a,b].
The effects of chronic stress on ACTH and corti-
costerone secretion vary, depending on the experi-
mental paradigm. It has been reported that when rats
were placed in a stressful environment for 24 hr with
intermittent additional exposure to inescapable foot-
shock, levels of plasma corticosterone were elevated
during the first days in the stressful environment but
returned to normal levels later. Levels of plasma
ACTH were similar in stressed and control rats
throughout this time [Kant et al., 1987]. Other inves-
tigations have revealed increases of plasma corticoster-
one concentrations after exposure to acute inescapable
shock. Plasma corticosterone concentrations were el-
evated irrespective of whether the animals received
single or repeated sessions of inescapable footshock
[Irwin et al., 1986]. There is also evidence that the ex-
perience of prior stress results in sensitized corticos-
terone responses to a subsequent stress exposure.
Animals exposed to footshocks 10 days before testing
exhibited a higher plasma corticosterone response to
testing than did control animals that were not prior
exposed to footshocks [Dallman and Jones, 1973;
Caggiula et al., 1989]. It is not exactly known which
factors determine whether adaptation or sensitization
of glucocorticoid activity will occur following chronic
stress [Yehuda et al., 1991].
The HPA-axis has important functional interactions
with the norepinephrine system that facilitate a so-
phisticated range of responses to stress. An enhance-
ment of the catecholaminergic system has stimulatory
effects on ACTH secretion. Subsequently, glucocorti-
coids inhibit stress-induced activation of catechola-
mine synthesis in the PVN [Kvetansky et al., 1993;
Pacak et al., 1993]. Data obtained from adrenalecto-
mized rats, with or without glucocorticoid replace-
ment, and from hypercortisolemic rats suggest that
glucocorticoids feedback to inhibit CRH release in the
PVN, via attenuation of noradrenergic activation
[Pacak et al., 1995]. CRF, on the other hand, increases
activity of the LC [Valentino and Foote, 1988; Valen-
tino and Wehby, 1988] and CRF injected into the LC
intensifies anxiety-related responses [Butler et al.,
1990]. Forced swim stress selectively altered regula-
tion of LC sensitivity to CRF 24 hr after the swim
stress, showing that stress functionally alters CRF re-
ceptors that have an impact on LC activity [Curtis et
al., 1999]. These findings support the notion of stress-
induced regulation of LC sensitivity to CRF and that
CRF serves as an excitatory neurotransmitter in the LC
in the initiation of stress responses, which may repre-
sent the pathway for the behavioral effects of CRF.
Adrenal gland - Cortisol. Adrenocortical produc-
tion of corticosteroids is regulated by pituitary release
of ACTH. Exposure to acute stress results in an in-
crease in glucocorticoids, which is mediated by CRF
and ACTH [McEwen et al., 1986]. Glucocorticoid se-
cretion is tightly regulated by negative feedback on
CRF and ACTH [McEwen, 1979]. The adrenal gland
combines essential components of the autonomic ner-
vous system and the HPA axis in close contact. The
chromaffin cells of the adrenal medulla and the steroid-
producing cells of the adrenal cortex are extensively in-
termingled and functionally interrelated. Cortisol is
converted from cholesterol in different steps. Binding
sites for glucocorticoids include the type I (corticoster-
one or mineralocorticoid) receptor and type II (gluco-
corticoid) receptor, with different affinities for cortisol
and the other glucocorticoids (such as dexamethasone).
The highest number of bindings sites for type I recep-
tor is in the hippocampus [Reul and de Koet, 1986],
while type II is found ubiquitously throughout the
brain. The type II receptor becomes more critically in-
volved as plasma levels rise.
Cortisol stimulates increased gluconeogenesis to
regulate energy utilization in the acute situation.
When stress lasts, it starts to exert a role in inhibition
of growth processes, inhibition of reproductive sys-
tems, and containment of inflammatory responses
[Baxter and Rousseau, 1979]. More recently a function
of cortisol role in rewarding processes has been hy-
pothesized, in which cortisol counteracts the aversive
effects of external aggression and also allows a better
coping with threatening situations [Piazza and Le-
 Review Article: Circuits and Systems in PTSD, Preclinical Data
Moal, 1997]. Some studies have shown a decrease in
glucocorticoid levels following exposure to chronic
stress, while others have shown an increase [see
Bremner, 2001]. Animals with a history of prior expo-
sure to stress respond to subsequent stressors with a
delay in the return of glucocorticoids to baseline fol-
lowing exposure to the stressor [reviewed in Nemeroff
and Schatzberg, 1988].
LOCUS COERULEUS/NOREPINEPHRINE
SYSTEM
Accumulated evidence suggests a relationship be-
tween alterations in noradrenergic brain systems and
stress [reviewed in Bremner et al., 1996a,b; Tanaka et
al., 2000]. The majority of noradrenergic cell bodies
are located in the brainstem, in the dorsal pontine teg-
mentum, with a dense network of axons that extend
throughout the cerebral cortex and to multiple corti-
cal and subcortical areas, including hippocampus,
amygdala, thalamus and hypothalamus, bed nucleus of
stria terminalis, and nucleus accumbens, as well as de-
scending projections that synapse at the level of the
thoracic spinal cord [Foote et al., 1983]. The locus co-
eruleus/norepinephrine (LC/NE) network serves glo-
bally as a generalized warning system and helps
determine whether, under threat, an individual turns
attention towards external sensory stimuli or to inter-
nal vegetative states [Nakamura and Sakaguchi, 1990].
The LC utilizes mainly NE as their neurotransmit-
ter, accounting for most of the noradrenergic input to
the limbic system [van Dongen, 1981]. Ascending NE
pathways project to the PVN and exert excitatory ef-
fects on HPA-axis. LC also uses peptides like neu-
ropeptide Y (NPY) and galanin, thereby showing
heterogeneity of transmitter content. The neuroana-
tomical formation of the LC/NE system makes it well
suited to rapidly and globally modulate brain function
in response to changes in the environment. Electrical
stimulation of the LC in the cat produces a behavioral
response similar to naturally occurring fear. The lim-
bic and cortical regions innervated by the LC are
those thought to be involved in the elaboration of
adaptive responses to stress, such as an arched back,
piloerection, flattened ears, increased heart rate and
blood pressure, and mydriasis [Foote et al., 1983;
Abercrombie and Jacobs, 1987a,b]. Decreasing func-
tion of the LC (interacting with inhibitory opiates,
benzodiazepines, and a2-receptors on LC) results in
decreases in fearful behavior. Acute stressors such as a
cat seeing a dog or another aggressive cat result in an
acute increase in firing of neurons in the LC [Levine
et al., 1990], the hippocampus, and medial prefrontal
cortex [Finlay et al., 1995]. If the cat would have been
chronically stressed, it would demonstrate an en-
hanced NE release [Nisenbaum et al., 1991]. Repeti-
tive stress in the form of re-exposure to a stressor after
a period of time without stress results in an increased
turnover and release of NE in the cortex, hippocam-
pus, amygdala, hypothalamus, and LC [Cassens et al.,
133
1980; Nisenbaum et al., 1991; Tanaka et al., 2000].
This sensitized NE release in LC and hippocampus
has been demonstrated to be dose-dependent in-
creased with subsequent stressors [Page and Aber-
crombie, 1999], illustrating the mechanism of stress
sensitization. This mechanism refers to a stressor-in-
duced increase in behavioral, physiologic, and bio-
chemical responding to subsequent stressors of the
same or lesser magnitude. Drugs that decrease the
function of the LC by interacting with inhibitory opi-
ate, benzodiazepine, and a2-adrenergic receptors on the
LC decrease fearful behavior and antagonize the effects
of electrical stimulation of the LC [Charney et al.,
1990]. Cocaine inhibits spontaneous LC neuron activ-
ity, which could be reversed by the specific a2-adrener-
gic antagonist piperoxone, and pretreatment with
another a2-adrenergic antagonist, yohimbine, also at-
tenuated the inhibitory effect of cocaine on the LC
[Redmond and Huang, 1979; Pitts and Marwah, 1987].
The LC/NE and CRF/HPA-axis system mutually
stimulate each other and respond similarly to messen-
gers in the neurochemical environment. What both
systems have in common is that they are inhibited by
opiates and γ-aminobutyric acidergic (GABA) agents,
and excited by serotonergic and cholinergic agents,
and both systems are inhibited by glucocorticoids
[Michelson et al., 1995]. They are different in their
temporal response patterns: the LC/NE system is fast
and depletes earlier than the CRF/HPA-axis that starts
after some minutes but lasts longer.
DOPAMINERGIC SYSTEM
In the central nervous system (CNS), dopamine is
predominantly released from the ventral tegmental
area and is involved in the control of locomotion, cog-
nition, affect, and neuroendocrine secretion [Smythe,
1977; Bunny et al., 1980; Jaber et al., 1996]. Dopam-
ine (DA) also has been assigned the capacity to in-
crease the gain of neuronal information processing
[Haracz et al., 2000]. Molecular biology and pharma-
cology studies have revealed existence of at least five
dopamine receptor subtypes, namely, D1, D2, D3,
D4, and D5. The widespread biological actions of DA
are mediated by two major classes of receptor, the
D(1) class [D(1) and D(5)] and the D(2) class [D(2),
D(3), and D(4)] [LaHoste et al., 2000]. Three major
dopaminergic neuronal systems have been described,
which include nigrostriatal (projecting from substantia
nigra to striatum), mesolimbic (projection from mid-
brain to nucleus accumbens), and mesocortical/meso-
prefrontal (projection from midbrain to prefrontal
cortex) systems. DA innervation of the medial pre-
frontal cortex (mPFC) appears to be particularly vul-
nerable to even mild and brief stress. Preclinical
studies are in support of the fact that both acute and
chronic stress may have a negative impact on the nor-
mal function of the DA system. Sufficiently low inten-
sity stress (such as that associated with conditioned
134 Vermetten et al.
fear) or brief exposure to stress increases dopamine re-
lease and metabolism in the prefrontal cortex in the
absence of overt changes in other mesotelencephalic
DA regions [Deutch et al., 1985; Deutch and Roth,
1990; Thierry et al., 1998]. Low intensity electric
footshock increases in vivo tyrosine hydroxylase and
dopamine turnover in the mPFC, but not the nucleus
accumbens or striatum [Roth et al., 1988]. Daily treat-
ments of inescapable footshocks to rats results in an in-
crease level of dopamine metabolites, DOPAC, in the
prefrontal cortex, and HVA in the nucleus accumbens
[Kalivas and Duffy, 1989]. Stress can enhance DA re-
lease and metabolism in other areas that receive DA
innervation, provided that greater intensity or longer
duration stress is used [Roth et al., 1988; Deutch and
Roth, 1990]. Thus, the mPFC DA innervation is
preferentially activated by stress compared with
mesolimbic and nigrostriatal systems, whereas the
mesolimbic dopamine innervation appears to be more
sensitive to stress than the striatal dopamine innerva-
tion [Deutch et al., 1985; Abercrombie et al., 1989;
Mantz et al., 1989; Deutch and Roth, 1990]. The fact
that the dopaminergic system after stress responds,
preferentially, in the mPFC, is thought to serve as a
protection against positive psychotic symptoms, since
the increased DA activity in the mPFC suppresses lim-
bic DA transmission. Mesoprefrontal DA neurons lack
or have decreased densities of specific autoreceptors af-
fecting autoregulatory capabilities, which is thought to
contribute to the fact that mesoprefrontal DA neurons
exhibit increased rates of burst firing and DA turnover
relative to other midbrain dopaminergic projections.
Stress-induced increases in mesoprefrontal cortical
dopamine release are susceptible to modulation by sev-
eral neurotransmitter systems, including GABA, N-
methyl-D-aspartate (NMDA), serotonin, excitatory
amino acid, substance P, opiate, and noradrenergic sys-
tems. Any or all of these factors can contribute to the
selective activation of mesoprefrontal DA neurons fol-
lowing exposure to low intensity stressors. Blockade of
these neurotransmitter systems prevents stress-induced
activation of the cortical dopamine system [Kalivas and
Abhold, 1987]. Despite empirical problems, intracra-
nial “self-stimulation” of dopaminergic systems has
been used as a model for anhedonia, or decreased plea-
sure to engage in activities, suggesting that numbing,
decreased interest, or being cut off may be related to
alterations in dopaminergic systems [Salamone et al.,
1997]. Serotonin is thought to play an important role
in lack of stimulation of dopamine release in the
nucleus accumbens, thus leading to anhedonia and lack
of motivation, and therefore may be a target for modu-
lation by antidepressant drugs [Zangen et al., 2001].
Long-term treatment with serotonergic agents (imi-
pramine and mirtazapine) has shown to inhibit the ef-
fect of footshock on cortical dopamine output in rats
[Dazzi et al., 2001].
The prefrontal cortex has been suggested to play a
role in “working memory” in conjunction with other
brain areas like hippocampus. A critical range of DA
turnover is necessary for keeping this “working
memory system” active and ready for optimal cogni-
tive functioning [Horger and Roth, 1996], a situation
that is impaired in situations extreme or chronic stress
[Arnsten, 2000]. In summary, the DA system is impor-
tant for general emotional responses, selective infor-
mation processing, for hedonic impact or reward
learning, and, in a broader sense, for reactivity to per-
turbation in environmental conditions, which are es-
sential functions in the ability (or failure) to cope with
the external world [reviewed in Pani et al., 2000].
SEROTONIN
Serotonin is involved in a wide variety of processes:
anxiety, arousal, vigilance, aggression, mood, impul-
sivity, and regulation of food-intake. The role of sero-
tonin in stress responsivity is best understood as
stressor specific. Anatomical as well as functional evi-
dence is supportive of a regulatory role for serotonin
on stress-induced HPA activity [Phelix et al., 1992;
Dinan, 1996]. At the same time however, serotonin is
able to increase corticosterone secretion at the adrenal
level [Bagdy et al., 1989]. Animals exposed to a variety
of stressors including footshock, tail shock, tail pinch,
and restraint stress have all been shown to produce an
increase in serotonin turnover in the medial prefrontal
cortex [Petty and Sherman, 1983; Adell et al., 1988;
Pei et al., 1990; Inoue et al., 1994], nucleus ac-
cumbens, amygdala, and lateral hypothalamus, and LC
[Kaehler et al., 2000] with preferential release during
conditioned fear in mPFC [Inoue et al., 1994]. A more
widespread activation after more severe stress is
thought to relate to behavioral changes that reflect an
augmentation of fear; chronic electric shock produc-
ing “learned helplessness” behavioral deficits were as-
sociated with reduced in-vivo release of serotonin in
frontal cortex [Petty et al., 1992], probably reflecting a
situation where synthesis is not able to keep pace with
demand. After inescapable stress, 5-HT2A receptor
density was decreased in the hypothalamus in helpless
rats as compared to control rats that were stressed but
not helpless. While there were no changes in density
in 5-HT1A receptors in any brain region, decreases
were found for 5-HT2A receptor density in hippocam-
pus and amygdala, related to stress but not related to
helplessness. In mPFC, the serotonin transport sites
showed decreased density in helpless rats as compared
to controls but not to nonhelpless rats [Wu et al.,
1999]. Chronic restraint, however, has shown to result
in a decrease in 5HT1A binding in the hippocampus
[Mendelson and McEwen, 1991; Watanabe et al.,
1993]. Animals exposed to social stress also had an in-
crease in binding of 5-HT1A receptors in hippocampus
and dentate gyrus, and a decrease in 5-HT2 binding in
parietal cortex [McKittrick et al., 1995]. Preclinical
studies have provided evidence that the capability to
increased serotonin metabolism during exposure to in-
escapable stress prevents helplessness [Ronan et al.,
 Review Article: Circuits and Systems in PTSD, Preclinical Data
2000]. Serotonin antagonists produce behavioral defi-
cits resembling those seen following inescapable
shock. Drugs that enhance serotonin neurotransmis-
sion (SSRI) are effective in reversing the learned help-
lessness [Sherman and Petty, 1980; Martin et al.,
1990]. Pre-administration of benzodiazepines or tricy-
clic antidepressants has been described to prevent
stress-induced decreases in serotonin and the acquisi-
tion of behavioral deficits [Petty et al., 1992], while
injection of serotonin (5HT) into the frontal cortex
after stress exposure reverses behavioral deficits [Sher-
man and Petty, 1982]. Administration of 5-HT1A ago-
nists such as buspirone resulted in a reversal of
stress-induced behavioral deficits [Drugan et al., 1989;
Przegalinski, et al., 1995]. A natural increase in the
level of 5-HIAA in the lateral septum seemed protec-
tive from adverse behavioral consequences of inescap-
able stress [Ronan et al., 2000].
ENDOGENOUS BENZODIAZEPINES
Endogenous benzodiazepines (Bz) also play an im-
portant role in the stress response and anxiety [re-
viewed in Guidotti et al., 1990]. Bz-receptors are
present throughout the brain with the highest concen-
tration in cortical gray matter. Benzodiazepines poten-
tiate and prolong the synaptic actions of the inhibitory
neurotransmitter GABA. Central Bz-receptors and
GABA receptors are part of the same macromolecular
complex. These receptors have distinct binding sites,
although they are functionally coupled and regulate
each other in an allosteric manner. Administration of
inverse agonists of Bz-receptors, such as β-carboline-
3-carboxylic acid ethyl ester (β-CCE), result in behav-
ioral and biological effects similar to those seen in
anxiety and stress, including increases in heart rate,
blood pressure, plasma cortisol, and catecholamines
[Braestrup et al., 1982]. These effects are blocked by
administration of Bz [Ninan et al., 1982] or pretreat-
ment with the benzodiazepine antagonist flumazenil
(formerly designated Ro-15-1788) [Drugan et al.,
1985]. Animals exposed to acute inescapable stress in
the form of cold swim or footshock develop a decrease
in Bz-receptor binding (Bmax) in frontal cortex, with
mixed results for cerebral cortex, hippocampus, and
hypothalamus, and no change in occipital cortex, stria-
tum, midbrain, thalamus, cerebellum, and pons [Lippa
et al., 1978; Skerritt et al., 1981; Medina et al.,
1983a,b; Drugan et al., 1986; Weizman et al., 1990].
Chronic stress in the form of footshock or cold swim
resulted in decreases in Bz-receptor binding in cere-
bral cortex, frontal cortex, hippocampus, and hypo-
thalamus, with mixed results for cerebellum, midbrain,
and striatum, and no changes in occipital cortex or
pons [Braestrup et al., 1979; Drugan et al., 1986,
1989; Weizman et al., 1990; Lehmann et al., 1999].
Decreases in Bz-receptor binding (Bmax) are associated
with alterations in memory manifested by deficits in
maze-escape behaviors [Weizman et al., 1989; Drugan
et al., 1989]. Changes in Bz-receptor function appear
135
to be specific to uncontrollable stress, as opposed to
controllable stress, and are prevented by pre-adminis-
tration of benzodiazepines [Drugan et al., 1984]. In
addition, animals exposed to inescapable stress exhibit
decreases in binding of the Bz-receptor antagonist
flumazenil [Drugan et al., 1989], which are associated
with deficits in learning, and decreased depolariza-
tion-induced release of GABA relative to controls
[Petty and Sherman, 1981]. A decrease in Bz-receptor
binding (Bmax) has been demonstrated in the so-called
Maudsley genetically fearful strain of rat in compari-
son to non-fearful rats in several brain structures in-
cluding the hippocampus [Robertson et al., 1978].
NEUROPEPTIDES
Exposure to stress has marked effects on the activity
of a number of other CNS neuropeptides systems.
The neuropeptides that are considered to mediate the
response to stress, based upon preclinical studies, are
CRF (see above), endogenous opioid peptides, neuro-
tensin, somatostatin, cholecystokinin (CCK), neuro-
peptide Y, and others, such as substance P, vasopressin,
oxytocin, vasointestinal polypeptide (VIP), and thy-
rotropin-releasing hormone (TRH) [Stout et al.,
1995]. Neuropeptides account for neurotransmission
at a very large percentage of synapses in the brain.
Since many neuropeptides are hypothalamic pituitary
hormones, directly controlling the secretion of ante-
rior pituitary hormones, they can function both as hor-
mones in the hypothalamic-hypophysial portal system
and as neurotransmitters in CNS. There is a different
response of specific neuropeptides circuits to distinct
stressors.
Endogenous opioids. All of the endogenous
opioids have a role in stress responsiveness. The opioid
peptides comprise three sets of peptide classes, β-en-
dorphin, enkephalins, and dynorphins [Olson et al.,
1985]. The β-endorphins are secreted by the pituitary
gland and reach all tissues present in the body by diffu-
sion. There are three major opioid receptor types: µ, δ,
and κ [Loh and Smith, 1990]. Naloxone or naltrexone
is an example of a rather selective µ-receptor antago-
nist. The design of more selective antagonists for each
of the opioid receptors has enabled more accurate dis-
section of the role of different opioid systems. The
neural circuitry of the opioid system is very complex
and is thought to produce its action through the mid-
brain periaquaeductal gray (PAG), projecting to the
medulla, including the nucleus raphe magnus, which
sends out noradrenergic and serotonergic projections
to the spinal cord [see review Vaccarino et al., 1999]. A
variety of stressful stimuli have been documented to
produce diminished responsiveness to pain or stress-
induced analgesia (SIA) [Terman et al., 1984]. Stress is
associated with an increase in endogenous opiate re-
lease [Madden et al., 1977; Grau et al., 1981] with de-
creased density of µ-opiate receptors [Stuckey et al.,
1989], which may mediate the analgesia associated with
stress. The reversal of some forms of SIA by naloxone
136 Vermetten et al.
has suggested that opioids play an important role in this
response. The opioids have another role in the stress
responsivity by their role to inhibit the hypothalamic-
pituitary-gonadal (HPG) axis. Exercise or psychological
stress in women has been described to result in amenor-
rhea or cause other dysregulations in fertility [Magiakou
et al., 1997; Dobson and Smith, 2000]. β-endorphins
[Norman and Smith, 1992] and CRF antagonists [Rivier
et al., 1986] have demonstrated to be able to block
stress-induced inhibition of HPG-axis function and thus
are both considered to be mediators of HPG-axis sup-
pression. CRF-opioid interactions are common in many
stress responses.
Neurotensin. Neurotensin (NT) also has a pri-
mary role as a neurotransmitter in CNS. NT and its
receptor are distributed in hypothalamus, septum,
amygdala, and hippocampus, and the receptors are
proximal to the cell bodies of origin of the classical
neurotransmitters [Jennes et al., 1982]. The modulatory
effect of NT, that is, the attenuation of DA-induced in-
hibition, has been most extensively examined [Shi and
Bunney, 1992]. A role for NT in stress is suggested by
the protective effects of centrally administered NT on
restraint-stress-induced gastric ulcers in rats [Nemeroff
et al., 1982], by its role as endogenous modulator of
body temperature or nociceptive sensory information
[Kalivas et al., 1982] and by its role in the acute increase
of the activity of mesolimbic dopamine neurons, the se-
cretion of ACTH, and an increase in serum corticoster-
oids after central administration [Gudelsky et al., 1989].
This leads to another role for NT in the CNS response
to stress, which comes from the functional and ana-
tomical association between NT- and DA-containing
neurons in the brain. Some studies have found support
for increases in concentration of NT in patterned de-
pendence of mesotelencephalic dopaminergic neurons
by conditioned stress experiments [Deutch et al., 1987;
Kilts et al., 1992].
Somatostatin. Somatostatin (somatotropin re-
lease-inhibiting factor, SRIF) is the major inhibitor of
growth hormone (GH) secretion. It is found widely
distributed in the brain with high concentrations in
PVN of the hypothalamus, amygdala, hippocampus,
cerebral cortex, median preoptic area, and nucleus
accumbens [Krisch, 1981]. Behavioral effects of cen-
trally administered SRIF include delayed extinction of
avoidant behavior, changes in sleep pattern, food in-
take, locomotor activity, and memory processes [Vec-
sei et al., 1984]. SRIF appears to be released in
response to CRF and increases in response to stress
immobilization [Benyassi et al., 1993a]. Chronic daily
immobilization stress has resulted in an increased
basal, as well as stress-induced SRIF release and de-
creased growth hormone release; prolonged increase
in SRIF has been reported to counter an increase in
GRF and suppresses GH secretion [Armario et al.,
1993; Benyassi et al., 1993b].
Cholecystokinin. Cholecystokinin (CCK) is a
potent anxiogenic gastrinlike neuropeptide synthe-
sized in the gastrointestinal tract and exerts its effects
there as well as widespread in the brain. It has only
recently been suggested as a neural substrate for hu-
man anxiety. CCK exists in the CNS both as an oc-
tapeptide (CCK-8) and as a tetrapeptide (CCK-4).
The octapeptide form CCK-8 in particular in the ce-
rebral cortex, the amygdala, and the hippocampus.
The CCK receptors are also found in the midbrain in-
cluding the periaqueductal gray, substantia nigra, and
raphe nuclei. CCK is co-localized with opioid pep-
tides and dopamine and modulates the activity of these
neurotransmitter systems. Two receptor subtypes have
been cloned; a CCKA and CCKB receptor. CCKB pre-
dominates in the brain. Preclinical data suggest that
agonists of CCKB produce anxiogenic-like effects,
while CCK B antagonists induce anxiolytic-like re-
sponses in several models of anxiety [Fekete et al.,
1984; Van Megen et al., 1994; Cohen et al., 1999].
CCKB is also involved in attention and memory, in de-
pendence of the dopaminergic system. More recently,
two different CCKB bindings sites have been hypoth-
esized, CCKB1 and CCK B2, of which in particular
CCKB1 appears to be responsible for the effects of anxi-
ety [Dauge and Lena, 1998]. Iontophoretic administra-
tion of CCK has depolarizing effects on pyramidal
neurons, suggesting that it may serve as an excitatory
neurotransmitter [Bradwejn and DeMontigny 1984,
1985]. Both CCK-4 and CCK-8 have stimulatory ef-
fects on action potentials in the dentate gyrus of the
hippocampus. Activation of hippocampal neurons to
CCK is suppressed by low-dose benzodiazepines, more
attributable to their role as anxiolytic drug than as seda-
tive drug [Bouthillier and DeMontigny, 1988].
Neuropeptide Y. Neuropeptide Y (NPY) is one of
the most abundant neuropeptides in the brain. It is
present in brainstem nuclei, nucleus accumbens,
amygdala, hypothalamus, and cerebral cortex [Adrian
et al., 1983]. Two receptor subtypes have been de-
scribed, the Y1 and Y2 receptor [Wahlestedt et al.,
1990]. It is suggested to act as an endogenous anxio-
lytic by diminishing the effects of other peptides as
CRF. Direct injection of NPY in the amygdala has an
anxiolytic effect [Heilig et al., 1993] and is protective
against restraint stress-induced gastric ulceration in
rats [Penner et al., 1993]. NPY-transgenic rats provide
a good model to examine the role of endogenous NPY
in control of stress- and anxiety-related behaviors.
Transgenic rats showed a markedly attenuated sensi-
tivity to behavioral consequences of stress; they were
insensitive to the normal anxiogenic-like effect of re-
straint stress and displayed absent fear suppression of
behavior in a punished drinking test. In these rats a
selective impairment of spatial memory acquisition
was found in conjunction with a decreased NPY-Y1
binding within the hippocampus, thus providing novel
evidence for a role of NPY in learning and memory
[Thorsell et al., 2000].
Other neuropeptides. Other neuropeptides and
their role in stress responsiveness have been less stud-
 Review Article: Circuits and Systems in PTSD, Preclinical Data
ied. However, some have important indirect contri-
butions to the stress responsiveness. The neurokinin
substance P (SP) has been previously shown to in-
hibit basal HPA-axis activity [Donnerer et al., 1991].
The SP receptor is highly expressed in areas of the
brain that are implicated in anxiety and stress but
also in other areas such as the nucleus accumbens,
which mediate the motivational properties. Recent
data show that endogenous SP does not inhibit the
initial magnitude of the HPA axis response to re-
straint stress but does act through neurokinin-1 re-
ceptors at a central level to reduce the duration of
the response to stress, suggesting that SP may be an
important central agent controlling the transition be-
tween acute and chronic stress [Jessop et al., 2000].
Its role as a regulatory peptide has also been de-
scribed in other studies involving SIA where it
modulates sensitivity to pain [De Felipe et al., 1998]
and acts as a mediator in stress induced immune ac-
tions [Fehder et al., 1997].
Vasopressin (VP) is released from the nerve termi-
nals in the pituitary and has a major role in fluid and
electrolyte balance in response to dehydration. It also
contributes to HPA-axis regulation, potentiating the
effect of CRF on ACTH release. It is also suggested
to have an effect on the firing rate of hippocampal
neurons.
Systemic effects of oxytocin (OT) include milk let-
down and uterine contractility at the time of parturi-
tion. It also stimulates prolactin secretion and, like
VP, it potentiates CRF-stimulated ACTH release
[Gibbs, 1986]. There is considerable evidence that
CRF and, to a lesser extent, VP and OT are not only
involved in the regulation of ACTH secretion in re-
sponse to stress, but are also major regulators of stress
responsiveness.
Vasoactive intestinal peptide (VIP) is a peptide first
isolated from the intestine and is distributed over the
entire body but primarily in the nervous system. It is
important in a variety of extra-intestinal actions,
which are typical of the body’s reaction to stress, such
as lipolysis, glycogenolysis, and modulation of anterior
pituitary hormone secretion. It is released in response
to stress and has demonstrated to have preventive ef-
fects on gastric ulcer formation in a cold-restraint
stress model [Tuncel et al., 1998].
Thyrotropin releasing hormone (TRH) and thyroid
stimulating hormone (TSH) have been less used in
animal models of stress, probably because the com-
plexity of the TSH response to stressors indicates that
this hormone is not an adequate index of the stress ex-
perienced by the animals [Armario and Jolin, 1989].
More neuropeptides are being found, such as Pro-
lactin (PRL)-releasing peptide (PRP), which is a re-
cently discovered hypothalamic peptide [Watanobe et
al., 2000]. Stress also has important effects on the im-
mune system that are not reviewed here in detail [for
more detail, see accompanying paper: Vermetten and
Bremner, 2002].
137
CENTRAL AMINO ACIDS
Of the central amino acids, glutamate and GABA
are the most important ones in stress research.
Glutamate is the main representative of excitatory
amino acids; GABA the prototypical inhibitory
amino acid. Both have a role in the organism’s re-
sponse to stress and are believed to influence emotive
states in the organism.
Glutamate. Glutamate has a role as a neurotransmit-
ter acting via several types of receptor, including the N-
methyl-D-aspartate (NMDA) receptor, non-NMDA
inotropic receptor subtypes, and glutamate receptors. It
is involved in long-term synaptic connectivity by initi-
ating long-term potentiating (LPT) and depression
(LTD) and produces long-lasting changes in synaptic
structure and function, neuronal migration, and neu-
ronal viability. Exposure to stress has been shown to
increase the outflow of glutamate in the prefrontal
cortex and hippocampus [Pepeu and Blandina, 1998].
Adrenalectomy attenuated the stress-induced outflow
of glutamate, which was abolished by glucocorticoid
replacement, showing that the outflow is mediated by
glucocorticoids [Moghaddam et al., 1994]. Blockade of
NMDA receptors can acutely increase glutamate re-
lease by reducing excitation of inhibitory GABA neu-
rons [Moghaddam et al., 1997]. Since NMDA receptors
have a unique role in modulating the mesoprefrontal
DA-ergic response to stress experiments with NMDA
receptor antagonists have been performed to block the
mesoprefrontal DA-ergic response to conditioned fear
[Goldstein et al., 1994]. This is a potential target for
blocking effects of stress and has been used in many
studies [see review Zigmond et al., 1998].
Excessive glutamate release, in situations of severe
stress, and subsequent glutamatergic neuronal stimu-
lation increase the production of reactive oxygen spe-
cies, which, through the process of oxidative stress,
induces excitotoxicity and neuronal damage [Coyle
and Puttfarcken 1993; Savolainen et al., 1995; Nico-
tera et al., 1997]. This process could interfere with neu-
ronal and glial proliferation and has been thought to
contribute to hippocampal neural toxicity and hippoc-
ampal neuronal necrosis. Protection by glutamate-re-
ceptor antagonists does not necessarily imply inhibition
of these excitotoxic abnormalities but may render the
cell more resistant to other deleterious mechanisms
(e.g., mitochondrial injury and oxidative stress) [Ob-
renovitch, 1999].
GABA. Stress has been shown to increase GABA
turnover in frontal cortex [Otero Losada, 1988]. Two
receptors types have been identified, GABA(A) and
GABA(B), of which GABA(A) is most prevalent in the
brain and extensively studied. Alterations in GABA re-
ceptors have been observed in response to various
stressors. This is accompanied by increased levels of
neurosteroids in the cortex, acting as a potent allos-
teric modulator of the GABA(A) receptor that could
serve as a possible coping to the stress. Like with
138 Vermetten et al.
glutamate, the effect stress of induced GABA increase
is prevented by adrenalectomy [Schwartz et al., 1987].
Mesoprefrontal DA neurons are uniquely modulated
by GABA-ergic systems, and since they are lacking
regulating autoreceptors, they rely heavily on the
GABA-ergic influence.
A functional role has been suggested for neuro-
steroids and GABA(A) receptors in the modulation of
emotional behavior and mood. Animals isolated for 30
days immediately after weaning have exhibited an
anxiety-like behavioral profile with reduced brain
GABA(A) receptor function [Serra et al., 2000]. The
GABA(A) receptor has been used as a target for a
number of anxiolytic drugs.
SYSTEMS INVOLVED IN
LEARNING AND MEMORY
Stress has effects on memory processes that are
regulated by neurohormonal modulation of the laying
down of memory traces. Animal studies have provided
evidence for the various ways in which exposure to
stressful experiences influences learning and memory
formation in animals [for review, see De Wied and
Croiset, 1991]. Apart from their principal role in
stress regulations, neurotransmitters can contribute to
memory formation in their role as neuromodulators
and in gene transcription. In addition, neurohormones
may modulate the strength of connections between
neurons, thus influencing the mechanism by which
memory traces are formed and stored [reviewed in
Martin et al., 2000]. We will briefly discuss the neuro-
biological correlates of the effects of stress on memory
in animal studies. Application to human learning and
memory systems will be discussed elsewhere [Vermet-
ten and Bremner, 2002].
MEMORY AND NORADRENERGIC
FUNCTION
Increased level of norepinephrine released during
stress can modulate memory formation through action
on the brain. A number of studies have shown that
norepinephrine modulates aspects of memory: acquisi-
tion of new information [Cole and Robbins, 1992], the
attentional component of memory storage [Brozoski
et al., 1979], and working memory [Arntsten and
Goldman-Rakic, 1985]. Studies with humans and pri-
mates have provided support for the view that norad-
renaline is important in cognitive functions associated
with the frontal lobes, particularly the prevention of
distractibility by irrelevant stimuli. The a2-receptors
of the prefrontal cortex appear to be of particular im-
portance in this respect. Pharmacological stimulation
with the a2-adrenoreceptor agent yohimbine in aged
monkeys that had a degenerated LC, with depletion of
noradrenaline in the prefrontal cortex, has shown to
reverse deficits in performance on a delayed response
task. It is hypothesized that this could be explained by
attenuation of the distracting properties of irrelevant
stimuli following stimulation of noradrenergic activity
[Coull, 1994]. Release of norepinephrine in projection
areas from the LC is thought to modulate neuronal
activity and gene transcription and therefore the lay-
ing down of memory traces. Epinephrine and norepi-
nephrine can therefore be considered as endogenous
memory-modulators in this respect since they are re-
leased during arousing and stressful circumstances.
Mizoguchi et al. [2000] examined whether chronically
stressed (4 weeks) and recovered (10 days) rats show a
working memory impairment caused by reduced DA
transmission in the PFC, demonstrating that the stress
impaired spatial working memory as evaluated by T-
maze task and induced a marked reduction of DA
transmission in the PFC. Another important role for
the medial prefrontal cortex is described in relation to
the neural basis of extinction [Morgan, 1993; Falls and
Davis, 1995]. This is discussed the accompanying pa-
per [Vermetten and Bremner, 2002].
HIPPOCAMPUS
The hippocampus, which is particularly vulnerable
to stress, has a unique role in mediating new learning
and memory (explicit recall), emotional memory re-
lated to a stressor, and modulation of neurobiological
systems, such as the HPA axis. Lesions of the hippoc-
ampus have been shown to block the acquisition of
conditioned fear responding to the context (i.e., the
box) of a stressor (i.e., electric footshock), suggesting
that the hippocampus plays an important role in
memory for the emotional context of a stressor [Ross
et al., 1984; Phillips and LeDoux, 1992; Kim and
Fanselow, 1992].
Recent data has demonstrated a biochemical se-
quence of events in the rat hippocampus that is neces-
sary for memory formation of the inhibitory avoidance
behavior [Izquierdo and Medina, 1997]. These events
involve regulation early after training by neurohor-
monal processes related to alertness, anxiety, and stress
(involving GABA-ergic, cholinergic, and noradrenergic
synapses and by connections with amygdala and possi-
bly the medial septum) and several hours after training
by pathways related to mood and affect (involving
dopamine D1, β-adrenergic, and 5HT1A receptors).
This activity is subsequently transmitted to other areas,
including the source of the dopaminergic, noradrener-
gic, and serotonergic pathways, and involves participa-
tion of entorhinal and posterior parietal cortex to
complete memory consolidation. Emotionally arousing
situations can modulate this process of memory con-
solidation [Cahill and McGaugh, 1996].
A number of studies have shown that stressors, such
as footshock or forced swim, result in deficits in new
learning as measured by paradigms as maze-escape be-
haviors in the rat [reviewed in Bremner et al., 1993,
1995]. Studies in a variety of animal species [Aus der
Muhlen and Ockenfels, 1969; Sapolsky et al., 1988]
 Review Article: Circuits and Systems in PTSD, Preclinical Data
suggest that direct glucocorticoid exposure results in
decreased dendritic branching [Woolley et al., 1990]
and a loss of neurons [Uno et al., 1990], which are ste-
roid- and tissue-specific [Sapolsky, 1985; Packan and
Sapolsky, 1990]. Monkeys who died spontaneously
following exposure to severe stress were found on au-
topsy to have multiple gastric ulcers, consistent with
exposure to chronic stress, and hyperplastic adrenal
cortices, consistent with sustained glucocorticoid re-
lease. High levels of glucocorticoids released during
stress in these monkeys were also associated with dam-
age to the CA3 region of the hippocampus [Uno et al.,
1989; Sapolsky et al., 1990; Sapolsky, 1996], associated
with direct exposure of glucocorticoids to the hippoc-
ampus [Sapolsky et al., 1988]. Damage to this region
of the hippocampus has been associated with deficits
in memory [Arbel et al., 1994; Luine et al., 1994;
McEwen et al., 1992; Sapolsky, 2000]. Prenatal expo-
sure to elevated levels of glucocorticoids has also
shown to result in hippocampal damage [Uno et al.,
1990]. Corticosterone treatment can also induce these
neuropathological alterations [Woolley et al., 1990].
Long-term subcutaneous implants of glucocorticoids,
which mimic the chronic stress situation, were shown
to result in deficits in new learning and memory for
maze-escape behaviors. Moreover, the magnitude of
deficits in new learning of T-maze escape behaviors
was correlated with the number of damaged cells in
the CA3 region of the hippocampus [Arbel et al.,
1994]. Applying chronic psychosocial stress as well as
long-term cortisol treatment for 15 weeks to tree
shrews impaired hippocampus-mediated memory with
a trend towards a reduction of the hippocampal vol-
ume [Ohl et al., 2000]. These studies provided evi-
dence in an animal model that the hippocampus is
affected by stress and stress hormones and that the
stress-induced damage to the hippocampus, which can
be reflected in its volume, is associated with deficits in
memory function.
Recently, neurons within the hippocampus (dendate
gyrus) were found to be unique within the brain in
showing the capacity to regenerate themselves [Gould
et al., 1998]. Studies in animals have demonstrated
several agents (e.g., phenytoin, tianeptine, dihydro-
epiandosterone, and fluoxetine) with potentially ben-
eficial effects on the reversibility of the glucocorticoid
mediated hippocampal toxicity [Watanabe et al., 1992;
Duman et al., 1997]. These in-vitro studies report on
neurogenesis in the hippocampus through a regulation
of brain-derived neurotrophic factor (BDNF) and
cAMP by SSRI, with long-term effects on brain func-
tion [Duman et al., 1999]. Only chronic administra-
tion of these drugs could induce the changes in
morphology [Nibuya et al., 1996].
Emerging studies have found evidence for the idea
that other factors besides glucocorticoids, such as
BDNF, trkB mRNA, and Nerve Growth Factor (NGF),
which have a regulatory effect on neuronal morphol-
ogy and proliferation, may mediate stress-induced al-
139
terations in hippocampal morphology [Nibuya et al.,
1995, 1996; Smith et al., 1995; Schaaf et al., 2000].
Following termination of stress and of corticosterone
treatment in rats, signs of structural reorganization in
hippocampal neurons and synapses have been re-
ported, correlating with performance on learning and
memory tests [Sousa et al., 2000].
AMYGDALA
The amygdala has long been implicated in condi-
tioned fear [Davis, 1992] and has a role in influencing
memory-storage processes in other brain regions, such
as the hippocampus, striatum, and neocortex [re-
viewed in Cahill and McGaugh, 1998]. Conditioned
fear, in which pairing of a neutral (“conditioned”)
stimulus to a fear-inducing (“unconditioned”) stimulus
results in fear responses to the neutral (“conditioned”)
stimulus alone, has been used as a probe of amygdala
function [LeDoux et al., 1990; Davis, 1992]. Lesions
of the central nucleus of the amygdala have been
shown to completely block fear conditioning [Hitch-
cock and Davis, 1986; Hitchcock et al., 1989], while
electrical stimulation of the central nucleus increases
acoustic startle [Rosen and Davis, 1988].
The central nucleus of the amygdala projects to a
variety of brain structures via the stria terminalis and
the ventral amygdalofugal pathway. One pathway is
from the central nucleus to the brainstem startle reflex
circuit (nucleus reticularis pontis caudalis) [Davis,
1992]. Pathways from the amygdala to the lateral hy-
pothalamus effect peripheral sympathetic responses to
stress [Iwata et al., 1986]. Early findings have been re-
ported of electrical stimulation of the amygdala in
cats, which resulted in peripheral signs of autonomic
hyperactivity and fear-related behaviors seen in the
wild when the animal is being attacked or is attacking,
including alerting, chewing, salivation, piloerection,
turning, facial twitching, arching of the back, hissing,
and snarling, associated with an increase in catechola-
mine turnover [Hilton and Zbrozna, 1963]. Electrical
stimulation of the amygdala in human subjects re-
sulted in signs and symptoms of fear and anxiety in-
cluding an increase in heart rate and blood pressure,
increased muscle tension, subjective sensations of fear
or anxiety [Chapman et al., 1954], and increases in pe-
ripheral catecholamines [Gunne and Reis, 1963].
These findings demonstrate that the amygdala plays an
important role in conditioned fear and emotional re-
sponses, as well as modulating peripheral stress re-
sponses. There are also important connections between
cortical association areas, thalamus and amygdala that
are important in shaping the emotional valence of the
cognitive response to stressful stimuli. In addition to
thalamo-cortico-amygdala connections, there are direct
pathways from thalamus to amygdala, which could ac-
count for fear responses below the level of conscious
awareness [Romanski and LeDoux, 1992].
Several neurotransmitter systems are involved in
140 Vermetten et al.
function of the amygdala. The mesencephalic dopam-
inergic system provides a rich innervation to the
amygdala [Fallon and Ciofi, 1992]. Specific activation
of the amygdaloid dopaminergic system has been re-
ported to occur in response to conditioned fear-arous-
ing stimuli [Coco et al., 1992], suggesting that dopamine
release in the amygdala on the D1 receptor may con-
tribute to the acquisition and/or expression of Pavlov-
ian conditioned fear [Guarraci et al., 1999]. Preclinical
studies in rats have also pointed to a role for β-adreno-
receptors in the basolateral nucleus of the amygdala
(BLA) in mediating acute effects of epinephrine and glu-
cocorticoids on memory consolidation [McGaugh et al.,
1996; Roozendaal, 2000]. This system mediates the in-
fluence of other neuromodulatory systems such as opioid
peptidergic and GABA-ergic systems on memory storage
[Ferry et al., 1999]. Lesions of the BLA or infusions of β-
adrenoceptor antagonists into the BLA appear to block
the memory-modulatory effects of systemic injections of
glucocorticoids. When shortly after the training GR
agonists are administered directly into the BLA an en-
hanced memory consolidation is seen, whereas a GR an-
tagonist impair this process. Lesions of the BLA or
inactivation of β-adrenoceptors within the BLA also
block the memory-modulatory effects of intrahippo-
campal administration of a GR agonist or antagonist, in-
dicating that the BLA interacts with the hippocampus in
mediating glucocorticoid-induced modulatory influences
on memory consolidation [Roozendaal, 2000].
CONCLUDING REMARKS
Stress leads to long-term dysregulation of neuro-
biological systems. Repeated stressors result in a po-
tentiated release of transmitters with exposure to
subsequent stressors (stress sensitization). These neu-
rochemical changes are accompanied by behavioral
changes (fear conditioning and learned helplessness)
that correlate with specific biological changes, are
similar to symptoms of human anxiety, and have an
impact on areas of the brain that regulate processes of
extinction (extinction of fear) [Weis and Simson,
1985; Charney et al., 1993; Morgan et al., 1993;
Lechin et al., 1996].
While the brain is the starting point for stress
responsivity, the brain has also shown to be a key target
organ for stress-related changes, e.g., through gluco-
corticoids, which contribute to its set point of function-
ing, with subsequent adult HPA-axis activity, behavior,
and cognition. As discussed, the set point of the HPA
responsivity to stress appears to be programmed early
in life [Shanks et al., 2000], potentially affecting devel-
oping organ systems, and permanently altering struc-
ture and function throughout life [Welberg and Seckl,
2001]. Key targets for this programming include GR
gene expression and the CRF system. Animals’ prior
experiences to the stress experiment can therefore have
important implications for the interpretation of various
data obtained in stress research. To compare results
from animal stress studies, between animals and be-
tween studies, it is important to know about the rearing
conditions.
The work in animal models of stress has shown that
coordinated functional interactions between the HPA-
axis and LC/NE system are critical in promoting
adaptive responses to stress, anxiety, or fear. These
two systems may differentially be employed by differ-
ent classes of stressors, e.g., acute vs. chronic; with or
without prior exposure; escapable or inescapable stress;
stressors that involve interpretation, and stressors that
do not involve interpretation of the stressful stimulus.
These stressors all excite different neural circuits, e.g.,
severe physiologic stress has shown to trigger brainstem
systems that project directly to the PVN, but stressors
that involve interpretation may require interaction with
homeostatic information prior to promoting an HPA
response and reach the PVN by way of multisynaptic
limbic pathways. They also differ in their mobilization
of a multiplicity of neurotransmitters and neuropep-
tides, allowing for a differential pattern of release in re-
sponse to a wide range of conditions, with involvement
of different brain structures.
Chronic stress can cause structural as well as func-
tional changes in the brain, involving the suppression
of ongoing neurogenesis in the dental gyrus of the
hippocampus, which is reflected in long-term changes
in change brain structure (neuronal loss and loss of
dendritic branching) and function (impairments in
memory function).
The review is not conclusive. It has highlighted the
main findings in the key systems in preclinical studies
in stress to lay the foundation for a working model for
human studies in PTSD. In addition it provides
knowledge to better understand the effects of stress on
the brain and delineates where pharmacological devel-
opments might be possible. Studies of the neurobiol-
ogy of PTSD in clinical populations are reviewed
elsewhere [Vermetten and Bremner, 2002]. Future
animal studies will be needed to further understand
when stress responsivity is adaptive and when it is
maladaptive. These issues will help to further under-
stand the nature of stress responsivity and prove the
basis for understanding findings in clinical research of
stress related disorders.
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