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The Physiology of Learning and Memory: Role of

Peptides and Stress
Article in Current Protein and Peptide Science January 2005
DOI: 10.2174/1389203043379341 Source: PubMed
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Current Protein and Peptide Science, 2004, 5, 000-000
The Physiology of Learning and Memory: Role of Peptides and Stress

M.A. Glpnar* and B.. Yegen
Marmara University School of Medicine, Departments of *Medical Education and Physiology, Istanbul, Turkey
Abstract: The neuropeptides, as well as their respective receptors, are widely distributed throughout the mammalian
central nervous system. During learning and memory processes, besides structural synaptic remodeling, changes are
observed at molecular and metabolic levels with the alterations in neurotransmitter and neuropeptide synthesis and
release. While there is consensus that brain cholinergic neurotransmission plays a critical role in the processes related to
learning and memory, it is also well known that these functions are influenced by a tremendous number of neuropeptides
and non-peptide molecules. Arginine vasopressin (AVP), oxytocin, angiotensin II, insulin, growth factors, serotonin (5HT), melanin concentrating hormone, histamine, bombesin and gastrin-releasing peptide (GRP), glucagon-like peptide-1
(GLP-1), cholecystokinin (CCK), dopamine, corticotropin releasing factor (CRF) have modulatory effects on learning and
memory. Among these peptides CCK, 5-HT and CRF play strategic roles in the modulation of memory processes under
stressful conditions. CRF is accepted as the main neuropeptide involved in both physical and emotional stress, with a
protective role during stress, possibly through the activation of the hypothalamo-pitiuitary (HPA) axis. The peptide CCK
has been proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed
upon stress exposure, suggesting that CCK may participate in the central control of stress response and stress-induced
memory dysfunction. On the other hand, 5-HT appears to play a role in behaviors that involve a high cognitive demand
and stress exposure activates serotonergic systems in a variety of brain regions. The physiological role and therapeutic
efficacy of various neuropeptides and the impact of stress exposure in the acquisition and consolidation of memory will be
reviewed thoroughly.
Keywords: Alzheimers disease (AD), acquisition, consolidation, stress, social memory, serotonin (5-HT), cholecystokinin
(CCK), corticotropin releasing factor (CRF), hypothalomo-pitiutary (HPA) axis.
PHYSIOLOGY OF LEARNING AND MEMORY
For every living organism, all behaviors including
learning and memory are modified by experience.
Throughout life, in order to cope with ongoing changes, the
brain constantly re-constructs itself, depending on both
genetic and epigenetic information. By this lifelong selfadjustment and self-optimization processes, to meet the
everchanging demands, the cognitive, behavioural and
emotional status of an organism is remodeled. All these
reconstructions associate with learning and memory, which
are essential for the living organism. During learning and
memory
processes,
with
the
involvement
of
neurotransmitters and neuropeptides, a number of structural
and molecular developments take place. Although genoma
can encode for a variety of neuronal morphologies, different
neurotransmitters and neuropeptides, diverse adhesion
molecules, etc., it certainly cannot specify the pattern of
neuronal connectivity [1], rather these specifications appear
throughout experience.
Since the idea of information storage by the
modification of interneuronal connections proposed by
Cajal,
and
the
experience-dependent
synaptic
strengthening postulated by Hebb, a huge number of studies
with abundant knowledge regarding the cellular and
*Address correspondence to this author at the Professor of Physiology,
Marmara University School of Medicine, Haydarpasa,
Istanbul 34668,
Turkey; Tel: +90-216-414-4736; Fax: +90-216-418-3327; E-mail:
byegen@marmara.edu.tr
1389-2037/04 $45.00+.00
molecular aspects of neuronal development, memory and

learning has been carried out. Although there is no clear
understanding of how experience gets into the brain, how the
brain organizes itself to get/remember/forget the knowledge,
contemporary theoretical formulations of learning and
memory are based on two plausible principles: one is
concerned with the activity (neuronal firing) and the other
with the plasticity of the neurons (sprouting of new axons
and dendrites, and new synapses) [1-4]. Neuronal plasticity
is a fundamental process by which the brain acquires
sensory, cognitive, emotional, social, as well as endocrine
inputs, or combinations of this information, and makes the
appropriate adaptive responses in future-related settings [5].
The phenomenon of long-term potentiation (LTP) has been
recently shown to be associated with the formation of new
synapses and long-term depression are currently regarded as
one of the best and universally accepted models of learning
and memory formation [2, 4, 6]. The discovery of longlasting potentiated synapses provided a possible cellular
mechanism for learning and memory. In addition to its
duration (lasting for several hours in vitro, several weeks in
vivo), LTP is rapidly induced, strengthened by repetition,
demonstrates specificity and associativity [4]. However, LTP
alone cannot provide enough explanation for the synaptic
model of learning and memory. During this process, along
with these increases in synaptic efficacy in the form of LTP,
decreases in synaptic efficacy, termed as long-term
depression (LTD), are also needed. Both LTP and LTD
occur prominently in the hippocampus (a structure
implicated in memory storage and retrieval processes) and
2004 Bentham Science Publishers Ltd.
Current Protein and Peptide Science, 2004, Vol. 5, No. 6
appear to be mediated by mechanisms that are triggered by

Ca2+ influx via activation of N-methyl-d-aspartate (NMDA)
receptors. In these mechanisms, while low levels of
intracellular Ca 2+ lead to the activation of phosphatases that
depress the synapse, high levels lead to the activation of
kinases, which potentiate the synapse [4].
Considering the synaptic plasticity, in some areas of the
neuronal system, once neuronal connections are established
during the brain development period, these networks tend to
be relatively stable (rigid synaptic connections). Whereas
in other areas, particularly the areas involved in the higher
brain functions (e.g., hippocampus, neocortical association
areas and the cholinergic basal forebrain neurons), the
structural synaptic remodeling of the brain continues
throughout life as a mechanism of self-adaptation (flexible
synaptic connections). Having the combination of these
flexible and rigid connections, the brain ensures the stability
of the principal characteristic functions on one hand, while it
has the opportunity to continously reoptimize and self-adjust
throughout the life [2].
According to the classical hypothesis, the information in
the brain is stored in a neural network. Strengthening of
certain synapses allows for the establishment of a neural
network specific to that information [7-10]. It is also likely
that some of the mechanisms used in information processing
are also involved in the reactivation of the neural network
during the retrieval of information [11]. Both in the
developing and mature brain, by the selective stabilization
of synapses (the strengthening of existing synapses, the
formation of new synapses and the destabilization of
previously established synaptic contacts) proposed by JeanPierre Changeux, the specification in the neuronal networks
allows for the achievement of new epigenetic information
[2]. So structural synaptic remodeling is not limited to the
developmental stage; besides the developmental one,
adaptive and restorative plasticity are also seen. The
experimental studies based on sensory deprivation, early
neonatal handling and enriched environmental conditions
indicate that the structural changes are seen not only in the
developmental stage, but are also evident in adulthood [2,
12, 13]. Many cortical maps, such as the representations of
different sensory stimuli in the neocortex, are not fixed; but
show experience-dependent plasticity. Besides the
organization of sensory cortical representations, experience
also influences the rate of neurogenesis derived from
progenitor cells in the hippocampus and this capability of
hippocampal cells is retained into adulthood in rodents, nonhuman primates and humans. Neurons generated from
progenitor cells then migrate into the granule cell layer,
differentiate, extend axons and express neuronal marker
proteins. In other words, behavioural experience, acquired
both during development and in the adult brain, not only
promote synaptic modification and synaptogenesis, but can
also influence neurogenesis and neuronal survival by
controlling activation and progression of the cell cycle in the
process of neuronal differentiation. Enriched environment in
young or even senescent rodents results in persisting changes
that dramatically reduce the rate of spontaneous apoptotic
cell death later in life and protect against age-related decline
of memory function. Social deprivation or stress, on the
contrary, either during development or in adult animals, is
Glpnar and Yegen
associated with an increased rate of apoptosis in the

hippocampus and a reduced rate of neurogenesis in
adulthood [2]. Early emotional experiences affect developing
brain systems that subsequently mediate adult learning and
memory in rodents [12].
During synaptic plasticity, morphoregulatory molecules
such as cell adhesion molecules (CAMs), substrate adhesion
molecules (SAMs) and cell junctional molecules (JAMs)
provide an essential link between genetic and epigenetic
mechanisms by exerting critical interactions at both the cell
surface and the cytoskeleton [2]. The neural cell adhesion
molecule (NCAM) is an important modulator of neuronal
development and plasticity associated with learning and
memory in rodents [14]. NCAM knock-out mice exhibit
deficient learning in the Morris water maze, and intracranial
injections of NCAM antibodies induce amnesia in rats and
chicks. NCAM-binding peptide, given intracerebroventricularly (icv) prior to training in rats and mice, impairs
learning or memory processes [14, 15-20]. Recent studies in
humans have also shown alterations in the regulation of
NCAMs in several neuropsychiatric and neurodegenerative
disorders, which are associated, to some extent, with stress
factors [21-26]. Other molecules that are required for the
lifelong and high turnover of synapses are: nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF),
insulin-like growth factor (IGF)-1, ciliary neurotrophic factor
(CNTF), interleukin (IL)-1, fibroblast growth factor (FGF),
transforming growth factor (TGF)-beta, growth-associated
proteins (GAP), synaptic proteins such as synaptophysin and
synapsin (SNAP), carrier proteins such as apolipoprotein E
and several microtubule-associated proteins and other
cytoskeletal proteins that undergo changes in the expression
and subcellular distrubution [2].
Among the neurotansmitters involved in learning and
memory processes, acetylcholine (ACh) is the well-known
neurotransmitter of the basal forebrain cholinergic neurons
that is associated with cognitive processes, including sensory
stimulus processing, alertness, aurosal and memory function
[27]. The basal forebrain cholinergic neurons innervate the
limbic and the cortical structures, such as the hippocampus,
anterior cingulate cortex, olfactory bulb, amygdala, frontal,
parietal and temporal cortices. In addition, the basal
forebrain cholinergic system contains many non-cholinergic
neurons, such as aminobutyric acid-releasing (GABA)
interneurons, that make connections with the cholinergic
neurons [27]. The involvement of the NMDA type of
glutamate receptor in both learning and its modulation by
experience is also well known [28]. Moreover, neuropeptides
are often co-localized in the cholinergic neurons of the basal
forebrain. For instance, in rodents (but not in higher
primates) galanin is found in septohippocampal cholinergic
and non-cholinergic neurons [27]. Also, cholinergic cells
within dorsolateral pontine regions contain co-existing
messengers, such as opioid dynorphin B and nitric oxide [29,
30]. There is also some integration between the cholinergic
system and other neurotransmitter systems: thyrotropin
releasing hormone (TRH) promotes cholinergic function and
release of ACh; changes in corticotropin releasing hormone
(CRH) and somatostatin immunoreactivity in the cerebral
cortex are correlated with a reduction in the choline
acetlytransferase activity [31]. As discussed in this review,
The Physiology of Learning and Memory
neuropeptides also play a critical role in learning behaviors

[32].
Throughout life, different biological and psychological
factors, such as stress, arousal, fear, anxiety and aging, affect
learning and memory processes [3]. Aged rats and mice
show decrements in spatial memory performance [33-37].
Several studies provided the evidences that ageing has a
negative effect on LTP formation, which may be secondary
to the structural and functional changes in the aged neurons.
In contrast, the other form of synaptic plasticity, LTD, is
increased during aging [38, 39]. In the normal aging process
or in Alzheimers disease (AD) reductions are observed in
the number of cholenergic neurons and in the brain
cholinergic function accompanied with the degeneration of
cholinergic neurons of the basal forebrain. In AD, the
aberrant plasticity, i.e. abnormal sprouting or a regenerative
failure are seen [2, 31, 40]. It prominently affects brain areas
such as the parietal and temporal cortices, the hippocampus,
the entorhinal cortex, and the amygdala and is associated
with many cognitive disturbances [27, 41].
According to free radical hypothesis of aging, the
generation and accumulation of reactive oxygen species
(such as superoxide and hydroxyl radicals) cause oxidative
damage in the brain, which results in diminished cognitive
performance. With ageing, due to significant reductions in
antioxidants, the brain becomes more vulnerable to the
deleterious effects of oxidative damage. Especially, the
hippocampus is sensitive to antioxidant glutathione (GSH)
depletion GSH deficiency, when observed in any tissue,
including the brain, results in less protection against
oxidative stress [39]. A number of studies have shown that
GSH protects catecholaminergic neurons against toxic
species and free radicals formed during metabolic processes.
When glutathione (GSH) deficiency is observed in the brain,
it results in reduced protection against oxidative stress, as
can be seen in any other tissue. It was shown that the
oxidative injury of the brain is ameliorated by the
administration of dopamine (DA) [33]. Furthermore, in the
hippocampus and frontal cortex, GSH depletion stimulates
the expression of NGF gene transcription factor AP-1 [39,
42, 43]. Besides its antioxidant role, GSH has also been
suggested to have neurotransmitter and neuromodulatory
functions [44]. It may serve for the intra- and intercellular
signaling in the brain, such as: (a) uptake, synthesis, and
release of glutamate and GABA; (b) as a substrate and an
allosteric modulator of eicosanoid biosynthesis; (c)
regulation of NMDA and non-NMDA glutamate receptor
activity; (d) neuronal depolarization by acting at its own
ionotropic receptor; and (e) activation of transcription factors
[44-50].
Stress and Learning-Memory Process
Any physical or psychological stressor that threatens
the homeostasis of an organism can initiate a set of
behavioral and neuro-endocrinological responses, which help
the organism to adapt to the altered situation. In conducting
the neuro-endocrine responses, hypothalomo-pitiutary (HPA)
axis and sympatheto-adrenal axis are two major pathways
mediating the major components of the stress response [5154]. Recent opinions on stress emphasize that individual
differences and several response patterns exist in coping with

environmental challenges. Depending upon the physical
(intensity, frequency, duration) and psychological
(predictability and controllability) nature of stressors and
individual differences -determined by the characteristics of
organism, the experimental and developmental variablesorganism may adapt an active (fight/flight, escape or
avoidance as a defense system) or a passive (immobility,
freezing or crouching as a behavioural inhibition) behavioral
strategy. These behavioral responses may be accompanied
by different neuroendocrine responses ranging from high
reactivity of the sympathetic response with increased plasma
noradrenaline and high baseline levels of testosterone (seen
with active coper) to lower plasma levels of testosterone,
with a predominance in parasympathetic response and a
more reactive HPA axis (seen with passive coper).
Psychological nature of stressors, in particular the subjects
ability to predict and control its occurrence, is more
important than its physical nature [51, 52, 55]. Considering
cognitive functioning, according to YerkesDodson law, an
inverted U-shaped relationship exists between a state of
stress or arousal and a cognitive task performance. The
effects of stress on cognition are associated with
catecholamines and glucocorticoids, which are involved in
the sympathetic-adrenomedullary and HPA stress response.
Low or moderate concentrations of circulating glucocorticoids and catecholamines can enhance learning and
memory formation, while excessively high or prolonged
elevations can lead to disruption [56-60]. In the other words,
stress can alter a cognition by modulating both
norepinephrine (NE) and cortisol activity [61]. Individuals
with normal HPA axis activity have a better ability to cope
with stressful life events and have a better cognitive
performance. The altered HPA axis function with aging or in
AD, associated with impaired feedback mechanisms
originating from a damaged hippocampus and hyperactivation of the HPA axis, results in learning and memory
disturbances [62] Glucocorticoids (GC), end-products of the
HPA axis, have diverse effects on many neuropeptide/
neurotransmitter systems, affecting cognitive functions such
as attention, perception, memory, and emotional processing.
When certain pathological emotional states with the
involvement of GC are present, suppression of hippocampal
activation, enhancement of amygdala activity, and dendritic
reshaping in particular brain regions were observed [63]. NE
depletion in rodents and monkeys was shown to cause
increased distractibility and deficits in spatial working
memory, while administration of NE agonists improved
memory performance [64-69].
According to the nature of stress, various brain structures
are involved and the neural circuits that underlie stress are
organised at different levels, reflecting the varying demands
for cognitive processing. Simple automatic responses are
mediated by the lower brain areas (periaqueductal grey
matter and locus coeruleus), while amygdala and
septohippocampal systems, which constitute the intermediate
brain level, mediate more practiced responses. At the higherlevel cortical regions are involved and the cognitively
demanding stimuli are managed [55]. A number of studies
have reported that acute and choric stresses have different
consequences. In general, acute stress causes (a)
hyperactivation in many central corticotropin releasing factor

(CRF)-containing neurons, those particularly found in
paraventricular nuclei (PVN) of the hypothalamus and
amygdala, (b) stimulation in most of the central serotonin (5HT)- and cholecystokinin (CCK)-containing neurons [7074]. Whereas, chronic stress or chronic infusion of CRF
causes (a) a reduction in CRF mRNA level in central
amygdala and a slight elevation in PVN, (b) a hypoactivation
in most of the central 5-HTergic system, (c) an increase in
hippocampal cholinergic system, amygdaloid glutaminergic
and GABAergic system, and (d) CRF-hypersensitivity in
locus coeruleus, resulting in sympathetic nervous system
activation [73, 75-78].
Central Nervous System (CNS) Structures Involved in
the Stress and Learning/Memory Processes
Both stress and cognitive processes are managed with the
involvement of more than one brain region at different
levels. Although the whole picture cannot be demonstrated
yet, we now have a basic understanding of the brain regions
involved in stress responses and cognitive processes, their
neuroanatomical and neurofunctional connections and the
participation of neuromessengers. For example, memory
processes with long-lasting changes in synaptic efficiency
takes place in the hippocampus, amygdala, medial septum,
and the neocortex and lesions in these brain regions impair
the learning process [79-81]. Not surprisingly, these brain
regions (eg. locus ceruleus, hippocampus, amgydala,
neocortex) and neuromessengers (eg. cholinergic,
monoaminergic and glutamatergic systems and CRF, 5-HT
and CCKergic systems) involved in learning and memory
also play prominent roles in stress responses. Furthermore,
both HPA and sympatho-adrenal axis with their hormones,
GC and NE, participate in both of these processes [54, 58,
62, 80, 81]. Because of this interaction, stress and elevated
stress hormone levels alter cognitive and emotional
responses. For instance, chronic stress or glucocorticoid
exposure can alter neuronal morphology in the hippocampus,
amygdala, and the prefrontal cortex, and decreases
neurogenesis in the dentate gyrus and results in cognitive
impairment [82- 84].
Among the CNS structures involved in cognitive function
and stress response, the hippocampus is the best-studied
brain region. The hippocampus does not only play a crucial
role in learning and memory process, including episodic,
declarative, contextual and spatial learning and memory, but
also is an important center for integrating cognitive,
neurohormonal, and neurochemical responses to stress.
Adults exposed to physical or sexual abuse at their childhood
show reduced hippocampal volume and, in some instances,
present with impairments in memory [85-89]. The
hippocampus, a plastic and adaptable brain region where the
physiological mechanisms (LTP and LTD) of memory
storage take place, is capable of considerable structural
reorganization and it is also vulnerable to damage during
aging and repeated stress. It has been reported that the ageand stress-related alterations in hippocampal LTP and LTD
correlate with impairments in hippocampal-dependent
learning and memory tasks [38, 88, 90-93].
Electrophysiological studies, in which a chronic
psychosocial stress was applied, showed that stress-induced
Glpnar and Yegen
memory impairment might be related to impairment of the

early form of LTP in the synapses [94]. In either age- or
stress-related hippocampal damage, glucocorticoids and
serotonin, which act through excitatory amino acids, and
nitric oxide are the two mediators [21, 82, 86, 95-102]. The
excitatory amino acids are also involved in adaptive
plasticity related to synapse formation, stabilization of
neuronal populations long-term potentiation and memory
[103-106]. The hippocampus, enriched with receptors for
corticosterone, plays a role in glucocorticoid negative
feedback and this makes some hippocampal functioning
particularly susceptible to stress. Basal levels of
corticosterone increase the magnitude of LTP, while during
stressful situations with higher levels of corticosterone, LTP
is attenuated and the induction of LTD is enhanced [4, 86,
107].
Several studies with exposure to different forms of stress
(e.g. immobilization, chronic restraint, or social stress)
concomitant with elevated levels of glucocorticoids indicated
that stress results in behavioral and cognitive changes,
including impairment in learning performance, in
conjunction with pathological changes in the hippocampal
neurons, ranging from a reversible damage to a permanent
neuronal loss [21, 97, 101, 102, 108, 109] such as reduction
in mRNA levels for neurotrophins and their high affinity
receptors in the brain, especially in the hippocampus,
atrophy of the dendrites of hippocampal CA1, CA3 neurons,
the neuronal death in the hippocampal CA3 and CA4
neurons [5, 21, 59, 87, 95, 101, 108, 110-117].
Chronic stress exposure in rats also reduced hippocampal
neural cell adhesion molecule, which plays a role in the
hippocampal structural remodelling [21]. As indicated in
several studies, stress also decreases neurotrophic factors
(NGF, BDNF and neurotrophins) in the hippocampus and
basal forebrain, resulting in structural and functional (transit
disturbance of perception and memory) changes in the brain
On the other hand, implantation of NGF-secreting fibroblasts
into the nucleus basalis magnocellularis of aged and
memory-impaired rats ameliorated memory impairment
significantly [87].
Besides the hippocampus, basal forebrain areas with
cholinergic innervation, amygdala, prefrontal cortex and
locus coeruleus also play crucial roles in both stress response
and learning/memory processes [8, 55, 61, 87, 118, 119].
Nicotinic and muscarinic ACh receptors in the hippocampus
are required for the expression of LTP. Cholinergic receptor
activation enhances the responsiveness of NMDA glutamate
receptors and facilitates the induction of LTP. Since defects
in hippocampal cholinergic neurotransmission lead to the
deficits of learning and memory under stressful conditions,
excessive glucocorticoid exposure through stress might be
implicated as the cause of the associated hippocampal
dysfunction [120-122].
By exposure to chronic stress, alterations are also seen in
behavioral, cognitive and morphological measures associated
with the limbic system (particularly amygdala and septal
regions) [46], which plays a central role in the genesis of
emotions as well as in the formation of emotional memory
and neuroendocrine control of emotions. [82,123-128].
Findings of many studies indicate that the amygdala, which
is also involved in attention and reward, modulates the

consolidation of long-term explicit memories of emotionally
arousing experiences by influencing other brain regions
involved in memory consolidation, such as hippocampus,
caudate nucleus, nucleus basalis and cortex [63, 127-131].
The amygdaloid complex has been implicated in fear
conditioning and aversive-emotional learning and memory
[55, 132]. It detects and organizes the physiological
responses to ``natural'' dangers, but acts also as a center to
learn about novel threats (classical conditioning). Therefore,
chronic restraint stress results in changes in limbic brain
regions that mediate learning, memory, and conditioned or
spontaneous emotional responses and cognitive processes. In
contrast to stress-induced neuronal pruning or remodeling
reported in the hippocampus, chronic stress results in
increased dendritic branching of pyramidal and stellate
neurons in the amygdala [82, 132, 133].
Prefrontal cortex with dopaminergic and glutaminergic
system is another CNS structure that is involved in stress
response and cognitive functioning. It is suggested that
activation of glutamatergic neurotransmission in the
prefrontal cortex represents a common mechanism by which
stress influences normal and abnormal processes that sustain
affection and cognition [134]. The prefrontal cortex is
involved in the acquisition and transfer of a new information
or skill [135]. Together with amygdaloid structures, frontal
cortex has been identified as a part of the neural system
mediating reward-related learning through complex
interactions with the mesolimbic dopaminergic system [136].
Stress causes changes in the prefrontal cortex and amygdala
dopaminergic system, dentate gyrus serotonergic system, and
norepinephrine levels in the CA3 region dopaminergic
system [110].
NEUROTRANSMITTERS
ABD
NEUROMODULATORS INVOLVED IN LEARNING AND MEMORY
Recent researches have demonstrated that learning and
memory functions are influenced by a tremendous number of
neuropeptides and non-peptide molecules. Neuropeptides
differ from classical neurotransmitters in several important
ways (Table 1). Classical neurotransmitters are small,
rapid-acting molecules that typically bring about a response
in the postsynaptic neuron within a few milliseconds or less,
usually a change in postsynaptic potential as a result of
triggering of the opening of specific ion channels. Classical
neurotransmitters are synthesized and packaged locally in
synaptic vesicles in the cytosol of the axon terminal. These
chemical messengers are primarily amino acids or closely
related compounds [137-139].
Neuropeptides are larger molecules made up of
anywhere from two to about forty amino acids. They are
synthesized in neuronal cell body in the endoplasmic
reticulum and Golgi complex and are subsequently moved
by axonal transport along the microtubular highway to the
axon terminals. They are known to diffuse locally and act on
the other adjacent neurons at much lower concentration than
classical neurotransmitters and may bring about slower more
prolonged response. Some neuropeptides released at synapse
may function as true neurotransmitters but most are believed
to function as neuromodulators. Neuromodulators are
Table 1.
Some of the Well-Known Neurotransmitters and

Neuropeptides[137]
Classical Neurotransmitters
acetylcholine
dopamine
gamma-aminobutyric acid
glutamate/aspartate
glycine
histamine
norepinephrine/epinephrine
serotonin
Neuropeptides
adrenocorticotropic hormone
angiotensin II
-melanocyte-stimulating hormone
-endorphin
bombesin
bradykinin
cholecystokinin
enkephalins
gastrin
glucagon
gonadotropin-releasing hormone
insulin
motilin
neurotensin
oxytocin
somatostatin
substance P
thyrotropin-releasing hormone
vasoactive intestinal polypeptide
vasopressin
chemical messengers that bind to neuronal receptors at nonsynaptic sites. They do not cause the formation of
postsynaptic potential but instead bring about long-term
changes that subtly depress or enhance synaptic effectiveness
often by activating second messenger systems. In several
instances neuropeptides co-exist in the same nerve terminal
with classical neurotransmitters (Table 2). In some of these
cases, the neuropeptide is released along with the
neurotransmitter in response to nerve stimulation [137].
Learning, Memory and Peptide/Non-Peptide Molecules
Although there is consensus that brain cholinergic
neurotransmission plays the major role in learning, memory
and attention, it is also well known that these functions are
influenced by a variety of neuropeptides [57] (Table 3). The
neuropeptides, as well as their respective receptors, are
widely distributed throughout the mammalian central
nervous system. Neuropeptides participate in learning and
memory processes by affecting attention, motivation,
concentration, arousal or vigilance, anxiety and fear.
Furthermore, several neuropeptides modulate the release of
stress hormones, which in turn enhance memory
consolidation [140].
Table 2.
Co-existence of Classical Neurotransmitters and

Neuropeptides within the Same Neuronal Terminal
[139]
Neurotransmitter
Neuropeptide
Acetylcoline
Vasoactive intestinal polypeptide
Dopamine
Cholecystokinin
Enkephalin
Epinephrine
Enkephalin
Norepinephrine
Somatostatin
Enkephalin
Neurotensin
Serotonin
Substance P
Thyrotropin-releasing hormone
Arginine 8-vasopressin (AVP) and oxytocin (OT) are

members of a large group of ancient neuropeptides that have
profound effects on a variety of mnemonic and social
processes. AVP in the ventral hippocampus is involved in
information processing, memory consolidation, storage, and
retrieval [7]. The mechanisms by which AVP and OT
facilitate social memory remain unclear. Social memory is
a unique form of memory, critical for reproduction,
territorial defense, and the establishment of dominance
hierarchies in nature. AVP and OT have been shown to
influence a number of forms of social behavior, including
affiliation, aggression, and reproduction. Experimental
studies have shown that AVP and OT are essential for social
memory, although they appear to influence different
cognitive processes and may modulate different neural
systems [141].
In rats, AVP appears more important for consolidation,
whereas in mice OT is essential for acquisition. Since the
neuroanatomical distribution of receptors for both OT and
AVP show differences among species, these peptides show
unique cognitive and behavioral effects depending upon the
species [141].
It has been known that AVP has central effects on
learning and memory. It was found that removal of the
posterior pituitary impaired learning in rats and this deficit
could be restored by treatment with exogenous AVP [142,
143]. AVP was demonstrated to facilitate both acquisition
and consolidation processes [144]. Brattleboro rats, which
are natural AVP-deficient mutants, also have serious
memory impairments [141, 145]. Peripheral administration
of AVP or its analogs and selected AVP metabolites were
shown to enhance social memory [146]. Intracerebroventricular injections of AVP also enhanced recognition
responses in normal rats [147]. In another study, stimulations
of the supraoptic and paraventricular nuclei, which resulted
in AVP release within the hypothalamus, or microinjections
of AVP into the olfactory bulbs were shown to improve
recognition responses in rats [141, 148].
AVP has been shown to improve memory consolidation
in various mnemonic tasks. Extensive research has
demonstrated that AVP affects many behaviors, especially
Glpnar and Yegen
learned ones [135, 142]. Systemic or central administration

of AVP was demonstrated to affect several types of learned
behaviors such as active or passive avoidance conditioning,
social recognition and behavior and appetite conditioning
[135, 141, 147, 149, 150]. It was found that AVP or AVP
fragments when injected subcutaneously facilitated the
processes of memory consolidation and retrieval [151].
It is believed that AVP interacts with NMDA,
noradrenergic and -adrenergic receptors, but more
interestingly, with the glutaminergic receptors [151, 152].
AVP also stimulates NGF secretion in the hippocampus and
the cerebral cortex [153]. In vitro experiments demonstrate
that AVP can exert a neurotrophic effect upon cerebral
cortical neurons, by the activation of V1 receptors. It is well
documented that extrahypothalamic vasopressinergic
pathways, in particular limbic structures, such as the septum
[154], the hippocampus [155], and the amygdala [156] are
involved in the effects of vasopressin. The behavioral
memory effect of vasopressin in all these structures is
mediated not only by vasopressin V1 receptors, but also by
oxytocin receptors [157]. AVP-deficient Brattleboro rats
exhibit deficits in cerebral cortical development as assessed
by decreases in the cortical weight, cortical lipid content and
DNA content of the cerebral cortex [158].
Considerable evidence indicates that a separate and
distinct reninangiotensin system is present within the
central nervous system. It has been reported that angiotensin
II (AII) is involved in learning and memory. AII and its
fragments were shown to facilitate acquisition and retrieval
processes [159]. In another study, AII did not affect the
acquisition of passive avoidance, but improved avoidance
performance when given before the retrieval process [160].
Apolipoprotein E (apoE) is one of the primary
apolipoproteins found in the brain, carrying important roles
in cholesterol metabolism and neural plasticity [161]. In aged
and apoE-deficient mice, impairments in cognitive
performance have been observed. In the cortices and
hippocampi of aged apoE-knockout animals, hyperlipidemia,
increased loss of synaptic terminals, and neuronal
cytoskeleton abnormalities were observed [162-164].
Amyloid-beta (A) peptide is the main constituent of
senile plaques found in the aging brain and -Amyloid
precursor proteins (-APPs) play a crucial role in the
pathogenesis of AD, but little is known about their
physiological function in normal brain [165]. Intracerebral
injections of A-related peptides to mice or rats impair the
learning and memory retention, as well as causing
neurodegeneration in brain areas related to cognitive
function [166, 167]. Similarly, degeneration of forebrain
cholinergic pathways is a critical factor in AD [9] and
intracerebral A has toxic effects on brain cholinergic
systems [168, 169]. In rats A induces impairments of
spatial and non-spatial short-term memory, rather than longterm memory [167]. A-induced amnesia does not only
involve neurodegeneration in specific brain regions related to
learning and memory processing, but it appears that A may
also modulate neurotransmission or the molecular cascades
linked with learning and memory [167]. A impairs
cholinergic neurotransmission, by suppressing choline
Table 3.
Effects of Peptides and Non-peptide Molecules on Learning and Memory
NEUROPEPTIDES
AVP and OT
AII
facilitate social memoryand learned behaviors

facilitate both acquisition/ consolidation processes
AVP-deficiency results in memory impairment
facilitates retrieval processes when given before acquisition and impairs retention when given after training
ANP, BNP, CNP
facilitatory action on memory consolidation
BN/GRP and NM
improve memory performance
CCK
CGRP, SP and NPY
Colostrinin
CRF
CCK-related peptides improve learning and memory performance

role for the CCK-B receptors in anxiety states
lack of CCK-A receptors cause impaired learning and memory functions
CCK-antiserum produces learning impairments
CCK-8 potentiates amnesia
CCK-4 interferes negatively with memory
pretreatment with CCK-8S prevents experimental amnesia
role in conditioned fear stress and anxiety
enhance memory retention
levels decreased in animals with hippocampal lesions
SP improves functional recovery and increases the learning ability
NPY can reverse drug-induced amnesi
NPY either enhances memory or induces amnesia (depending on the site of injection)
NPY antibodies induce amnesia
facilitates the acquisition of spatial learning in aged rats
improves memory retention and improves learning performance
long-lasting enhancement of synaptic efficacy
increased immunoreactivity in amyloid plaques of Alzheimers disease (AD) brains
lower levels in the cerebrospinal fluid of AD pateints
receptor antagonist given prior to training impairs fear conditioning
lack of receptors impairs speed in learning
Galanin
impairs the learning and memory performances

overexpression impairs cognition
GLP-1
mediates or exacerbate amyloid protein-induced neurotoxicity, its antagonist prevents memory impairment
HCNP
abnormal accumulation and expression associated with memory and learning disorders
Insulin
improves short-term memory
MCH
modulates memory by acting on amygdala and hippocampus
N/OFQ
Orexin-A
PACAP
VIP
impairs spatial learning

receptor deficiency facilitates LTP and memory
improves scopolamine-induced impairment of learning and memory
inhibits LTP and retards spatial learning
facilitates learning (consolidation and retrieval)
ameliorates spatial cognitive deficits
NON-PEPTIDE MOLECULES
ApoE
deficiency causes impairments in cognitive function
intracerebral injections impair learning and memory retention (spatial and non-spatial short-term memory)
PE abolishes the formation of amyloid beta peptide
DA
it has a beneficial impact on spatial working memory but excessive or insufficient levels lead to impairments
Glpnar and Yegen
(Table 3) contd
NON-PEPTIDE MOLECULES
GLUTAMATE
HISTAMINE
NO
OPIOIDS
5-HT
malfunction is associated with the impairment of memory

hypoactivation and hyperactivation cause impeded cognitive processing
post-training administration attenuates memory retention
depletion causes attenuation of acquisition
inactivation of H1 receptors increases memory retention or memory recall
promotes LTP
higher synthesis in aged and cognitively impaired animals
role in acquisition, but not retention, of spatial memory
role in in memory acquisition
administration impairs learning and memory
chronic morphine treatment induces memory impairment
lack of -opioid receptors causes spatial memory impairment
dynorphin impairs spatial learning
decreased levels block the effect of stress on memory
stimulation of 5-HT1A receptors has detrimental effects on learning and working memory
decrease in 5HT1A-binding causes memory impairment
5-HT4 agonists have potent cognitive enhancing activity
AD patients display a reduction in 5-HT4 receptor binding sites
AVP: angiotensin-vasopressin, OT: oxytocin, AII: angiotensin II, ANP: atrial natriuretic peptide, BNP: brain-derived natriuretic peptide, CNP: C-type natriuretic peptide, ApoE:
apolipoprotein E, A: Amyloid-beta peptide, BN/GRP and NM: bombesin/gastrin releasing peptide and neuromedin, CCK: cholecystokinin, CGRP: calcitonin-gene related peptide,
SP: substance P, NPY: neuropeptide Y, CRH: corticotropin releasing hormone, DA: dopamine, GLP-1: glucagon-like peptide, HCNP: hippocampal cholinergic neurostimulating
peptide, MCH: melanin-concentrating hormone, N/OFQ: nociceptin/orphanin FQ, NO: nitric oxide, PACAP: pituitary adenylate cyclase activating polypeptide,PE: Proline
endopeptidase, 5-HT: serootonin,VIP: vasoactive intestinal peptide.
acetyltransferase (ChAT) activity, and induces glutamatergic

dysfunction [170].
Nitric oxide (NO) is a neurosignaling molecule with
significant roles in cognition [171]. Due to its oxidative
properties, NO has been implicated in several
neurodegenerative diseases [172]. Neuronal nitric oxide
synthase (nNOS) messenger RNA expression in a variety of
brain regions was significantly higher in aged and
cognitively impaired animals than that in aged cognitively
unimpaired animals [173]. Increased NOS activity was
shown to contribute to cognitive impairments in aged or
apoE-knockout mice due to excess accumulation of oxidative
damages in areas involved in learning and memory [164]. In
the brain, nNOS is expressed in diffused cortical areas and in
the hippocampus [174]. NO has a number of neurological
functions, such as modulating glutamate-linked guanosine
cyclic monophosphate (cGMP) production, and appears to be
a retrograde messenger in promoting LTP [164, 175]. Since
glucocorticoids have been shown to modulate LTP and
short-term potentiation in the hippocampus [151], where
NOS is described, it was suggested that glucocorticoids may
have a direct impact on NOS, thereby modulating LTPrelated processes. Since NOS is present in the HPA axis, it
appears that the stress axis, mediated by nitric oxide in the
hippocampus, is involved in the regulation of the synaptic
plasticity process [85]. It has been postulated that NO takes a
role in acquisition, but not retention, of spatial memory [39,
176].
Specific proteins play essential roles during the

development and regeneration of specific neurons, which
include NGF and related members of the neurotrophin
family, ciliary neurotrophic factor (CNTF), interleukin-3
(IL-3), fibroblast growth factors, and the glial-cell-linederived neurotrophic factor (GDNF). [177]. NGF and brainderived neurotrophic factor (BDNF) in the hippocampus play
an important role not only in the development and
regeneration of the system, but also in learning and memory
formation through neuronal plasticity [178]. The multimodal
mechanism of cerebrolysin, the brain-derived peptidergic
drug, has been found to support the survival of neurons in
vitro and in vivo , which appears to depend on neutrotrophic
factor-like activity [179]. Apamin, a highly selective and
potent peptide that blocks the calcium-activated potassium
channels, is predominantly localized in the cortical and
limbic structures. Apamin was shown to improve the
cognitive performance of mice and was suggested to be a
cognition enhancer [180].
It was demonstrated that soluble extracts from the
hippocampus of young rats enhance the development and
growth of cholinergic neurons in rat medial septal nucleus,
which led to the purification of a novel undecapeptide
(hippocampal cholinergic neurostimulating peptide; HCNP).
HCNP enhances the production of ChAT, but not of
acetylcholine esterase (AChE). Certain types of memory and
learning disorders are found to be associated with abnormal
accumulation and expression of HCNP analogue peptide
and/or its precursor protein mRNA in the hippocampus
[177].
Several studies reported that peripheral administration of

bombesin (BN) and gastrin-releasing peptide (GRP)
improved some forms of memory performance in rats and
mice, suggesting that endogenous BN-like peptides have
some role(s) for the modulation of learning and memory
[181]. Neuromedin B (NMB) is a mammalian BN-like
peptide that plays a role in regulating the stress response via
the neural system, which also controls learning and memory
[182]. Endogenous glucagon-like peptide (GLP-1) has been
demonstrated to mediate or exacerbate amyloid proteininduced neurotoxicity. On the other hand, infusion of GLP-1
antagonist was shown to prevent the memory impairment
induced by -amyloid alone [183]. Vasoactive intestinal
peptide (VIP) appears to have an ameliorating effect on
spatial cognitive deficits induced by scopolamine in the rat
[184]. The pituitary adenylate cyclase activating polypeptide
(PACAP), isolated first from the ovine hypothalamus, was
shown to facilitate the learning, the consolidation of learning
and the retrieval of the passive avoidance response [185].
Proline endopeptidase (PE), a serine endooligopeptidase
involved in the degradation of various neuropeptides, has
been reported to abolish the formation of amyloid beta (A )
peptide and post mortem levels of human PE were affected
in AD brains [186]. Thus, PE inhibitors are seen as potential
pharmacological agents aimed at slowing down or abolishing
the degenerating process taking place in AD [187].
Orexin-A, which is released from the axon terminals of
the glucose-sensitive neurons in the lateral hypothalamus to
act on its hippocampal receptors, was shown to inhibit LTP
in the hippocampus and retard spatial learning [188, 189].
Colostrinin, a complex of proline-rich polypeptides
isolated from early milk, was speculated to facilitate the
early postnatal development of the cerebral neurons and their
plasticity. Initial observations in humans indicated that
colostrinin, facilitates cognitive functioning in patients with
Alzheimers disease [190]. In rats, colostrinin administration
facilitated the acquisition of spatial learning in aged rats,
bringing it to the level observed in young subjects [191].
Insulin is reported to improve short-term memory,
through its action on hippocampo-frontocortical circuitry.
Clinical studies provide compelling evidence for a beneficial
effect of insulin in AD. Higher fasting concentrations of
insulin in plasma and lower concentrations of insulin in
cerebrospinal fluid (CSF), which are indicative of insulin
resistance, have been detected in AD patients compared with
healthy controls. Furthermore, clinical observations show
that induced hyperglycemia results in an increased plasma
level of insulin and enhanced cognitive performance in
patients with mild AD. Conversely, induced hyperglycemia
does not increase the plasma concentration of insulin and
does not improve cognitive function in patients with severe
AD [192].
Nociceptin, also known as orphanin FQ (N/OFQ), is an
endogenous ligand for the orphan opioid receptor-like
receptor 1 (ORL1), and resembles to some extent the
endogenous opioid peptide dynorphin A. Both the ORL1
receptor and N/OFQ are widely distributed in the central
nervous system (CNS) [193]. It was shown that nociceptin
microinjected into the hippocampus impairs spatial learning
in rats [194] and long-term potentiation and memory are

facilitated in mice lacking nociceptin receptors [195].
N/OFQ inhibits the release of several neurotransmitters,
including serotonin [196] and dopamine [197, 198].
Moreover, nociceptin injection improves scopolamineinduced impairment of learning and memory [199].
Dopamine (DA) has been implicated in learning and
memory and its receptors are involved in the control of
movement, cognition, emotion, and neuroendocrine secretion
[200]. It has been shown that DA has a beneficial impact on
spatial working memory [201], but excessive or insufficient
levels of DA lead to impairments [110, 202, 203].
Central administration of the neuropeptide galanin to
rodents was shown to impair the performances on learning
and memory tasks [204]. On the other hand, galanin is
overexpressed in the basal forebrain of Alzheimers patients,
suggesting that galanin overexpression contributes to the
memory deficits that characterize Alzheimers disease [205].
Similarly, galanin-overexpressing transgenic mice were
shown to perform poorly on challenging cognitive tasks
[206].
L-Glutamate, produced by deamidation of glutamine via
glutaminase, is the most abundant free amino acid in brain
and it plays an important role in neuronal differentiation,
migration, synaptic maintenance and plasticity. It contributes
to learning and memory [207], while malfunction in
glutamatergic activity is associated with the impairment of
memory seen in Alzheimer patients. In Alzheimers disease,
glutamatergic neurotransmission in neocortical regions and
hippocampus is severely disrupted and corticocortical
association fibers arising from glutamatergic pyramidal cells
are disconnected [208, 209]. Both hypoactivation and
hyperactivation of glutamatergic systems seem to cause
impeded cognitive processing in animals. Stress appears to
have deleterious effects on cognition caused by glutamate
neurotoxicity leading to attenuated synaptic activity [208].
Stress results in enhanced glutamate response, which
probably increases the vulnerability of the aging brain to
neuronal damage. There is evidence that increased
concentrations of corticosterone can elevate the basal level
of glutamate in the hippocampus of rats [208, 210].
Isatin, which is an endogenous indole with a highest
concentration in the hippocampus [211], has been shown to
counteract the behavioural effects of atrial natriuretic peptide
(ANP), brain natriuretic peptide (BNP) and C-type
natriuretic peptide (CNP) in vitro and in vivo. It has been
shown that the facilitatory action of BNP and CNP, as well
as ANP, on memory consolidation can be inhibited by isatin
[212-214].
The tachykinins are a family of peptides with putative
neurotransmitter roles in the brain regions associated with
emotion, sensation, learning and memory [215]. Calcitonin
gene-related peptide (CGRP), substance P (SP) and
neuropeptide Y (NPY) are postulated to play important roles
in cognitive functions, including memory and mood
regulation [216]. CGRP, SP and NPY levels were shown to
be decreased in the hippocampus and a significant decrease
of NPY in the cortex was observed in mice with lupus. On
the other hand, SP treatment improved functional recovery
10
and increased the learning ability in animals with

hippocampal lesions [217]. It was suggested that the
behaviour deficits observed in these lupus mice are
associated with an altered availability of NGF [216].
Considerable evidence indicates that NPY is involved in
cognitive functions [218]. and NPY enhances memory
retention in mice [219]. NPY-like immunoreactivity and
NPY receptors have been shown to be present throughout the
brain, but are concentrated in the hippocampus, which is
implicated in the modulation of cognition [220]. NPY can
reverse drug-induced amnesia [219] and its injection into the
rostral hippocampus and the septal area enhances memory
retention, while its injection into the amygdaloid body and
the caudal hippocampus induces amnesia. Immunization
with NPY antibodies also induces amnesia [221]. NPY-like
immunoreactivity was shown to decrease in cortical,
amygdaloid and hippocampal areas and temporal cortex in
AD brains [222], suggesting that the degenerative processes
occurring in Alzheimers disease may involve changes in
NPY-related innervation [220].
It is well-known that acute opioid administration impairs
learning and memory [223]. and this opioid-induced
impairment can be modulated by opioid antagonists [224]. It
was also reported that chronic treatment with morphine
induces memory impairment [225] , which is thought to be
related to the the inhibition of the cholinergic system.
Moreover, recently it was demonstrated that -opioid
receptor knock-out mice exhibit a spatial memory
impairment, suggesting that these receptors play an
important role in the modification of spatial learning and
memory [226]. Microinjection of dynorphin B into the dorsal
hippocampus impairs spatial learning in rats. These findings
suggest that the hippocampal dynorphin system plays a
significant role in hippocampal learning processes and that
dynorphin peptides have a regulatory function in memory
acquisition and the early stages of memory formation [227].
Recent evidence has established that histamine plays an
important role in the symptomatology of Alzheimers disease
as a central neurotransmitter in the brain. The studies
indicated that post-training administration of different doses
of histamine attenuated memory retention, while depletion of
histamine by the administration of a selective inhibitor of the
histamine-synthesizing enzyme caused an attenuation of
acquisition in rats [228]. It has been shown that the
inactivation of histamine H1 receptors by histamine receptor
antagonists increases memory retention, while contradictory
reports indicate that histamine H1 receptor activation may
increase memory recall. It was also indicated that the
memory improvement induced by acetylcholine or nicotine
can be impaired by histamine, implicating that histaminergic
system may interact with the cholinergic system on memory
retention [229].
Immunocytochemical studies have demonstrated that
melanin-concentrating hormone (MCH), which is mainly
located in the lateral hypothalamic area and projects to
various other brain areas and modulates memory by acting
on both the amygdala and hippocampus [230, 231].
Octopamine (OA), a biogenic monoamine structurally
related to noradrenaline, acts as a neurohormone, a
Glpnar and Yegen
neuromodulator and a neurotransmitter only in invertebrates.

In the central nervous system, OA is involved in
desensitization of sensory inputs, has an influence on
learning and memory, and regulates the `mood' of the
animal. It is believed that OA is a stress hormone that is
released in times of stress, as they occur during manipulation
of the animal, to enable the animal to cope with stressors
[232-234].
Major Strategic Molecules in the Modulation of Memory
Processes in Stress
Among all these peptides that are found to be associated
with learning and memory, cholecystokinin (CCK),
serotonin (5-HT) and corticotropin releasing factor (CRF)
play a strategic role in the modulation of memory processes
under stressful conditions. CRF is accepted as the main
neuropeptide involved in both physical and emotional stress.
The results of a number of studies have suggested that the
central CRF, which modulates memory performance, exerts
a protective role during stress, possibly through the
activation of HPA axis [54, 235, 236]. The peptide CCK has
been also proposed to facilitate memory processing and
CCK-like immunoreactivity in the hypothalamus was
observed upon stress exposure, suggesting that CCK may
participate in the central control of stress response and stressinduced memory dysfunction. On the other hand, 5-HT
appears to play a role in behaviors that involve a high
cognitive demand and stress exposure activates serotonergic
systems in a variety of brain regions.
A. CHOLECYSTOKININ (CCK)
Cholecystokinin, one of the most abundant
neurotransmitter peptides in the mammalian cerebral cortex
and hippocampus [237], is involved in higher functions to
act as a neurotransmitter and/or neuromodulator [238]. The
characteristic distribution of CCK and the presence of
specific CCK receptive sites in the brain indicate the role of
CCK-fragments in brain function. Neuronal CCK has been
implicated in the control of feeding, pain perception and
exploratory behaviors [239]. Two CCK receptor subtypes
(designated A and B) are found within the central nervous
system (CNS), although CCK-B receptors are far more
numerous and widely distributed [240]. CCK or CCK
receptors are found in brain areas involved with cognitive or
emotional aspects of behavior, such as prefrontal cortex,
cingulate, hippocampus, amygdala, and the locus coeruleus
[241, 242].
Interest on the anxiogenic quality of CCK occurred when
rats or healthy human volunteers were observed to have
panic attacks when given CCK-4 intravenously, supporting a
role for the CCK-B receptor in anxiety states and panic
attacks [55, 243, 244]. There is also evidence that the CCKB receptors play a role in modulating activity within the
hypothalamicpituitary adrenal (HPA) axis [245],
implicating that CCK may be a modulator of emotional
behavior and stress responsiveness [246].
Several studies have attempted to demonstrate the role of
CCK in learning and mnemonic processes [247]. OLETF
rats, which lack CCK-A receptor because of a genetic
abnormality, have impaired learning and memory functions
[248]. It was demonstrated that CCK-related peptides could

improve learning [249, 250], whereas injection of a CCKantiserum was found to produce learning impairments [251].
On the contrary, CCK-8 was found to potentiate the amnestic
effects of scopolamine, while CCK-4 interfered negatively
with memory [252-254].
Extensive studies were carried out on the involvement of
the CCKergic system in anxiety-, panic- and stress-related
behaviour. It was found that stress resulted in a significant
decrease in the extracellular levels of CCK-like
immunoreactivity in the hippocampus, and partially
suppressed the increase obtained during the acquisition phase
of memory, suggesting that the CCKergic system in the
hippocampus is involved in stress-induced impairment of
memory [56]. Moreover, memory performance is
physiologically improved when the CCK-B receptor in the
rat hippocampus is stimulated with endogenous CCK8.
Furthermore, CCK-like immunoreactivity and CCK-B
receptor-mediated amygdaloid regulation of hypothalamus
were observed upon stress exposure, suggesting that CCK
may participate in the central control of neuro-endocrine
response to stress [72, 74]. Systemic or icv pretreatment with
CCK-8S prevents experimental amnesia. It was suggested
that the CCK-B receptor might play an important role in
conditioned fear stress and that it might be related to anxiety
[247, 255, 256].
Intravenous administration of CCK-B receptor agonist,
pentagastrin, produces dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis
that CCK-B agonists pharmacologically activate the HPA
axis [257]. In accordance with these findings, we recently
demonstrated that acute stress activates HPA axis with the
participation of central CCK receptors [54].
B. CORTICOTROPIN-RELEASING HORMONE AND
GLUCOCORTICOIDS
Corticotropin-releasing hormone (CRH, or corticotropin
releasing factor, CRF) is a peptide with both neuroendocrine
and neurotransmitter properties [258]. CRH originates from
clusters of peptidergic cells in the hypothalamic
paraventricular nucleus (PVN) [259] as the key mediator of
the stress response and also functions as a neuromodulator in
a number of limbic and autonomic brain circuits. It was
reported that acute stress causes hyperactivation in many
central CRH-containing neurons, particularly found in PVN
of hypothalamus and amygdala. However, chronic stress
causes a reduction in CRF mRNA level in central amygdala
and a slight elevation in PVN and CRF-hypersensitivity in
locus coeruleus resulting in sympathetic nervous system
activation [25].
Localization of the CRH in the limbic system suggests
that it plays an important role in activating the sympathetic
nervous system for adaptive, autonomic, behavioral and
immune responses to stress in mammals and in modulating
learning and memory performance. Intrinsic activation of
brain CRH systems influences information processing [260262]. Intra-amygdala injection improves memory retention
and intra-hippocampal administration improves learning
performance [263, 264]. On the other hand, it is also evident
that both endogenous and exogenous increases in
11
glucocorticoids are associated with deficits in both memory

and attention [265] Since glucocorticoids can compromise
the functioning of the hippocampus investigators have
speculated that hippocampal-based cognitive functions may
be at particular risk from the deleterious effects of
glucorticoids [266]. It was concluded that cortisol can
modulate cognitive processes and that the effects of
corticosteroids on cognitive function are selective [267].
While most data suggest that increased glucocorticoid levels
is the major component of the stress response that promotes
detrimental effects in the brain, other data suggest that
glucocorticoid-independent mechanisms involving CRH
mediate neuronal damage. There is evidence that CRH may
not be directly neurotoxic [268]; however, in AD brain,
abnormal and increased CRH immunoreactivity has been
observed in the axons associated with amyloid plaques in the
amygdala [269]. On the other hand, in primary embryonic
hippocampal cultures CRH was found to protect the cells
from degeneration caused by an amyloid-peptide and other
insults related to the pathogenesis of AD. Furthermore, a
correlation was found between the cognitive impairment in
AD and lower levels of CRH in the cerebrospinal fluid. HPA
axis function is altered with normal aging and the variability
in HPA axis function between individuals may be the result
of combined environmental and genetic factors including
different CRH or stress responses [62, 270].
Based on several behavioral effects, it was suggested that
CRH enhances the anxiogenic nature of environmental
stimuli and anxiety has profound effects on learning and
memory processes. CRH was shown to induce a long-lasting
enhancement of synaptic efficacy in the hippocampus [271].
In contrary, when a CRH receptor antagonist is injected prior
to training, the induction of fear conditioning was impaired
[272]. Similarly, CRH receptor knock-out mice showed an
impaired speed in learning; but it is not clear whether the
acquisition deficit is a learning deficit, or it is due to
impaired attention or arousal [66].
Neurochemical and anatomical evidence suggests that
cholinergic and the CRH systems have important reciprocal
interactions. It was reported that frontoparietal cortical CRH
release was inhibited by ACh, while hypothalamic CRH
activity was enhanced following ACh administration. In
Alzheimers disease, decreased cholinergic function is well
documented, which coincides with a decrease in cortical
CRH and a reciprocal increase in cortical CRH receptors.
Thus, stimulation of parts of the CRH system has been
proposed as a potential treatment in Alzheimers disease
[273-281].
It has been proposed that elevated concentrations of
glucocorticoids, such as those seen during stress, can lead to
accelerated impairment and aging in the hippocampus [282].
Earlier studies indicated that both in aging and after chronic
glucocorticoid treatment, neurons were killed, but more
recent studies indicate the presence of hippocampal
impairment, which is observed as a reduction in neuron size,
electrophysiological alterations, and behavioral deficits [283286].
Exposure to acute stressful experience induces enhanced
memory formation by the activity of glucocorticoids. When
exposed to such stressors as those that enhance learning, the
12
organism responds by activating a complex series of

physiological and behavioral responses that often involve the
HPA axis and autonomic nervous system. The release of
glucocorticoids from the adrenal cortex and epinephrine
from the adrenal medulla constitute an important part of the
stress response, which enhances the organisms ability to
deal with stress [287]. If an animal learns a stressful task, the
consolidation of this task is enhanced by glucocorticoids
secreted during the task [288] and if the learning is made
more stressful, the performance of the animal is further
enhanced. Similarly, memory-enhancing effects can be
obtained if glucocorticoids are given immediately after
training [289]. If the animal is placed in a stressful
environment during the time between the learning and the
subsequent delayed recall, the memory performance is
impaired. It was suggested that exposure to glucocorticoids
does not just enhance performance of the response, but rather
enhances learning. Endogenous glucocorticoids are
necessary for transiently enhancing acquisition of new
memories and also for the persistent enhancement of
learning after stress [289].
Exogenous administration of glucocorticoids enhances
some processes of learning [290]. Both low and high
glucocorticoid levels are also associated with deficits in
memory performance, indicating that optimal concentrations
of glucocorticoids are necessary for memory consolidation.
It is also evident that the complete absence of glucocorticoids as the result of adrenalectomy, also causes
memory impairment [291]. Glucocorticoid administration or
stress can enhance declarative memory performance and can
lead to increased spontaneous cell firing in the amygdala and
decreased glucose utilization in the hippocampus. Both
human and animal research suggests that the memory
enhancing effects of glucocorticoids are especially relevant
to emotional memory [289-291].
Glucocorticoid receptors have been found in the
hippocampus (declarative or spatial memory), amygdala
(emotional memory) and prefrontal cotex (working
memory), which are relevant to cognition, and are actively
involved in the feedback regulation of the HPA axis [292293]. Glucocorticoids may specifically influence the
production of emotional and social behaviors such as
attachment, temperament and mood [35]. Glucocorticoids
facilitate cognition and behavior associated with fear and
anxiety responses, by initiating changes in various functional
brain systems that underlie cognitive mechanisms.
Elevations in glucocorticoid may enhance focused attention
toward an emotionally arousing stimulus by increasing the
availability of norepinephrine [35, 294].
Chronic glucocorticoid administration can lead to deficits
in verbal and declarative memory and spatial memory
performance [295]. It has been hypothesized that the
disruption of cognitive functions, due to chronic
glucocorticoid elevation during repeated stress may result
from neural atrophy in the hippocampus via facilitation of
excitatory
amino
acid-mediated
toxicity
[296].
Administration of commonly used therapeutic doses of
glucocorticoids [297], dexamethasone [298], or cortisol
[299] resulted in impairments in verbal declarative memory
function in healthy human subjects. Cortisol levels were
Glpnar and Yegen
related to memory function, with evidence of exacerbation of

memory deficits with stress-induced cortisol elevations [299]
and improvement in memory function with reduction in
cortisol levels [48, 300].
Chronic stress influences several neurotransmitters in the
forebrain as well as in the amygdala [301, 302] and can lead
to increased HPA activity via the CRH system in the
amygdala and the noradrenergic system in the brainstem
[303, 304]. Several studies have observed that patients with
Cushings disease, which involves excessive release of
cortisol for long periods, have deficits in attention and
memory that are correlated with hippocampal volume
reduction [305]. In addition, patients receiving
glucocorticoid treatment for a medical condition also show
evidence of cognitive impairment [306]. Prolonged exposure
to elevated cortisol concentrations can result in fatigue,
depression, apathy, and impaired concentration [307].
It is believed that ageing is accompanied by increased
basal cortisol levels and reduced feedback sensitivity of the
HPA axis [308]. AD is also characterized by HPA
hyperactivity and hippocampal atrophy. Increased levels of
glucocorticoids during ageing are associated with a
worsening of memory and hippocampal damage/atrophy in
both animals and humans [309]. Experimental studies in
rodents have shown that behavioral or pharmacological
manipulations, which are targeted to prevent the ageinginduced HPA hyperactivity, also prevented memory
impairments [56, 310].
C. SEROTONIN (5-HT)
5-HT has been implicated in the neurochemistry of
anxiety for a long time. There are two major serotonergic
systems in the brain, the medial raphe nuclei (MRN) and the
dorsal raphe nuclei (DRN), which are believed to be
important in anxiety, fear and in modulating cognitive
processes [27].
The serotonergic system appears to play a role in
behaviors that involve a high cognitive demand and in
memory improvement or recovery from impaired cognitive
performance. These serotonin receptor subtypes are localized
on cognitive pathways, the hippocampus and frontal cortex.
The 5HT1A receptor has a high concentration in the limbic
system, where autoreceptors influence cognitive functions.
Stimulation of 5-HT1A receptors has detrimental effects on
learning and working memory, whereas their inactivation
selectively antagonizes these effects. Different cerebral
structures that are rich in 5-HT receptors (such as the lateral
septum, the hippocampus, the frontal cortex and the
amygdala) are involved in the interaction between cognition
and emotion, which includes mnemonic as well as attentional
components [311].
A large body of evidence supports that 5-HT4 receptor,
which has a relatively high expression in the limbic system,
has a major role in learning and memory [312]. Accordingly,
post-mortem brains of AD patients display a reduction in the
number of 5-HT4 receptor binding sites in the hippocampal
region [313, 314]. Recently, the role of 5-HT4 receptors in
the neuronal mechanism of memory enhancement and the
cognitive process was demonstrated using selective 5-HT4
agonists [315] and 5-HT4 agonists were shown to have a

potent cognitive enhancing activity [314].
[13]
Stress-dependent alterations in memory were suggested

to be mediated by the serotonergic system, demonstrating
increased 5-HT activity [54]. It has been shown that many
experimental stressors activate serotonergic systems in a
variety of brain regions. Both animal and human studies
indicate that stress and glucocorticoids influence cognitive
function and repeated restraint stress and administration of
high concentrations of corticosterone were shown to activate
5-HT systems in the hippocampus and impair performance in
memory tasks [316]. Others have suggested that the 5-HT
system activates the HPA axis during stress, producing a
sustained increase in serum corticosterone concentrations
that damage hippocampal neurons and result in cognitive
deficits [317, 318]. Stress resulted in a decrease in 5HT1Abinding within the hippocampus with associated atrophy in
the hippocampus and led to memory impairment. Tianeptine,
which decreases serotonin levels within the hippocampus,
blocked the effect of stress on memory, suggesting that
serotonin released during stress may also play a role in the
etiology of hippocampal damage [48, 319].
[14]
Recent studies have shown that the 5-HTergic activity

takes part in the modulation of HPA axis and ascending 5HTergic fibers increase the activities of HPA axis by the
release of CRF [320, 321]. We have observed that stressinduced stimulation of the HPA axis is blocked by a 5-HT3
antagonist, suggesting the interaction of 5-HT and
glucocorticoids in the modulation of stress response
(unpublished observations).
Further studies are required to elucidate the physiological
role and therapeutic efficacy of various neuropeptides and
the impact of stress exposure in the acquisition and
consolidation of memory. A thorough understanding of the
mechanisms of neuropeptidergic control in the physiology
and pathophysiology of cognitive functions will provide
rational trends for the development of preventive and
therapeutic strategies for the learning and memory
impairments.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
REFERENCES
[37]
[1]
[2]
[3]
[38]
[39]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
Chialvo, D.R. and Bak, P. (1999) Neuroscience, 90(4), 11371148.

Arendt, T. (2001) Neuroscience, 102(4), 723-765.
Schrijver, N.C., Bahr, N.I., Weiss, I.C. and Wrbel, H. (2002)
Pharmacol. Biochem. Behav., 73, 209224.
Kim, J.J. and Yoon, K.S. (1998) Trends Neurosci., 21, 505509.
Duman, R.S. (2002) Eur. Psychiatry, 17(3), 306-310.
Hlscher, C. (1999) Behav. Brain Res., 100, 225235.
Lynch, G., Larson, J., Staubli, U. and Granger, R. (1991) in
Memory: Organization and Locus of Change (Squire, L.R.,
Weinberger, N.M., Lynch, G. and McGaugh, J.L. Eds.). pp.
330363. Oxford University Press, New York.
Laroche, S., Doyere, V., Richter-Levin, G., Errington, M.L. and
Bliss, T.V.P. (1997) in Long-term Potentiation (Baudry, M. and
Davis, J.L. Eds.). pp. 117135. MIT Press, Cambridge.
Hampson, R.E. and Deadwyler, S.A. (1997) in Long-term
Potentiation (Baudry, M. and Davis, J.L. Eds.). pp. 199214. MIT
Press, Cambridge.
Roman, F.S., Truchet, B., Marchetti, E., Chaillan, F.A. and
Soumireu-Mourat, B. (1999) Prog. Neurobiol., 58, 6187.
Alescio-Lautier, B., Paban, V. and Soumireu-Mourat, B. (2000)
Eur. J. Pharmacol., 405, 6372.
Lyons, D.M. and Schatzberg, A.F. (2003) Neurobiol. Learn Mem.,
80(2), 97-104.
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
13
Fernandez-Teruel, A., Gimenez-Llort, L., Escorihuela, R.M., Gil,

L., Aguilar, R., Steimer, T. and Tobena, A. (2002) Pharmacol.
Biochem. Behav., 73, 233245.
Hartz, B.P., Shoel, A., Berezin, V., Bock, E. and Scheel-Krger, J.
(2003) Pharmacol. Biochem. Behav., 75(4), 861-7.
Alexinsky, T., Przybyslawski, J., Mileusnic, R., Rose, S.P. and
Sara, S.J. (1997) Neurobiol. Learn Mem., 67, 1420.
Arami, S., Jucker, M., Schachner, M. and Welzl, H. (1996) Behav.
Brain Res., 81, 8187.
Doyle, E., Nolan, P.M., Bell, R. and Regan, C.M. (1992) J.
Neurochem., 59, 15701573.
Roullet, P., Mileusnic, R., Rose, S.P. and Sara, S.J. (1997)
Neuroreport, 8, 19071911.
Scholey, A.B., Rose, S.P., Zamani, M.R., Bock, E. and Schachner,
M. (1993) Neuroscience, 55, 499 09.
Mileusnic, R., Rose, S.P., Lancashire, C. and Bullock, S. (1995) J.
Neurochem., 64, 2598 2606.
Sandi, C., Merino, J.J., Cordero, M.I., Touyarot K. and Venero, C.
(2001) Neuroscience, 102(2), 329-339.
Barbeau, D., Liang, J.J., Robitaille, Y., Quirion, R. and Srivastaka,
L.K. (1995) Proc. Natl. Acad. Sci., 92, 2785-2789.
Mikkonen, M., Soininen, H., Kalviainen, R., Tapiola, T., Ylinen,
A., Vapalahti, M., Paljarvi, L. and Pitkanen, A. (1998) Ann.
Neurol., 44, 923-934.
Mikkonen, M., Soininen, H., Tapiola, T., Alafuzoff, I. and
Miettinen, R. (1999) Eur. J. Neurosci., 11, 1754-1764.
Poltorak, M., Frye, M.A., Wright, R., Hemperly, J.J., George, M.S.,
Pazzaglia, P.J., Jerrels, S. A., Post, R.M. and Freed, W.J. (1996) J.
Neurochem., 66, 1532-1538.
Poltorak, M., Khoja, I., Hemperly, J.J., Williams, J.R., El-Mallakh,
R. and Freed, W. (1995) Exp. Neurol., 131, 266-272.
Auld, D.S., Kornecook, T.J., Bastianetto, S. and Quirion, R. (2002)
Prog. Neurobiol., 68, 209245.
Shors, T.J., Beylin, A.V., Wood, G.E. and Gould, E. (2000) Behav.
Brain Res., 110, 3952.
Fodor, M, Grcs, T. and Palkavits, S. (1992) Neuroscience, 46,
891-908.
Dawson, V.L., Dawson, T.M., London, E.D., Bredt, D.S. and
Snyder, S.H. (1991). Proc. Natl. Acad. Sci., 88, 6368-6371.
Bennett, G.W., Ballard, T.M., Watson, C.D. and Fone, K.C.F.
(1997) Exp. Gerontol., 32(4/5), 451-469.
McLay, R.N., Pan, W. and Kastin, A.J. (1997) Peptides, 18(10),
16511688.
Shukitt-Hale, B., Erat, S.A. and Joseph, J.A. (1998) Free Radic
Biol. Med., 24(7/8), 11491158.
Ingram, D.K., Jucker, M. and Spangler, E.L. (1994) in
Pathobiology of the Aging Rat. (Mohr, U., Cungworth, D.L. and
Capen, C.C., Eds.). pp.149 170. ILSI Press, Washington, D.C.
Barnes, C. A. (1988) Neurobiol. Aging, 9, 563568.
Brandeis, R., Brandys, Y. and Yehuda, S. (1989) Int. J. Neurosci.,
48, 2969.
Gallagher, M. and Pelleymounter, M.A. (1988) Neurobiol. Aging,
9, 549 556.
Foy, M.R. (2001) Neurobiol. Learn Mem., 76, 239252.
Cruz-Aguado, R., Almaguer-Melian, W., Daz, C.M., Lorigados,
L. and Bergado, J. (2001) Brain Res. Bull., 55(3), 327333.
Tuszynski, M.H., Smith, D.E., Roberts, J., McKay, H. and Mufson,
E. (1998) Exp. Neurol., 154, 573582.
Liu, L., Ikonen, S., Heikkinen, T., Tapiola, T., van Groen, T. and
Tanila, H. (2002) Exp. Neurol., 173, 196204.
Fornstedt, B., Pileblad, E. and Carlsson, A. (1990) J. Neurochem.,
55, 655659.
Pileblad, E., Magnusson, T.A. and Fornstedt, B. (1989) J.
Neurochem., 52, 978-980.
Oja, S.S., Janaky, R., Varga, V. and Saransaari, P. (2000)
Neurochem. Int., 37, 299306.
Ogita, K., Enomoto, R., Nakahara, F., Ishitsubo, N. and Yoneda, Y.
(1995) J. Neurochem., 64, 10881096.
Weber, G.F. (1999) Neurosci. Biobehav. Rev., 23, 1079 1086.
Yang, C.-S., Lin, N.-N., Liu, L., Tsai, P.-J. and Kuo, J.-S. (1995)
Brain Res., 698, 237240.
Chang, M., Rao, M.K., Reddanna, P., Li, C.H., Tu, C.P.D., Corey,
E.J. and Reddy, C.C. (1987) Arch Biochem. Biophys., 259, 536
547.
Li, Y., Maher, P. and Schubert, D. (1997) Neuron, 19, 453 463.
14
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]

Hazui, T., Ogita, K., Hitayama, T. and Oneda, Y. (1999) J.
Neurochem., 73(l), 114.
Koolhaas, J.M., De Boer, S.F., De Ruiter, A.J.H., Meerlo, P. and
Sgoifo, A. (1997) Acta Physiol. Scand., 16( 640), 69-72.
Glavin, G.B., Murison, R., Overmier, J.B., Pare, W.P., Bakke,
H.K., Henke, P.G. and Hernandez, D.E. (1991) Brain Res. Brain
Res Rev., 16, 301-343.
Schouten, W.G.P. and Wiegant, V.M. (1997) Acta Physiol. Scand.,
161(40), 88-91.
Glpnar, M.A., zbeyli, D., Arbak, S. and Yegen,
B.. (2004)
Life Sci., 75, 77-91.
Sandford, J.J., Argyropoulos, S.V. and Nutt, D.J. (2000)
Pharmacol. Ther., 88, 197- 212.
Dauge, V., Pophillat, M., Crete, D., Melik-Parsadaniantz, S. and
Roques, B.P. (2003) Neuroscience, 118, 1923.
Klenerova, V., Jurcovicova, J., Kaminsky, O., Sda, P., Krejci, I.,
Hlinak, Z. and Hynie, S. (2003) Behav. Brain Res., 142, 143149.
Liu, L., Tsuji, M., Takeda, H., Takada, K. and Matsumiya, T.
(1999) Brain Res., 821, 134140.
Larsson, F., Winblad, B. and Mohammed, A.H. (2002) Pharmacol.
Mendl, M. (1999) Appl. Anim. Behav. Sci., 65, 221244.
Skosnik, P.D., Chatterton Jr., R.T., Swisher, T. and Park, S. (2000)
Int. J. Psychophysiol., 36, 59-68.
Pedersen, W.A., Wan, R. and Mattson, M.P. (2001) Mech. Ageing
Dev., 122, 963983.
Erickson, K., Drevets, W. and Schulkin, J. (2003) Neurosci.
Biobehav. Rev., 27, 233246.
Arnsten, A.F.T. and Contant, T.A. (1992) Psychopharmacolgy,
108, 159-169.
Arnsten, A.F.T. and Leslie, F.M. (1991) Neuropharmacology, 30,
1279-1289.
Arnsten, A.F.T., Cai, J.X. and Goldman-Rakic, P.S. (1988) J.
Neurosci., 8, 427- 4298.
Carli, M., Robbins, T.W., Evenden, J.L. and Everitt, B.J. (1983)
Behav. Brain Res., 9, 361-380.
Brozoski, T.J., Brown, R.M., Rosvold, H.E. and Goldman, P.S.
(1979) Science, 215, 929-932.
Roberts, D.C.S., Price, M.T.C. and Fibiger, H.C. (1976) J. Comp.
Physiol. Pyschol., 90, 363-372.
Collins, S.M. (2001) Am. J. Physiol. Gastrointest Liver Physiol.,
280, G315-G318.
Dantzer, R. (1997) Acta Physiol. Scand., 161(640), 43-46.
Daug, V. and Lna, I. (1998) Neurosci. Biobehav. Rev., 22(6),
815-825.
Day, J.C., Koehl, M., Deroche, V., Le Moal, M. and Maccari, S.
(1998) J. Neurosci., 18(5), 1886-1892.
Fink, H., Rex, A. and Voits, M. (1998) Exp. Brain Res., 123, 77-83.
Albeck, D.S., McKittirick, C.R., Blanchard, D.C., Blanchard, R.J.,
Nikulina, J,, McEwen, B.S. and Sakai, R.R. (1997) J. Neurosci.,
17(12), 4895-4903.
Linthorst, A.S.C., Flachskamm, C., Hopkins, S.J., Hoadley, M.E.,
Labeur, M.S., Holsboer, F. and Reul, J.M.H.M. (1997) J.
Neurosci., 17(11), 4485-4460.
Pavcovich, L.A. and Valentino, R.J. (1997) J. Neurosci., 17(1),
401-408.
Walker, D.L. and Davis, M. (1997) J. Neurosci., 17(23), 93759383.
DHooge, R. and De Deyn, P.P. (2001) Brain Res. Brain Res. Rev.,
36, 6090.
Bevilaqua, L., Ardenghi, P., Schroder, N., Bromberg, E., Schmitz,
P.K., Schaeffer, E., Quevedo, J., Bianchin, M., Walz, R., Medina,
J.H. and Izquierdo, I. (1997) Behav. Pharmacol., 8, 331338.
OMalley, A., OConnell, C. and Regan, C. M. (1998)
Neuroscience, 87, 607 613.
Wood, G.E.L., Young, T., Reagan, L.P. and McEwen, B.S. (2003)
Horm. Behav., 43, 205213.
Herman, J-P., Dolgas, M. and Carlson, S-L. (1998) Neuroscience,
86, 449459.
McEwen, B-S. and Sapolsky, R-M .(1995) Curr. Opin. Neurobiol.,
5, 205216.
Lopez-Figueroa, M.O., Itoi, K. and Watson, S.J. (1998)
Neuroscience, 87(2), 439446.
Bremner, J.D. (1999) Biol. Psychiatry, 45, 797805.
Ueyama, T., Kawai, Y., Nemoto, K., Sekimoto, M., Tone, S. and
Senba, E. (1997) Neurosci. Res., 28, 103110.
Glpnar and Yegen
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
McEwen, B.S. Magarinos, A.M. and Reagan, L.P. (2002) J.

Psychosom Res., 53, 883 890.
Nelson, C.A. (1999) Infant. Behav. Dev., 22(4), 415-429.
Bodnoff, S.R., Humphreys, A.G., Lehman, J.C., Diamond, D.M.,
Rose, G.M. and Meaney, M.J. (1990) J. Clin. Endocrinol. Metab.,
70, 155161.
Diamond, D.M.and Rose, G.M. (1994) Ann. N.Y. Acad. Sci., 746,
411414.
Foy, M.R., Stanton, M.E., Levine, S. and Thompson, R.F. (1987)
Behav. Neural. Biol., 48, 138149.
Fuchs, E. and Flugge, G. (1998) Neurosci. Biobehav. Rev., 23,
295300.
Gerges, N.Z., Stringer, J.L. and Alkadhi, K.A. (2001) Brain Res.,
922, 250260.
McEwen, B.S., Conrad, C.D., Kuroda, Y., Frankfurt, M.,
Magarinos,
A.M.
and
McKittrick,
C.
(1997)
Eur
Neuropsychopharmacol., 7, 323328.
Magarinos, A.M. and McEwen, B.S. (1995) Neuroscience, 69(1),
83-88.
Magarinos, A.M., McEwen, B.S., Flgge, G. and Fuchs, E. (1996)
J. Neurosci., 16, 3534-3540.
Reagan, L.P., McKittrick, C.R. and McEwen, B.S. (1999)
Neuroscience, 91, 211-219.
McKittrick, C.R., Blanchard, D.C., Blanchard, R.J., McEwen, B.S.
and Sakai, R.R. (1995) Biol. Psychiatry, 37, 383393.
Conrad, C.D., LeDoux, J.E., Magarinos, A.M. and McEwen, B.S.
(1999) Behav. Neurosci., 113, 902913.
Magarinos, A.M. and McEwen, B.S. (1995) Neuroscience, 69,
8998.
Watanabe, Y., Gould, E. and McEwen, B.S. (1992) Brain Res.,
588, 341345.
Pavlides, C., Watanabe, Y. and McEwen, B.S. (1993) Behav.
Neural. Biol., 3, 183192.
Bliss, T.V.P. and Collingridge, G.L. (1993) Nature, 361, 3139.
Gould, E. and McEwen, B.S. (1993) Curr. Opin. Neurobiol., 3,
676682.
Woolley, C. And McEwen, B.S. (1994) J. Neurosci., 14,
76807687.
Xu, L., Anwyl, R. And Rowan, M.J. (1997) Nature, 387, 497500.
Mizoguchi, K., Kunishita, T., Chui, D.H. and Tabira, T. (1992)
Neurosci. Lett., 138, 157160.
Woolley, C.S., Gould, E. and McEwen, B.S. (1990) Brain. Res.,
531, 225-231.
Bowman, R.E., Ferguson, D. and Luine, V.N. (2002) Neuroscience,
113(2), 401-410.
Luine, V.N., Villegas, M., Martinez, C. and McEwen, B.S. (1994)
Brain Res., 639, 167170.
Mondadori, C. and Weiskrantz, L., (1993) Behav. Neural. Biol., 60,
205210.
Arbel, I., Kadar, T., Silbermann, M. and Levy, A. (1994) Brain
Res., 657, 227 235.
Luine, V., Martinez, C., Villegas, M., Magarinos, A.M. and
McEwen, B.S. (1996) Physiol. Behav., 59, 27 2.
Uno, H., Tarara, R., Else, J.G., Suleman, M.A. and Sapolsky, R.M.
(1989) J. Neurosci. 9, 17051711.
Kerr, D.S., Campbell, L.W., Applegate, M.D., Brodish, A. and
Landfield, P.W. (1991) J. Neurosci., 11, 13161324.
Stein-Behrens, B., Mattson, M.P., Chang, I., Yeh, M. and Sapolsky,
R. (1994) J. Neurosci., 14, 53735380.
Berridge, C.W. and Waterhouse, B.D. (2003) Brain Res. Rev., 42,
3384.
Wolf, O.T. (2003) Best Pract. Res. Clin. Endocrinol. Metab., 17(2),
287299.
Nishimura, J.I., Endo, Y., Kimura, F. (1999) Neurosci. Lett., 273,
125-128.
Tozaki, H., Matsumoto, A., Kanno, T., Nagai, K., Nagata, T.,
Yamamoto, S. and Nishizaki T. (2002) Biochem. Biophys. Res.
Commun., 294, 4245.
Stillman, M.J., Shukitt-Hale, B., Levy A. and Lieberman, H.R.
(1998) Physiol. Behav., 64(5), 605609.
Gallagher, M. (2000). in The Amygdala: A Functional Analysis
(Aggleton, J.P., Ed.). pp. 391423. Oxford University Press,
London.
Everitt, B.J., Cardinal, R.N., Hall, J., Parkinson, J.A. and Robbins,
T.W. ( 2000). in The amygdala (Aggleton J.P., Ed.). pp. 353390.
Oxford University Press, Oxford.

[125]
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
[163]
[164]
Easton, A. and Gaffan, D. (2000) Behav. Neurosci., 114,

10411057.
Lupien, S.J. and McEwen, B.S. (1997) Brain Res. Brain Res. Rev.,
24, 127.
McGaugh, J.L. (2002) Trends Neurosci., 25(9), 456.
McGaugh, J.L., McIntyre, C.K. and Power, A.E. (2002) Neurobiol.
Learn Mem., 78, 539552.
Cahill, L. and McGaugh, J. L. (1998). Trends Neurosci., 21,
294299.
McGaugh, J.L. (2000) Science, 287, 248251.
McGaugh, J.L., Ferry, B., Vazdarjanova, A. and Roozendaal, B.
(2000) in The amygdala: A functional analysis (Aggleton, J.P.,
Ed.). pp. 391423. Oxford University Press, London.
Simson, P.E., Naylor, J.C. Gibson, B. Schneider, A.M. and Levin,
D. (2001) Pharmacol. Biochem. Behav., 69, 85-92.
Vyas, A., Mitra, R., Shakaranarayana Rao, B.S. and Chattarji, S.
(2002) J. Neurosci., 22, 68106818.
Moghaddam, B. (2002) Biol. Psychiatry, 51, 775787.
Paban, V., Soumireu-Mourat, B. nad Alescio-Lautier, B. (2003)
Behav. Brain Res., 141, 1-9.
Steckler, T. and Holsboer, F. (1999) Biol. Psychiatry, 46,
14801508.
Sherwood, L. (1997) in Human Physiology from Cells to Systems.
pp. 98-101. Wadsworth Publishing Company, Belmont, California.
Shepherd, G.M. (1988) in Neurobiology. pp. 164-167. Oxford
University Press, New York.
Berne, R.M. and Levy, M.N. (1996) in Principles of Physiology.
pp. 52-57. Mosby-Year Book, Inc., St. Louis, Missouri.
Croiset, G., Marjoleen, J.M.A. and Nijsen, P.J.G.H. (2000) Eur. J.
Pharmacol., 405, 225234.
Ferguson, J.N., Young, L.J. and Insel, T.R. (2002) Front
Neuroendocrinol., 23, 200224.
de Weid, D. (1965) Int. J. Neuropharmacol., 4, 157167.
de Wied, D., Witter, A. and Lande, S. (1970) Prog. Brain Res., 32,
213220.
de Wied, D. (1976) Life Sci., 19, 685690.
van Wimersma Greidanus, T.B. (1982) Ann. N.Y. Acad. Sci., 394,
655662.
Popik, P., Wolterink, G., De Brabander, H. and van Ree, J.M.
(1991) Physiol. Behav., 49, 10311035.
Le Moal, M., Dantzer, R., Michaud, B. and Koob, G.F. (1987)
Neurosci. Lett., 77, 353359.
Dluzen, D.E., Muraoka, S., Engelmann, M. and Landgraf, R.
(1998) Peptides, 19, 9991005.
Ferris, C.F., Delville, Y., Irvin, R.W. and Potegal, M. (1994)
Physiol. Behav., 55, 755759.
Murphy, H.M., Babey, E.M. and Widman, C.H. (1994) Peptides,
15, 13351341.
Dietrich, A., Taylor, J.T. and Passmore, C.E. (2001) Brain Res.,
919, 4147.
Wisniewski, M.P., De Wied, D. and Van Ree, J.M. (1996) Acta
Physiol. Hung., 84, 477479.
Zhou, A.W., Li, W.X., Gou, J. and Du, Y.C. (1997) Peptides, 18
,11791187.
Everts, H.G.J. and Koolhaas, J.M. (1997) Brain Res., 760, 17.
Van Wimersma Greidanus, T.J.B. and Maigret, C. (1996) Brain
Res., 713, 153-159.
Roozendaal, B., Wiersma, A., Driscoll, P., Koolhaas, J.M. and
Bohus, B. (1992) Brain Res., 596, 3540.
Paban, V., Alescio-Lautier, B., Devigne, C. and Soumireu-Mourat,
B. (1998) Eur. J. Pharmacol., 361, 165173.
Chen, Q., Patel, R., Sales, A., Oji, G., Kim, J., Monreal, A.W. and
Brinton, R.D. (2000) Neuroscience, 101(1), 1926.
Winnicka, M.M. and Wisniewski, K. (1999) Pharmacol. Res.,
40(1), 53-59.
de Souza, F.A., Sanchis-Segura, C., Fukada,S.Y., de Bortoli, V.C.,
Zangrossi, H.Jr. and de Oliveira, A.M. (2004) Neurobiol. Learn
Mem., 81, 100-103.
Mahley, R.W., Nathan, B.P. and Pitas, R.E. (1996) Ann. N.Y. Acad.
Sci., 777, 139145.
Gordon, I., Grauer, E., Genis, I., Sehayek, E., Michaelson, D.M.
(1995) Neurosci. Lett., 199(1), 14.
Masliah, E., Samuel, W., Veinbergs, I., Mallory, M., Mante, M.
and Saitoh, T. (1997) Brain Res., 751(2), 30714.
Law, A. and Quirion, R. (2003) Neurobiol. Aging, 24, 187190.

[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179]
[180]
[181]
[182]
[183]
[184]
[185]
[186]
[187]
[188]
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
15
Nakamura, S., Murayama, N., Noshita, T., Annoura, H. and Ohno,

T. (2001) Brain Res., 912, 128136.
Yu, M., Stepanichev, I.M., Zdobnova, A.A., Yakovlev, M.V.,
Onufriev, N.A., Lazareva, I.I., Zarubenko, N.V. and Gulyaeva, J.
(2003) Neurosci. Res., 71, 110120.
Stepanichev, M.Y., Moiseeva, Y.V., Lazareva, N.A., Onufriev,
M.V. and Gulyaeva, N.V. (2003) Brain Res. Bull., 61, 197205.
Abe, E., Casamenti, F., Giovannelli, L., Scali, C. and Pepeu, G.
(1994) Brain Res., 636, 162164.
Malin, D,H., Crothers, M.K., Lake, J.R. Goyarzu, P., Plotner, R.E.,
Garcia, S.A., Spell, S.H. and Tomsic, B.J. (2001) Neurobiol. Learn
Mem., 76, 125137.
Tran, M.H., Yamada, K. and Nabeshima T. (2002) Peptides, 23,
12711283.
Dawson, T.M., Dawson, V.L. and Snyder, S.H. (1992) Ann.
Neurol., 32, 297311.
Law, A., Gauthier, S. and Quirion, R. (2001) Brain Res. Brain Res.
Rev., 35, 7396.
Law, A., Dore, S., Blackshaw, S., Gauther, S. and Quron, R.
(2000) Neuroscience, 100(4), 6977.
Bredt, D.S., Glatt, C.E., Hwang, P.M., Dawson, T.M. and Snyder
S.H. (1991) Neuron, 7, 615624.
Zhuo, M., Small, S.A., Kandel, E.R. and Hawkins, R.D. (1993).
Science, 260, 19461950.
Cai, Z., Xiao, F., Lee, B., Paul, I.A. and Rhodes, P.G. (1999) Brain
Res. Bull., 49, 359365.
Ojika, K., Mitake, S., Tohdoh, N., Appel, S.H., Otsuka, Y., Katada,
E. and Matsukawa, N. (2000) Prog. Neurobiol., 60, 37-83.
Matsukawa, N., Tooyama, I., Kimura, H., Yamamoto, T., Tsugu,
Y., Oomura, Y. and Ojika, K. (1999) Neuroscience, 88(1), 7992.
Gschanes, A. and Windisch, M. (1999) Behav. Brain Res., 100,
161166.
van der Staay, F.J., Fanelli, R.J., Blokland, A. and Schmidt, B.H.
(1999) Neurosci. Biobehav. Rev., 23, 10871110.
Santo-Yamada, Y., Yamada, K., Wada, E., Goto, Y. and Wada, K.
(2003) Neurosci. Lett., 340, 6568.
Yamada, K., Santo-Yamada, Y. and Wada K. (2003) Physiol.
Behav., 78, 303 309.
Oka, J.I., Suzuki, E. and Kondo, Y. (2000) Brain Res., 878, 194198.
Yamaguchi, Y. and Kobayashi, H. (1994) Neuropeptides, 26(3),
153-158.
Telegdy, G. and Kokavszky, K. (2000) Brain Res., 874, 194199.
Ichai, C., Chevallier, N., Delaere, P., Dournaud, P., Epelbaum, J.,
Hauw, J. J., Vincent, J. P., and Checler, F. (1994) J. Neurochem.,
62, 645655.
Barelli, H., Petit, A., Hirsch, E., Wilk, S., De Nanteuil, G., Morain,
P. and Checler, F. (1999) Biochem. Biophys. Res. Commun., 257,
657661.
Moriguchi, T., Sakurai, T., Nambu, T., Yanagisawa, M. and Goto,
K. (1999) Neurosci. Lett., 264, 101104.
Aou, S., Li, X.-L. LI, A.-J., Oomura, Y., Shiraishi, T., Sasaki, K.,
Imamura, T. and Wayner, M.J. (2003) Neuroscience, 119,
12211228.
Inglot, A.D., Leszek, J., Janusz, M. and Lisowski, J. (1996) Eur.
Cytokine Netw., 7, 458.
Popk, P., Bobula, B., Janusz, M., Lsowsk, J. and Vetulan, J.
(1999) Pharmacol. Biochem. Behav., 64(1), 183189.
Gasparini, L., Netzer, W.J., Greengard, P. and Huaxi, X. (2002)
Trends Pharmacol. Sci., 23(6), 288-293.
Meunier, J.C. (1997) Eur. J. Pharmacol., 340, 115.
Sandin, J., Georgieva, J., Schott, P.A., Ogren, S.O. and Terenius, L.
(1997) Eur. J. Neurosci., 9(1), 194197.
Manabe, T., Noda, Y., Mamiya, T., Katagiri, H,. Houtani, T., Nishi,
M., Noda, T., Takahashi, T., Sugimoto, T., Nabeshima, T. and
Takeshima, H. (1998) Nature, 394, 57781.
Siniscalchi, A., Rodi, D., Beani, L. and Bianchi, C. (1999) Br. J.
Pharmacol., 128, 119123.
Murphy, N.P., Ly, H.T. and Maidment, N.T. (1996) Neuroscience,
75, 14.
Masayuki, H. and Inoue, K. (1999) Eur. J. Pharmacol., 367,
151155.
Masayuki, H. and Inoue, K. (2000) Eur. J. Pharmacol., 395,
149156.
Grabowski, P.J. and Douglas, L.B. (2001) Prog. Neurobiol., 65,
289308.
16
[201]
[202]
[203]
[204]
[205]
[206]
[207]
[208]
[209]
[210]
[211]
[212]
[213]
[214]
[215]
[216]
[217]
[218]
[219]
[220]
[221]
[222]
[223]
[224]
[225]
[226]
[227]
[228]
[229]
[230]
[231]
[232]
[233]
[234]
[235]
[236]
[237]
[238]
[239]
[240]

Bubser, M. and Schmidt, W.J. (1990) Behav. Brain Res., 37, 157168.
Murphy, B.L., Arnsten, A.F., Goldman-Rakic, P.S. and Roth, R.H.
(1996). Proc. Natl. Acad. Sci., 93, 1325-1329.
Zahrt, J., Taylor, J.R., Mathew, R.G. and Arnsten, A.F. (1997) J.
Neurosci., 17, 8528-8535.
McDonald, M.P., Gleason, T.C., Robinson, J.K. and Crawley, J.N.
(1998) Ann. N.Y. Acad. Sci., 863, 305322.
Counts, S.E., Perez, S.E., Kahl, U., Bartfai, T., Bowser, R.,
Deecher, D.C., Mash, D.C., Crawley, J.N. and Mufson, E.J. (2001)
CNS Drug Rev., 7, 445470.
Wrenn, C., Marriott, C.L.K., Kinney, J.W., Holmes, A., Wenk,
G.L. and Crawley, J.N. (2002) Neuropeptides, 36(6), 413426.
Tapiero, H., Math, G., Couvreur, P. and Tew, K.D. (2002)
Biomed. Pharmacother., 56, 446457.
Myhrer, T. (1998) Neurosci. Biobehav. Rev., 23, 131139.
Maragos, W.F., Greenamyre, J.T., Penney, J.B. and Young, A.B.
(1987) TINS, 10, 6568.
Stein-Behrens, B.A., Elliott, E.M., Miller, C.A., Schilling, J.W.,
Newcombe, R. and Sapolsky, R.M. (1992) J. Neurochem., 58,
17301735.
Watkins, P.J, Clow, A., Glover, V., Halket, J., Przyborowska, A.
and Sandler, M. (1990) Neurochem. Int., 17, 321323.
Telegdy, G., Adamik, A. and Glover, V. (2000) Brain Res. Bull.,
53(3), 367370.
Telegdy, G. (1994) Rev Neurosci., 5, 309 316.
Telegdy, G., Kokavszky, K. And Nyerges, A. (1999) Eur. J.
Neurosci., 11, 33023306.
Yip, J. and Chahl, L.A. (1999) Neuroscience, 94(2), 663673.
Bracci-Laudiero, L., Aloe, L., Lundeberg, T., Theodorsson, E. and
Stenfors, C. (1999) Neurosci. Lett., 275, 57-60.
Sprick, U., Hasenohrl, R.U., Krauth, J., Klapdor, K. and Huston,
J.P. (1996) Peptides, 17, 275-285.
Beal, M.F., Mazurek, M.F., Chattha, G.K., Svendsen, C.N., Bird,
E.D. and Martin, J.B. (1986) Ann. Neurol., 20, 282288.
Flood, J.F., Hernandez, E.N. and Morley, J.E. (1987) Brain Res.,
421, 280-290.
Redrobe, J.P., Dumont, Y., St-Pierre, J.A. and Quirion, R. (1999)
Brain Res., 848, 153166.
Flood, J.F., Baker, M.L., Hernandez, E.N. and Morley, J.E. (1989)
Brain Res., 503, 7382.
Martel, J.C., Alagar, R., Robitaille, Y. and Quirion, R. (1990)
Brain Res., 519, 228235.
Stone, W.S., Walser, B., Gold, S.D. and Gold, P.E. (1991) Behav.
Neurosci., 105, 264271.
Canli, T., Cook, R.G. and Miczek, K.A. (1990) Pharmacol.
Sala, M., Braida, D., Leone, M.P., Calcaterra, P., Frattola, D. and
Gori, E. (1994) Behav. Pharmacol., 5, 570580.
Jang, C.G., Lee, S.Y., Yoo, Ji-H., Yan, Ji-J., Song, D.K., Loh, H.H.
and Ho, I.K. (2003) Brain Res. Mol. Brain Res., 117, 6872.
Sandn, J., Nylander, I., Georgeva, J., Schtt, P.A., gren, S.O.
and Terenus, L. (1998) Neuroscience, 85(2), 375382.
Kamei, C., Okumura, Y. and Tasaka, K. (1993) Psychopharmacology, 111, 376 382.
Eidi, M., Zarrindast, M.R., Eidi, A., Oryan, S. and Parivar, K.
(2003) Eur. Pharmacol., 465, 91 96.
Varas, M., Perez, M., Ramirez, O. and de Barioglio, S.R. (2002)
Peptides, 23, 151155.
Monzon, M.E., de Souza, M.M., Izquierdo, L.A., Izquierdo, I.,
Barros, D.M. and de Barioglio, S.R. (1999) Peptides, 20,
15171519.
Roeder, T. (1999) Prog. Neurobiol., 59, 533-561.
Davenport, A. P. and Evans, P. D. (1984) Insect. Biochem., 14,
135-143.
Hirashima, A. and Eto, M. (1993) Comp. Biochem. Physiol., 105,
279-284.
Million, M., Tache, Y. and Anton, P. (1999) Am. J. Physiol.
Gastrointest. Liver Physiol., 39, 1027-1037.
Gue, M., Bonbonne, C., Fioramonti, J., More, J., Del Rio-Lacleze,
C. and Bueno, L. (1997) Am. J. Physiol. Gastrointest. Liver
Physiol., 272, 84-91.
Dockray, G. J. (1976) Nature, 264, 568570.
Rehfeld, J. F. (1985) J. Neurochem., 44, 110.
Crawley, J.N. and Corwin, R.L. (1994) Peptides, 15, 731755.
Hill, D.R. and Woodruff, G.N. (1990) Brain Res., 526, 276283.
Glpnar and Yegen
[241]
[242]
[243]
[244]
[245]
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
[256]
[257]
[258]
[259]
[260]
[261]
[262]
[263]
[264]
[265]
[266]
[267]
[268]
[269]
[270]
[271]
[272]
[273]
[274]
[275]
[276]
Lindefors, N., Lindn, A., Bren, S., Sedvall, G. and Persson, H.

(1993) Prog. Neurobiol., 40, 671690.
Saito, A., Sankaran, H., Goldfine, I.D. and Williams, J.A. (1980)
Science, 208, 11551156.
Harro, J. and Vasar, E. (1991) Eur. J. Pharmacol., 193, 379381.
Charrier, D., Dangoumau, L., Hamon, M., Puech, A. and Thiebot,
M.-H. (1994) Pharmacol. Biochem. Behav., 48, 281289.
Abelson, J.L., Nesse, R.M. and Vinik, A.I. (1994) Biol. Psychiatry,
36, 8496.
Abelson, J.L. and Liberzon, I. (1999) Neuropsychopharmacology,
21, 485494.
Itoh, S., Takashima. A. and Igano. K.I.K. (1989) Peptides, 10, 843
848.
Nomoto, S., Miyake, M., Ohta, M., Funakoshi A. and Miyasaka, K.
(1999) Physiol. Behav., 66(5), 869872.
Gaudreau, P., Quirion, R., St-Pierre, S. and Pert, C.B. (1983)
Peptides, 4, 755762.
Flood, J.F., Merbaum, M.O. and Morley, J.E. (1995) Neurobiol.
Learn Mem., 64, 39145.
Meziane, H., Devigne, C., Tramu, G. and Soumireu-Mourat, B.
(1993) Peptides, 14, 6773.
Harro, J. and Oreland, L. (1993) Pharmacol. Biochem. Behav., 44,
509517.
Derrien, M., Dauge, V., Blommaert, A. and Roques, B. P. (1994)
Behav. Brain Res., 65, 139 146.
Huston, J. P., Schildein, S., Gerhardt, P., Privou, C., Fink H. and R.
U. Haseno HRL. (1998) Peptides, 19(1), 2737.
Katsuura, G. and Itoh, S. (1986) Drug Dev. Res., 7, 269276.
Tsutsumi, T., Akiyoshi, J., Isogawa, K., Kohno, Y., Hikichi, T. and
Nagayama, H. (1999) Neuropeptides, 33(6), 483486.
Abelson, J.L. and Young, E.A. (2003) Psychoneuroendocrinology,
28, 169180.
Owens, M.J., Nemeroff, C.B. (1991) Pharmacol. Rev., 43,
425473.
Merchenthaler, I. (1984) Peptides, 5, 5369.
Heinrichs, S.C., Vale, E.A., Lapsansky, J., Behan, D.P., Mcclure,
L.V., Ling, N., De Souza, E.B. and Schulteis, G. (1997) Peptides,
18(5), 711716.
Song, C., Earley, B. And Leonard, B.E. (1995) Ann. N.Y. Acad.
Sci., 29(771), 5572.
Wu, H.C, Chen, K.Y., Lee, W.Y. and Lee, E.H. (1997)
Neuroscience, 78(1), 147153.
Rebaudo, R., Melani, R., Balestrino, M. and Izvarina, N. (2001)
Brain Res., 922, 112117.
Lee, E.H.Y., Lee, C.P., Wang, H.I. and Lin, W.R. (1993) Synapse,
14, 144153.
Lupien, S.J., DeLeon, M.J. De Santi, S., Convit, A., Tarshish, C.,
Nair, N.P.V., Thakur, M., McEwen, B.S., Hauger, R.L. and
Meaney, M.J. (1998) Nat. Neurosci., 1, 6973.
Meaney, M., Aitken, D., Berkel, H., Bhatnager, S. and Sapolsky, R.
(1988) Science, 239, 766768.
Vedhara, K., Hyde, J., Gilchrist, I.D., Tytherleigh, M. and
Plummer, S. (2000) Psychoneuroendocrinology, 25, 535549.
Craighead, M.W., Boutin, H., Middlehurst, K.M., Allan, S.M.,
Brooks, N., Kimber, I. and Rothwell, N.J. (2000) Brain Res., 881,
139143.
Powers, R.E., Walker, L.C., DeSouza, E.B., Vale, W.W., Struble,
R.G., Whitehouse, P.J. and Price D.L. (1987) Synapse, 1, 405410.
Pomara, N., Singh, R.R., Deptula, D., LeWitt, P.A., Bissette, G.,
Stanley, M. and Nemeroff, C.B. (1989) Biol. Psychiatry, 26,
500504.
Wang, H.L., Wayner, M.J., Chai, C.Y. and Lee, E.H.Y. (1998) Eur.
J. Neurosci., 10(11), 3428-3437.
Deak, T., Nguyen, K.T., Ehrlich, A.L., Watkins, L.R., Spencer,
R.L., Maier SF, Licinio, J., Wong, M.L., Chrousos, G.P., Webster,
E. and Gold, P.W. (1999), Endocrinology, 140, 7986.
Behan, D.P., Heinrichs, S.C., Troncoso, J.C., Liu, X.J., Kawas,
C.H., Ling, N. and De Souza, E.B. (1995) Nature, 378, 284287.
Bhatnagar, S., Costall, B. and Smythe, J.W. (1997) Brain Res., 766,
244248.
Davis, K.L. Mohs, R.C., Martin, D.B., Purohit, D.P., Perl, D.P.,
Lantz, M., Austin, G. and Haroutunian, V. (1999) Arch Gen.
Psychiatry, 56, 981987.
De Souza, E.B., Whitehouse, P.J., Kuhar, M.J., Price, D.L. and
Vale, W.W. (1986) Nature, 319, 593595.

[277]
[278]
[279]
[280]
[281]
[282]
[283]
[284]
[285]
[286]
[287]
[288]
[289]
[290]
[291]
[292]
[293]
[294]
[295]
[296]
[297]
[298]
[299]
De Souza, E.B., Whitehouse, P.J., Kuhar, M.J., Price, D.L. and

Vale, W.W. (1987) Ann. N.Y. Acad. Sci., 512, 237247.
Ohmori, N., Itoi, K., Tozawa, F., Sakai, Y., Sakai, K., Horiba, N.,
Demura, H. and Suda, T. (1995) Endocrinology, 136, 48584863.
Tizabi, Y. and Calogero, A.E. (1992) Synapse, 10, 341348.
Coyle, J.T., Price, D.L.and Delong, M.R. (1983) Science, 219,
1184-1190.
Steckler, T. and Holsboer, F. (2001) Brain Res., 906, 4659.
Sapolsky, R.M., Uno, H., Rebert, C.S. and Finch, C.E. (1990) J.
Neurosci., 10, 28972902.
Uno, H., Lohmiller, L., Thieme, C., Kemnitz, J.W., Engle, M.J.,
Roecker EB and Farrell, P.M. (1990) Brain Res. Dev. Brain Res.,
53,157167.
Lawrence, M.S. and Sapolsky, R.M. (1994) Brain Res., 646,
303306.
Joels, M. (2001) J. Neuroendocrinol., 13, 657669.
Mclay, R.N., Freeman, S.M. and Zadina, J.E. (1998) Physiol.
Behav., 63(5), 933937.
Munck, A., Guyre, P.M. and Holbrook, N.J. (1984) Endocr. Rev.,
1, 339376.
Shors, T.J. (2001) Neurobiol. Learn Mem., 75, 1029
Beylin, AV. and Shors, TJ. (2003) Horm. Behav., 43, 124131.
Roozendaal, B. and McGaugh, J. (1997) Neurobiol. Learn Mem.,
67, 176179.
Vaher, P.L., Luine, V., Gould, E. and McEwen, B.S. (1994) Ann.
N.Y. Acad. Sci., 746, 407.
Watts, A.G. and Sanchez-Watts, G. (1995) J. Physiol., 484(3),
72136.
Sanchez, M.M., Young, L.J., Plotsky, P.M. and Insel, T.R. (2000)
J. Neurosci., 20, 46574668.
Irwin, J., Ahluwalia, P., Zacharko, R.M. and Anisman, H. (1986)
Pharmacol. Biochem. Behav., 24, 11511154.
Young, A.H., Sahakian, B.J., Robbins, T.W. and Cowen, P.J.
(1999) Psychopharmacology, 145, 260-266.
McEwen, B. (1998) N. Engl. J. Med., 338, 171179.
Keenan, P.A., Jacobson, M.W., Soleyman, R.M. and Newcomer,
J.W. (1995) Ann. N.Y. Acad. Sci., 761, 400402.
Newcomer, J.W., Craft, S., Hershey, T., Askins, K., and Bardgett,
M.E. (1994) J. Neurosci., 14, 2047-2053.
Kirschbaum, C., Wolf, O.T., May, M., Wippich, W. and
Hellhammer, D.H. (1996) Life Sci., 58, 14751483.

[300]
[301]
[302]
[303]
[304]
[305]
[306]
[307]
[308]
[309]
[310]
[311]
[312]
[313]
[314]
[315]
[316]
[317]
[318]
[319]
[320]
[321]
17
Wolkowitz, O.M., Reus, V.I., Roberts, E. Manfredi, F., Chan, T.,

Raum, W.J., Ormiston, S., Johnson, R., Canick, J., Brizendine, L.
and Weingartner, H. (1997) Biol. Psychiatry, 41, 311318.
Luine, V.N., Spencer, R.L. and McEwen, B.S. (1993) Brain Res .,
616, 6570.
Wellman, C.L. (2001) J. Neurobiol., 49, 245-253.
Makino, S., Hashimoto, K. and Gold, P.W. (2002) Pharmacol.
Gold, P.W., Drevets, W., Charney, D. and Drevets W. (2002) Biol.
Psychiatry, 52, 381.
Starkman, M.N., Gebarski, S.S, Berent, S. and Schteingart, D.E.
(1992) Biol. Psychiatry, 32, 756765
Wolkowitz, O.M., Reus, V.I., Canick, J., Levin, B. and Lupien, S.
(1997) Ann. N.Y. Acad. Sci., 823, 8196.
Alabsi, M., Hugdahl, K. and Lovallo, W.R.(2002)
Psychophysiology, 39, 9599.
van Cauter, E., Leproult, R. and Kupfer, D.J. (1996) J. Clin.
Endocrinol. Metab., 81, 24682473.
Issa, A.M., Rowe, W., Gauthier, S. and Meaney, M.J. (1990) J.
Neurosci., 10, 32473254.
Landfield, P.W., Baskin, R.K. and Pitler, T.A. (1981) Science, 214,
581584.
Buhot, M.C. (1997) Curr. Opin. Neurobiol., 7, 243-254.
Eglen, R.M., Wong, E.H.F., Dumuis, A. and Bockaert, J. (1995)
Trends Pharmacol. Sci., 16, 391397.
Reynolds, G.P., Mason, L., Meldrum, A., De Keczer, S., Parnes, H.
and Wong, E.H.F. (1995) Br. J. Pharmacol., 114, 993998.
Lezoualch, F. and Robert S.J. (2003) Exp. Gerontol., 38, 159166.
Matsumoto, M., Togashi, H., Mori, K., Ueno, K., Ohashi, S.,
Kojima, T. and Yoshioka, M. (2001) J. Pharmacol. Exp. Ther.,
296, 676682.
Luine, V. N., Spemcer, R. L. and McEwen, B. S. (1993) Brain
Res., 616, 6570.
Dinan, T. G. (1996) Life Sci., 58, 16831694.
Youngblood, B.D., Smagin, G.N., Elkins, P.D., Ryan D.H. and
Harris R.B.S. (1999) Physiol. Behav., 67(5), 643649.
McEwen, B.S. and Magarinos, A.M. (1997) Ann. N.Y. Acad. Sci.,
821, 271284.
Chaouloff, F. (1993) Brain Res. Brain Res. Rev., 18, 1-32.
Brodin, E., Linderoth, B., Giony, M., Yamamato, Y., Gazeliuo, B.,
Millhorn, D.E., Hokfelt, T. and Ungerstedt, U. (1990) Brain Res.,
535, 227-236.

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The Physiology of Learning and Memory: Role of

Available from: Berrak C Yeen

Current Protein and Peptide Science, 2004, 5, 000-000

The Physiology of Learning and Memory: Role of Peptides and Stress

molecular aspects of neuronal development, memory and

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

appear to be mediated by mechanisms that are triggered by

Glpnar and Yegen

associated with an increased rate of apoptosis in the

The Physiology of Learning and Memory

neuropeptides also play a critical role in learning behaviors

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

differences and several response patterns exist in coping with

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

hyperactivation in many central corticotropin releasing factor

Glpnar and Yegen

memory impairment might be related to impairment of the

The Physiology of Learning and Memory

is also involved in attention and reward, modulates the

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

Some of the Well-Known Neurotransmitters and

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

Co-existence of Classical Neurotransmitters and

Vasoactive intestinal polypeptide

Arginine 8-vasopressin (AVP) and oxytocin (OT) are

Glpnar and Yegen

learned ones [135, 142]. Systemic or central administration

The Physiology of Learning and Memory

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

Effects of Peptides and Non-peptide Molecules on Learning and Memory

facilitate social memoryand learned behaviors

ANP, BNP, CNP

facilitatory action on memory consolidation

improve memory performance

CGRP, SP and NPY

CCK-related peptides improve learning and memory performance

impairs the learning and memory performances

improves short-term memory

modulates memory by acting on amygdala and hippocampus

impairs spatial learning

deficiency causes impairments in cognitive function

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

Glpnar and Yegen

malfunction is associated with the impairment of memory

acetyltransferase (ChAT) activity, and induces glutamatergic

Specific proteins play essential roles during the

The Physiology of Learning and Memory

Several studies reported that peripheral administration of

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

in rats [194] and long-term potentiation and memory are

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

and increased the learning ability in animals with

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neuromodulator and a neurotransmitter only in invertebrates.

The Physiology of Learning and Memory

[248]. It was demonstrated that CCK-related peptides could

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

glucocorticoids are associated with deficits in both memory

Current Protein and Peptide Science, 2004, Vol. 5, No. 6

organism responds by activating a complex series of

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related to memory function, with evidence of exacerbation of