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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 5, Number 5, October 2006
Contents
How Brain Faces Stressors, Regulates Stress Response
and Undergoes Stress Consequences
Guest Editor: Juan C. Leza
Editorial Pp. 481-483
The Hypothalamic-Pituitary-Adrenal Axis: What can
it Tell us About Stressors? Pp. 485-501
Antonio Armario
[Abstract]
Stress and Brain Atrophy Pp. 503-512
J. Douglas Bremner
[Abstract]
Individual Differences in Vulnerability to Drug
Abuse: The High Responders/Low Responders Model Pp.
513-520
Mohamed Kabbaj
[Abstract]
Stress, Corticosteroid Hormones and Hippocampal
Synaptic Function Pp. 521-529
Deborah N. Alfarez, Olof Wiegert and Harm J.
Krugers
[Abstract]
Stress, Depression and Hippocampal Apoptosis
Pp. 531-546
Paul J. Lucassen, Vivi M. Heine, Marianne B. Muller, Eline
M. van der Beek, Victor M. Wiegant, E. Ron De Kloet, Marian
Joels, Eberhard Fuchs, Dick F. Swaab and Boldizsar Czeh
[Abstract]
Cytokine-Purine Interactions in Traumatic Stress,
Behavioral Depression, and Sickness Pp. 547-560
Thomas R. Minor, Qingjun Huang and Alexis E. Witt
[Abstract]
Stress-Induced Oxidative Changes in Brain
Pp. 561-568
José L.M. Madrigal, Borja García-Bueno,
Javier R. Caso, Beatriz G. Pérez-Nievas and Juan C.
Leza
[Abstract]
Abstracts
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Editorial
Stress scientists cross the line between physiology and pathology,
trying to understand the broad physiological responses of
stress that can convert to pathology, depending on the coping
ability of the organism, under conditions of extreme intensity
and/or long duration. These “pathological” changes
are sometimes reversible without treatment. The tremendous
intellectual challenge for understanding the basis of this
response has generated new and exciting data on the possibility
to treat or prevent some CNS diseases ranging from depression
to Alzheimer. In this volume of CDT-CNS, experts in the field
address different aspects of the effects of stress on brain
function, including a discussion of whether the consequences
of stress are permanent or not, if it can provoke or predispose
humans to diseases such as depression, drug abuse or others,
and the molecular basis of the brain damage.
Antonio Armario begins with the most important question: What
is stress? People use the term stress in a broad sense, synonymous
with scare -more or less prolonged, preoccupations from a
variety of origins or overload of work. The consequences of
stress were described in Selye’s seminal paper in 1936:
A syndrome produced by diverse nocuous agents [1].
However, after 70 years, the definition of stress remains
to be a subject of debate. In biological systems, the classical
definition is that stress is condition that seriously perturbs
the physiological/psychological homeostasis of an organism.
Indeed, biological stress occurs every day to organisms in
their relation with other organisms and also with themselves,
provoking a double-faced response: it can be an adaptive mechanism,
allowing the organism to survive or fight the stressful experience,
but stress also has a negative impact on the individual, mainly
after very intense, long lasting stressful stimuli. These
consequences might be a direct neuropsychopathology or vulnerability
to diseases.
Current terminology distinguishes between the stimulus (stressful
stimulus or stressor), the state generated in the organism
(stress) and the response to the situation (stress response).
In the broadest sense, as initially defined by Selye, a stressor
is any stimulus able to alter homeostasis [1], the term coined
by Cannon, to refer to the mechanisms that allow the organisms
to adapt to the challenges and to maintain critical biological
parameters for survival. Several decades after, McEwen [2]
extended the term of homeostasis to explain that these mechanisms
of stability are continuously changing and called it allostasis.
The price the organisms pay to maintain (or try to maintain)
the stability is called allostatic load. The development of
stress-induced permanent changes depends on factors such as
chronicity, controllability, predictability and habituation,
in part because they are influencing the way an organism can
reduce the impact of stressors (coping strategies).
This first article of this volume also raises other important
points about the two different kinds of physiological responses
to a stimulus: (i) a specific response to the particular stimulus,
not related to its stressful properties; and (ii) a nonspecific
response, common to all stressful stimuli. Therefore, the
physiological response that one evaluates in a particular
situation is the sum of both the specific and the non-specific
responses. Furthermore, it is necessary to distinguish between
the term stress marker, indicating that a particular variable
is sensitive to stress, and the term marker of stress intensity,
that refers to the fact that the magnitude of a particular
variable is proportional to the intensity of the stressor.
There are a number of stress markers, but only a few reasonably
good indices of stress intensity: increases in plasma levels
of catecholamines (particularly adrenaline), glucose, prolactin
and HPA hormones, and a reduction of food intake.
Work from the studies reviewed by Douglas Bremner in his paper
and, of course, the studies from his lab demonstrates that
stress leads to damage to the hippocampus in human subjects,
as determined by neuroimaging techniques [3,4]. There is a
percentage of the population affected with traumatic stress,
who develop mental disorders, including posttraumatic stress
disorder (PTSD), depression, drug abuse, dissociation, anxiety
and borderline personality disorder. Based on the high overlap
amongst these stress-related disorders, Bremner argues that
they should be considered together as “traumaspectrum
disorders” [5]. In 1995, he and his colleagues carried
out the first study in PTSD patients using magnetic resonance
imaging (MRI) to measure the volume of the hippocampus [4].
This study showed an 8% decrease in MRI-based measurement
of right hippocampal volume in patients with combat-related
PTSD in comparison to matched controls. Similar decreases
have been replicated several times in the published literature
and not only in hippocampus, but also in other brain areas.
Bremner pointed out the chronicity of trauma exposure and
illness as important factors to consider when studying reversibility
or response to treatments; patients with long-standing and
chronic PTSD do not respond to treatment, as well as patients
with acute onset PTSD [6]. These findings are convergent with
research in animal studies suggesting that once traumatic
memories have become established as indelible memories in
the brain, they are resistant to subsequent modification and
alteration. Patients with early onset PTSD show increased
depression, substance abuse and character pathology, while
adult onset PTSD is characterized by a greater degree of classical
PTSD symptoms, including increased anxiety and hyperarousal.
Mohamed Kabbaj discusses one of these comorbid states associated
with PTSD in his review: the substance abuse. Some individuals
initiate a behavior consisting involuntary participation in
risky activities that initiate stress and anxiety, yet provide
the participant with a thrill. Some authors have suggested
indeed, that substance abuse is related to a human personality
trait termed novelty seeking behavior [7,8], which can be
a consequence of previous stressful negative emotional and
social experiences [9]. Some authors have suggested that activation
of stress responses during risky behaviors is the critical
variable underlying expression of this behavior in individuals
who are predisposed to sensation seeking [10].
These data are supported by animal models: individual differences
in stress responsiveness have been reported with self administration
of drugs: when naïve rats are exposed to mild stress
(i.e. novel environment), some rats known as high responders
(HR) exhibit high rates of exploratory locomotion, while others
known as low responders (LR) exhibit low rates of locomotor
activity. Interestingly, HR rats exhibit high rates of behavioral
sensitization to psychostimulants and self administration
than LR rats do [11]. These individual differences in drug
addiction and how stress and glucocorticoids alter drug taking
behaviors seems to be caused by a combination of genetics
and environmental factors, especially maternal behaviors,
in determining the HR/LR phenotypes.
The following contributions raise important aspects of inter
and intracellular mechanisms affected by stress in brain.
Harm Krugers reviews experimental evidences of whether exposure
to stressful events and corticosteroid hormones affect hippocampal
neuronal function, and how they alter hippocampal synaptic
function. These findings are discussed in the context of learning
and memory processes, in which the hippocampal formation is
critically involved: the memory for fearful or stressful events
may be beneficial; the individual may appraise the situation
and, if necessary, avoid that situation in the future or cope
with it. However, exposure to aversive events hampers the
retrieval of already stored information and the acquisition
and storage of novel information.
This review is an extensive analysis of these seemingly conflicting
effects that are at least in part, mediated by corticosteroid
hormones. Studies reveal that exposure to aversive situations,
novelty and elevated corticosterone levels can facilitate
synaptic plasticity when applied in discrete time windows
before or after high frequency stimulation. In contrast, stressful
experiences and elevated corticosterone levels suppress synaptic
plasticity and facilitate synaptic depression when examined
later on. These studies emphasize that timing is important
in determining the direction, i.e. facilitation or suppression,
of hippocampal synaptic function by exposure to aversive events.
Recent studies indicate that exposure to stressful events
and elevated corticosteroid hormone levels enhance synaptic
plasticity when delivered shortly before or after high frequency
stimulation [12]. In contrast, synaptic potentiation is, in
general, suppressed when stressful events and elevated corticosteroid
hormones occur with longer time intervals until the moment
of high frequency stimulation [13]. These studies imply that
timing, i.e. the exact moment when corticosteroid hormone
levels are elevated or when animals are exposed to stressful
experiences with respect to high frequency stimulation, determines
whether synapses are facilitated or weakened. Similar effects
are observed at the behavioral level: elevated corticosterone
levels in the context of a (stressful) learning task facilitate
learning and memory processes [14]. Exposure of experimental
animals to stressful situations or elevated corticosteroid
hormone not in the context of a learning task, in general,
suppresses learning and memory processes [15].
Paul Lucassen and colleagues discuss another important aspect
of changes in structural plasticity, particularly apoptosis,
induced by stress. Stress-induced neuronal loss in CA3 region
of the hippocampus was initially expected to be mediated through
apoptosis [16]. In this regard, there are three important
issues to be taken into account: i) to discriminate between
physiological and pathological changes, since apoptosis occurs
even in control animals in the hippocampal dentate gyrus,
in relation with the neurogenesis seen in control adult animals;
ii) the relatively small time window to see any apoptotic
change after stress, usually less than 72 hours [17], and
iii) the heterogeneity of apoptotic changes in the different
hippocampal areas. Stress seems to alter the balance between
apoptosis and neurogenesis in hippocampus. This review gives
some very interesting data on the tree shrew model of major
depression, in particular on the possibility that changes
can be reversed by antidepressants and some investigative
drugs.
The brain has the capacity to either augment or abrogate inflammatory
processes: whereas brain norepinephrine can initiate an acute
phase response, the brain triggers anti-inflammatory pathways
after stress [18]. Thomas Minor reviews possible mechanisms
by which stress automatically triggers an adaptive response
termed conservation-withdrawal, and the role of proinflammatory
cytokines on it. The sensory unresponsiveness, cognitive dullness
and behavioral depression that characterize this state are
adaptive mechanisms for saving limited resources and facilitating
the recovery of homeostasis. Often, these symptoms are confused
with major depression, traumatic psychological stress or distress
syndrome. Minor reviews from his laboratory and others research
on the potential contribution of two signaling pathways, the
purine nucleoside adenosine, and the proinflammatory cytokine
IL-1β
to the induction of conservation-withdrawal response.
Activation of brain IL-1β
receptors appear to contribute to conservation-withdrawal
by exacerbating the immediate impact of a stressor or by enhancing
and prolonging the overall reaction to traumatic stress, major
depression, and illness. Moreover, brain cytokine signalling
is capable of recruiting adenosine signalling at adenosine
receptor A2A level, which directly mediates symptoms
of behavioral depression. These densely populate spiny GABAergic
neurons in the striopallidal tract in the striatum and form
part of an A2A/D2/mGLU receptor complex.
The activation of these A2A receptors functionally
uncouples dopamine’s excitatory motivational influence
on ongoing behavior, which is thought to be the basis of conservation-withdrawal
response.
There are a number of potentially important implications to
these data. First, downregulating this form of signaling should
hasten recovery. More important, the affect-less, fatigue
components of stress, depression, and illness should be directly
alleviated by manipulating the A2A/D2/mGLU
heteromeric receptor complex. Minor present data clearly suggest
that blockade of the A2A receptor should produce
direct benefit. Additional benefit should be derived from
a combination of A2A antagonists, D2
agonists, and mGLU, antagonists. Such a combination should
minimize fatigue and recouple motivation influences on ongoing
behavior.
Finally, José Madrigal describes in his paper one of
the possible pathways through which stress induces the accumulation
of free radicals in brain. Free radicals such as reactive
oxygen species are formed during a variety of biochemical
reactions and cellular functions (such as mitochondria metabolism).
In normal conditions, the steady-state formation of pro-oxidants
(free radicals) is balanced by a similar rate of consumption
by antioxidants. This process is generally known as “oxidative
stress”, resulting from an imbalance between formation
and neutralization of pro-oxidants [19]. After stress exposure,
one of the earliest changes is the release of glutamate, which
after binding to NMDA receptors initiates a “chain reaction”
including the activation and release of cytokines such as
TNFα.
One of the multiple effects exerted by this cytokine is the
induction of the translocation of the transcription factor
NFκB
to the nucleus in brain cells. NFκB
activation results in the induction of inducible nitric oxide
synthase (iNOS) and inducible cyclooxygenase (COX2), two free-radical
forming enzymes responsible of structural and functional damage
to brain cells (energy production, altered functioning of
glucose or neurotransmitter uptake mechanisms).
Yes, we are on the edge between physiology and pathology.
I hope the present special volume will contribute to the knowledge
of how brain faces stress and how it can be affected by stress.
Obviously, much more research is needed until specific pharmacological
agents are available to diminish the negative effects of stress
on brain function, including alteration in memory or even
atrophy of certain areas, as well as to decrease the vulnerability
to other neuropsychiatric diseases such as depression, neurodegenerative
diseases or drug abuse.
REFERENCES
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[3] Bremner, J.D. Psych. Annal., 1998,
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[4] Bremner, J.D.; Randall, P.R.; Scott, T.M.; Bronen, R.A.;
Delaney, R.C.; Seibyl, J.P.; Southwick, S.M.; McCarthy, G.;
Charney, D.S.; Innis, R.B. Am. J. Psychiat., 1995,
152, 973.
[5] Bremner, J.D. Does Stress Damage the Brain? Understanding
Trauma-related Disorders from a Mind-Body Perspective. (W.W.
Norton, New York, 2002).
[6] Meadows, E.A.; Foa, E.B., in Posttraumatic Stress
Disorder: A Comprehensive Text. Saigh, P.A.; Bremner,
J.D., Eds. (Allyn & Bacon, Needham Heights, MA, 1999)
pp. 376-390.
[7] Zuckerman, M.; Neeb, M. Psychiatry Res., 1979,
1, 255.
[8] Zuckerman, M. Behav. Brain Sci., 1984,
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[9] Sinha, R. Psychopharmacology (Berl), 2001,
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[10] Piazza, P.V.; Deroche, V.; Deminiere, J.M.; Maccari,
S.; Le Moal, M.; Simon, H. Proc. Natl. Acad. Sci. USA,
1993, 90, 11738.
[11] Hooks, M.S.; Jones, D.N.; Holtzman, S.G.; Juncos, J.L.;
Kalivas, P.W.; Justice, J. B. J. Psychopharmacology (Berl),
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[12] Li, S.; Cullen W.K.; Anwyl R.; Rowan M.J.; Nat. Neurosci.,
2003, 6, 526.
[13] De Kloet E.R.; Oitzl M.S.; Joels, M. Trends Neurosci.,
1999 22, 422.
[14] Oitzl M.S.; de Kloet E.R. Behav. Neurosci.,
1992, 106, 62.
[15] Krugers, H.J.; Douma, B.; Andringa, G.; Bohus, B.; Korf,
J.; Luiten, P.G. Hippocampus,1997,
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[16] Landfield, P.W., McEwen, B.S., Sapolsky, R.M. and Meaney,
M.J. Science, 1996, 272,
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[17] Hu, Z., Yuri, K., Ozawa, H., Lu, H. and Kawata, M. J.
Neurosci., 1997, 17, 3981.
[18] García-Bueno, B.; Madrigal, J.L.M.; Lizasoain,
I.; Moro, M.A.; Lorenzo, P.; Leza, J.C. Biol. Psychiatry,
2005, 57, 885.
[19] Ischiropoulos, H., Beckman, J.S. J. Clin. Invest.,
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Juan C. Leza
Department of Pharmacology
Faculty of Medicine
University Complutense
Madrid
Spain
E-mail: jcleza@med.ucm.es
[Back to top]
The Hypothalamic-Pituitary-Adrenal Axis: What can
it Tell us About Stressors?
Antonio Armario
The hypothalamic-pituitary-adrenal (HPA) axis is an extremely
sensitive physiological system whose activation, with the
consequent release of ACTH and glucocorticoids, is triggered
by a wide range of psychological experiences and physiological
perturbations (stressors). The HPA axis is also activated
by a high number of pharmacological agents that markedly differ
in structure and function, although the precise mechanisms
remain in most cases unknown. Activation of the HPA axis is
the consequence of the convergence of stimulatory inputs from
different brain regions into the paraventricular nucleus of
the hypothalamus (PVN), where the most important ACTH secretagogues
(corticotrophin releasing factor, CRF, and arginin-vasopressin,
AVP) are formed. Plasma levels of ACTH and corticosterone
(the latter under more restricted conditions), are considered
as good markers of stress for three main reasons: (a) their
plasma levels are proportional to the intensity of emotional
and systemic stressors, (b) daily repeated exposure to a stressor
usually resulted in reduced ACTH response to the same stressor,
that is termed adaptation or habituation; and (c) chronic
exposure to stressful situations results in tonic changes
in the HPA axis that can be used as indices of the accumulative
impact of these situations. These changes can be evaluated
under resting conditions (i.e. adrenal weight, CRF and AVP
gene expression in the PVN) or after some challenges (administration
of CRF, ACTH or dexamethasone) that are classical endocrinological
tests. There is also evidence that the activation of the HPA
axis may also reflect subtle changes in the characteristics
of the stressful situations (unpredictability, lack of control,
omission of expected rewards, presence of conspecifics), although
this is a topic that requires further studies.
[Back to top]
Stress and Brain Atrophy
J. Douglas Bremner
Studies in animals showed that stress is associated with
changes in hippocampal function and structure, an effect mediated
through decreased neurogenesis, increased glucocorticoids,
and/or decreased brain derived neurotrophic factor. Antidepressants
and some anticonvulsants block the effects of stress and/or
promote neurogenesis in animal studies. Patients with posttraumatic
stress disorder (PTSD) have been shown to have smaller hippocampal
volume on magnetic resonance imaging and deficits in hippocampal-based
memory. Symptom activation is associated with decreased anterior
cingulate and medial prefrontal function, which is proposed
as the neural correlate of a failure of extinction seen in
these patients. Treatment with antidepressants and phenytoin
reverse hippocampal volume reduction and memory deficits in
PTSD patients, suggesting that these agents may promote neurogenesis
in humans.
[Back to top]
Individual Differences in Vulnerability to Drug
Abuse: The High Responders/Low Responders Model
Mohamed Kabbaj
In this review we shall attempt to summarize the literature
published on the high responders/low responders’ animal
model of drug addiction. This model is based on the locomotor
activity of rats in the mild stress of a novel environment.
Rats that exhibit high rates of exploratory behaviours are
deemed high responders (HR) and rats that exhibit low exploratory
behaviours are deemed low responders (LR). Interestingly,
the rate of these exploratory behaviours predicts the response
of these animals to drugs of abuse. In this manuscript we
will review the behavioural and physiological differences
between HR and LR rats in response to d-amphemtamine, cocaine,
morphine, alcohol and nicotine.
[Back to top]
Stress, Corticosteroid Hormones and Hippocampal
Synaptic Function
Deborah N. Alfarez, Olof Wiegert and Harm J.
Krugers
Exposure to stressful events has profound impact on hippocampus-dependent
learning and memory processes. Traumatic and stressful experiences
are remembered well in general, but have also been reported
to suppress learning and memory processes. These bi-directional
effects are, at least in part, modulated by corticosteroid
hormones that are released during exposure to stressful experiences.
An important question that remains to be addressed is how
exactly exposure to stressful situations and elevated corticosteroid
hormone levels affect learning and memory processes. Evidence
is accumulating that exposure to stressful situations and
elevated corticosteroid hormone levels modulates fast excitatory
amino acid mediated synaptic transmission and synaptic plasticity,
which are considered to underlie learning and memory processes
in the hippocampus. In particular, exposure to stressful events
has been reported to facilitate synaptic plasticity when delivered
shortly before or after high frequency stimulation. By contrast,
stressful events and elevated corticosteroid hormones suppress
synaptic potentiation when stress precedes high frequency
stimulation. From the mechanistic point of view, it is potentially
important that exposure to stressful events and elevated corticosteroid
hormone levels target key mechanisms that are involved in
synaptic plasticity, i.e. AMPA receptors and NMDA receptors.
[Back to top]
Stress, Depression and Hippocampal Apoptosis
Paul J. Lucassen, Vivi M. Heine, Marianne B. Muller, Eline
M. van der Beek, Victor M. Wiegant, E. Ron De Kloet, Marian
Joels, Eberhard Fuchs, Dick F. Swaab and Boldizsar Czeh
In this review, we summarize and discuss recent studies
on structural plasticity changes, particularly apoptosis,
in the mammalian hippocampus in relation to stress and depression.
Apoptosis continues to occur, yet with very low numbers, in
the adult hippocampal dentate gyrus (DG) of various species.
Stress and steroid exposure modulate the rate of apoptosis
in the DG. Contrary to earlier studies, the impact of chronic
stress on structural parameters of the hippocampus like cell
number and volume, is rather modest, and requires prolonged
and severe stress exposure before only small reductions (<
10 %) become detectable.
This does not exclude other structural parameters, like synaptic
terminal structure, or dendritic arborization from being significantly
altered in critical hippocampal subregions like the DG and/or
CA3. Neither does it imply that the functional implications
of the changes after stress are also modest. Of interest,
most of the structural plasticity changes appear transient
and are generally reversible after appropiate recovery periods,
or following cessation or blockade of the stress or corticosteroid
exposure.
The temporary slowing down of both apoptosis and adult proliferation,
i.e. the DG turnover, after chronic stress will affect the
overall composition, average age and identity of DG cells,
and will have considerable consequences for the connectivity,
input and properties of the hippocampal circuit and thus for
memory function. Modulation of apoptosis and neurogenesis,
by drugs interfering with stress components like MR and/or
GR, and/or mediators of the cell death cascade, may therefore
provide important drug targets for the modulation of mood
and memory.
[Back to top]
Cytokine-Purine Interactions in Traumatic Stress,
Behavioral Depression, and Sickness
Thomas R. Minor, Qingjun Huang and Alexis E. Witt
This paper reviews recent research on the contribution
of the proinflammatory cytokine interleukin-1β
(IL-1β)
and the purine nucleoside adenosine in mediating behavioral
depression and related symptoms of conservation-withdrawal
in animal models of traumatic stress, major depression, and
illness. Activation of brain IL-1β
receptors appears to contribute to conservation-withdrawal
by exacerbating the immediate impact of a stressor or by enhancing
and prolonging the overall reaction. Moreover, brain cytokine
signaling is capable of recruiting adenosine signaling at
A2A, which directly mediates symptoms of behavioral
depression. The adenosine receptors densely populate spiny
GABAergic neurons in the striopallidal tract in the striatum
and form part of an A2A/D2/mGLU receptor
complex. Activation of these A2A receptors functionally
uncouples dopamine’s excitatory motivation influence
on ongoing behavior, leading to a state of conservation-withdrawal.
[Back to top]
Stress-Induced Oxidative Changes in Brain
José L.M. Madrigal, Borja García-Bueno,
Javier R. Caso, Beatriz G. Pérez-Nievas and Juan C.
Leza
Numerous systems and organs are affected by stress. In
this review we will focus on the effects in brain. Some of
the most impressive effects of the stress in brain are the
atrophy of hippocampal dendrites or even the reduction of
the hippocampal size observed in brains from subjects exposed
to severe or chronic stress. Obviously, before reaching this
point of damage there are many other processes taking place
in the stressed CNS. The release of glucocorticoids is one
of the first features of the stress response. Glucocorticoids
can result in neurotoxicity through different mechanisms,
including modifications in the energy metabolism or via
an increase in excitatory amino acids such as glutamate in
the extracellular space. Glutamate can induce neuronal excitotoxicity.
This sequence of events leads to the activation of TNFα
convertase (TACE) and TNFα
release in brain of rats subjected to restraint stress. One
of the multiple effects exerted by this cytokine is to initiate
the translocation of the transcription factor NFκB
to neuronal nuclei. NFκB
activation results in the induction of iNOS and COX2, two
enzymes responsible for a great portion of the neurological
damage produced in models of stress.
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