1) The document proposes that metabolic depression, an adaptive process of energy preservation seen in hibernation, is responsible for major depression in humans. 2) It suggests bears are a good animal model for studying depression because they hibernate with only mild hypothermia, unlike other hibernating animals. 3) Many similarities are seen between hibernation in bears and major depression in humans, including neurobiological changes, symptoms, and the underlying metabolic processes. This supports the theory that metabolic depression underlies both.

1. Medical Hypotheses (2005) 65, 829–840
http://intl.elsevierhealth.com/journals/mehy
Metabolic depression in hibernation and
major depression: An explanatory theory and
an animal model of depression
John A. Tsiouris *
George A. Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities,
1050 Forest Hill Road, Staten Island, NY 10314, USA
Received 20 May 2005; accepted 23 May 2005
Summary Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor,
hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is the
process underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptoms
of major depression in humans. The process of metabolic depression is reactivated via differential gene expression in
response to perceived adverse stimuli in predisposed persons. Behavior inhibition by temperament, anxiety disorders,
genetic vulnerabilities, and early traumatic experiences predispose persons to depression. The proposed theory is
supported by similarities in the presentation and neurobiology of hibernation in bears and major depression and
explains the yet unexplained neurobiological changes of depression. Although, gene expression is suppressed in other
hibernators by deep hypothermia, bears were chosen because they hibernate with mild hypothermia.
Pre-hibernation in bears and major depression with atypical features are both characterized by fat storage through
overeating, oversleeping, and decreased mobility. Hibernation in bears and major depression with melancholic features
are characterized by withdrawal from the environment, lack of energy, loss of weight from not eating and burning stored
fat, changes in sleep pattern, and the following similar neurobiological findings: reversible subclinical hypothyroidism;
increased concentration of serum cortisol; acute phase protein response; low respiratory quotient; oxidative stress
response; decreased neurotransmitter levels; and changes in cyclic-adenosine monophosphate-binding activity.
Signaling systems associated with protein phosphorylation, transcription factors, and gene expression are responsible
for the metabolic depression process during pre-hibernation and hibernation. Antidepressants and mood stabilizers
interfere with the hibernation process and produce their therapeutic effects by normalizing the fluctuation of activities
in the different signaling systems, which are down-regulated during hibernation and depression and up-regulated during
exodus from hibernation and the hypomanic or manic phase of mood disorders.
The ways individuals cognitively perceive, understand, communicate, and react to the vegetative symptoms of
depression, from downregulation in energy production, and in the absence of known medical causes, produce the other
characteristics of depression including guilt, helplessness, hopelessness, suicidal phenomena, agitation, panic attacks,
psychotic symptoms, and sudden switch to hypomanic or manic episodes. The presence of one or more of these
characteristics depends on the person’s neuropsychological function, its social status between the others, and the
other’s response to the person.
* Tel.: +1 718 494 5237; fax: +1 718 494 2258.
E-mail address: john.tsiouris@omr.state.ny.us.
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2005.05.044

2. 830 Tsiouris
Neurobiological changes associated with metabolic depression during entrance, maintenance, and exodus from
hibernation in bears is suggested as a natural animal model of human depression and mood disorders.
c 2005 Elsevier Ltd. All rights reserved.
Introduction ities [2,3] including the observed brain metabolic
changes [15], except the ones associated with cer-
Hippocrates introduced the terms melancholia and tain temperamental characteristics [13]. What has
mania 2400 years ago, yet his description of melan- not yet been identified is the mechanism that pro-
cholia and mania is still clinically valid today. He duces the neurobiological findings observed in
was the first to attribute the origin of melancholia depressive disorders in the vulnerable individuals
to natural causes, the excess generation of black above in response to environmental stressors.
bile in the spleen. The high prevalence of depressive disorders at
Theories explaining many aspects of depressive all ages and both sexes in humans [16] and the data
disorders have been proposed since then, espe- accumulated up to date suggest that depressive
cially in the last 100 years. To date, no clear expla- disorders result from the expression of an old adap-
nation has been offered for the signs, symptoms, tive pattern from our phylogeny for energy preser-
and state-dependent neurobiological abnormalities vation, which in the past had survival value. It has
observed in depressive disorders [1]. been proposed that a form of metabolic depression
Treatment of depressive disorders with psycho- homologous to the metabolic depression observed
tropics; the effects of antidepressants in animal during mammalian hibernation is the underlying
models of depression; and studies in the blood, old adaptive process responsible for the neurobio-
cerebrospinal fluid, brains, and brain tissue of logical changes and the core somatic signs and
depressed patients versus normal controls have symptoms of depressive disorders in humans [17].
generated many etiological hypotheses to explain I have proposed [18] that the process of meta-
the accumulated data. Many of these hypotheses bolic depression in different forms is activated
describe the effects of psychotropics with antide- via differential gene expression of existing normal
pressant qualities on the physiology and neuro- genes, in individuals with behavior inhibition by
chemistry of the brain at different levels or have temperament [7], anxiety disorders, and overall
documented state-dependent abnormalities, but genetic vulnerabilities [11–13], or early traumatic
they do not explain the neurobiology of depressive experiences [10] in response to adverse external
disorders [2–4]. or internal stimuli [6,19]. It is postulated that these
Many common environmental stressors that can adverse external or internal stimuli (environmental
precipitate depressive disorders in predisposed stressors or signs and symptoms of medical illness)
individuals have been identified [5,6]. Behavior are perceived by the individuals predisposed to
inhibition by temperament in children predisposes depression [7,10–13] as a threat to their psycho-
to anxiety disorders later in life [7]. High comorbid- logical or somatic survival.
ity has been reported between anxiety, neuroti- Metabolic depression is defined as a drop in stan-
cism, female sex, and depressive disorders [8] or dard metabolic rates, to less than the normal value
bipolar disorders [9]. Also, early traumatic experi- [20]. Hibernation, torpor and estivation are adap-
ences have been reported to contribute to the tive states of organisms, whose basic mechanism
pathophysiology of anxiety and affective disorders is probably plesiomorphic (= ancestral/primitive)
[10]. in evolutionary terms [21], and involves metabolic
Current research has identified the genetic vul- depression, with energy-saving benefits that have
nerabilities of women predisposed to depression well-known survival value for the organism exhibit-
[11] as variations in cyclic adenosine monophos- ing them in response to life-threatening environ-
phate (cAMP) response element-binding protein mental stressors [22–25].
(CREB 1) [12]. In addition, a polymorphism in the If metabolic depression, the underlying process
5-HTT gene was found to predispose both sexes of hibernation, is also responsible for the neurobio-
to anxiety and especially to depression in response logical findings and the core somatic symptoms of
to life stressors [13,14]. major depression, as has been proposed [17,18],
It has become evident after much investigation predictable similarities would be expected in the
that the abnormal neurobiological findings ob- presentation and neurobiological findings at differ-
served during the depressive or manic phase of ent levels between hibernation in bears and major
affective disorders are state-dependent abnormal- depression in humans.

3. Metabolic depression in hibernation and major depression 831
These similarities will be outlined in the rest of this Major depression with atypical features or sea-
paper. The non-active state bears fall into from the sonal affective disorder (SAD) is characterized by
middle of October to the end of March has been la- overeating, craving for carbohydrates, weight gain,
beled winter sleep or dormancy and not true hiberna- oversleeping, a special type of fatigue called lea-
tion [26–28], but it has now been confirmed that den paralysis (e.g., heavy, leaden feeling in arms
bears are the largest animals that hibernate [29–33]. and legs), and low energy expenditure; [39,45].
Hibernation in bears has been chosen as an ani- Similar characteristics have been observed in bears
mal model for major depression because: during their preparation for hibernation (pre-hiber-
nation state) [46].
(a) Major depression is not associated with Differences have been observed in immune re-
hypothermia; sponse between pre-hibernation and hibernation
(b) Bears are the only animals that do not become states in bears [18,47,48] and between major
hypothermic during hibernation, except for a depression with atypical features, or SAD and ma-
drop of 2–4 °C in body temperature jor depression with melancholic features [49,50].
[27,34,35]. The literature also suggests that there are major
(c) Deep hypothermia during hibernation of other differences in many neurobiological findings be-
organisms suppresses gene expression and the tween the above two types of depression [1].
translation and transcriptional machinery of
many proteins [27,36,37].
Direct metabolic depression process
The process of metabolic depression during indicators
hibernation in bears as a natural animal model for
understanding the neurobiology of depression is In bears during hibernation, metabolic rate (MR)
being designed and discussed according to the five decreases by about 50% [51], oxygen consumption
steps proposed by Sackett and Gould [38]. decreases by about 50% [52,53], and red blood cell
The following similarities between hibernation (RBC) oxidative stress increases [54]. The low
in bears and major depression in humans are sup- respiratory quotient (RQ) of 0.6–0.73 observed in
portive evidence for the metabolic depression the- bears during hibernation [34,41] represents pure
ory of major depression. fat combustion [55]. In humans, no studies have di-
Where data are not available from studies in rectly evaluated the metabolic depression process
bears, similarities between findings in major during major depression, but in one study, low RQ
depression and torpor, hibernation, or estivation (0.71) was reported in treatment-resistant de-
from other organisms will be cited. pressed patients versus controls [56]. This low RQ
was thought to be clinically insignificant, but it
demonstrated for the first time that oxygen was
Presentation – signs and symptoms used for oxidation of ‘‘other than carbohydrate
substances’’ [56], mainly fat, in the depressed pa-
According to the DSM IV [39], the core characteris- tients, as observed in mammals during hibernation.
tics of major depression (unipolar or bipolar type), Metabolic depression in non-depressed humans has
especially with melancholic and catatonic fea- been observed in the absence of hypothermia [57]
tures, are insomnia, loss of appetite, weight loss, and in the presence of hypothermia after acciden-
lack of interest in the environment, fatigue or loss tal exposure to the cold [58], suggesting that the
of energy, and psychomotor retardation with occa- ability of the human organism to undergo meta-
sional immobility. Psychomotor retardation is a bolic depression has not been lost.
central psychobiological feature of depression
[40]. Similarly, during hibernation, bears withdraw
into their den and are mostly immobile. They do Acute phase protein response
not eat or drink, and they lose 25% of their body
weight [41–43]. Bears appear to sleep constantly, Elevated levels of mRNA a2macroglobulin (a2M),
but sleep EEG studies that would determine this without acute phase protein response, were ob-
definitively have not been done on bears. Studies served in the liver of hibernating squirrels [59]. In-
in other animals, however, revealed that during creased levels of haptoglobin were reported in
hibernation, they are sleep-deprived and spend hibernating brown bears [47], and a2M levels were
many calories through gluconeogenesis to reach found to be elevated in black bears during hiberna-
euthermic states to have rapid eye movement tion [48], but with an acute phase response [18].
(REM) sleep [44]. Hypothermia suppresses the acute phase response

4. 832 Tsiouris
in other hibernating organisms [36,37], except the norepinephrine, suppresses the norepinephrine
a2M [60], but not in bears [18,48], as their temper- neuron’s firing activity at the locus ceruleus (LC)
ature drops only mildly (2–4 °C) during hibernation [84,85]. Norepinephrine injection also increases
[27]. The theory of metabolic depression during thermogenesis through gluconeogenesis, promot-
major depression [18] explains the previous finding ing exit from hibernation in ground squirrels [86].
of acute phase response to depression [61–68] for Furthermore, depression is observed in humans
which different hypotheses have been proposed secondary to psychostimulant withdrawal [2], and
[69,70]. decreased secretion of norepinephrine from the
During hibernation in bears and depression in hu- LC is noted during metabolic depression without
mans, levels of the acute phase proteins increase, comorbid anxiety disorder [87,88].
but modestly in comparison to the increase ob-
served during inflammation, trauma, or surgery.
Activation of the inflammatory response system
Hormones
has been suggested as an adaptive defense mecha-
The reversible subclinical hypothyroidism of hypo-
nism against the consequences of metabolic
thalamic origin observed in black bears during
depression and oxidative stress observed during
hibernation [30,89] and in patients with major
hibernation [51]. The same mechanism has been
depression [90] is caused by reduced stimulation
proposed for the acute phase response observed
of the hypothalamus by the LC [91]. In addition,
during major depression [17,18]. In individuals
the increased serum cortisol concentration during
without the predisposition to the adaptive process
hibernation in captive and wild black bears
of metabolic depression or when the process of
[92,93] and during depression in humans [94,95]
metabolic depression is interrupted voluntarily or
suggests similar hypothalamic-pituitary-adrenal
involuntarily, in periods of acute and chronic
(HPA) axis activation during hibernation in bears,
stress, the elastase unchecked by a1antitrypsin
as during depression in humans [96,97].
can lead to extensive tissue damage [71]. Tissue
damage can cause autoimmune reactivity and pro-
gress to autoimmune disorders, often associated
with depressive disorder, if the acute phase pro- Second messengers and intracellular
teins, especially the C-reactive protein (CRP), can- signaling
not fully regulate phagocytic leukocyte activities
[72], remove the injured cells [73], and interact Current research on how antidepressants, lithium,
with the nuclear antigens released from necrotic and mood stabilizers exercise their therapeutic ef-
cells to prevent repositioning of these antigens in fects has focused on cyclic-adenosine monophos-
tissue [74]. The role of elevated CRP levels in heart phate (cAMP), inositol 1,4,5 trisphosphate (IP3)
attacks is currently under investigation [75,76]. and pathways associated with transcription factors
The modest increase of CRP in individuals predis- and gene expression [4,98,99]. Levels of cAMP
posed to heart attacks, similar to the increase ob- binding activity, IP3, protein kinase A (PKA), cAMP
served during depression, hibernation, and the response element binding (CREB), protein kinase
stress of captivity in bears [18] suggests that CRP C (PKC), brain-derived neurotrophic factor (BDNF),
is only an indicator of stress and depression, both glucogen synthase kinaseÀ3 (GSKÀ3), b-arrestin-1
of which have been associated with heart attacks. [100–103] and other second messengers, which
are associated with energy generation and preser-
vation, were found to be decreased or altered dur-
Neurotransmitters ing depression but to be increased or normalized
after treatment with antidepressants or mood sta-
At the neurotransmitter level, norepinephrine, bilizers [4,98,104,105].
serotonin, and dopamine levels are decreased dur- cAMP and PKA play a role in the oxidative phos-
ing mammalian [77] and reptilian [78] hibernation phorylation and regulation of enzymes involved in
as well as during major depression in humans intermediate metabolism [106,107]. Reversible
[56,79,80]. Drugs that increased the levels of the phosphorylation is considered one of the main
neurotransmitters above in the synapses reverse mechanisms initiating metabolic depression during
the symptoms of depression in humans and disrupt hibernation [22], and selective changes of cAMP
the hibernation process [81–83]. Reversal of RQ in and IP3 were observed during estivation in the
treatment-resistant depressed patients after injec- hepatopancreas of otala lactae [108]. Also, de-
tion of desipramine [56] can be explained by the creased levels of cAMP binding activity were mea-
fact that systemic injection of desipramine, like sured during hibernation in the white blood cells

5. Metabolic depression in hibernation and major depression 833
of black bears versus the end of the hibernating depression [125] contributes the additional charac-
state, but increased cAMP binding activity was teristics of depression, including feelings of worth-
measured during the switch from prehibernating lessness; guilt; inability to concentrate; and
to hibernating state [109]. This increase in cAMP suicidal ideations, threats, or attempts. Descrip-
levels may be associated with the cAMP signaling tions, explanations, and treatment of depressive
pathways involved in gene transcription when bears disorders through the years have been heavily influ-
enter into the complete state of metabolic enced not only by medical knowledge of depressive
depression. disorders but also by society’s understanding and
Depression of ion leakage and pumping (Na+ response to the presentation of depressive disor-
pump) through changes in the lipid components of ders at given periods in different places of the
the membranes has been suggested as an energy- world.
saving mechanism during hibernation [20]. Sodium Bipolar disorder was suggested by Lange to be
influx with voltage-gated sodium channels is regu- part of the same internal biological cyclical process
lated by neuronal Na+/K+ATPase through significant as sleep and menses [126]. Hibernation was pro-
ATP energy consumption [110]. Decreased activi- posed previously by others as a model for endoge-
ties of Ca2+/Mg2+-ATPase and Na+/K+-ATPase, which nous depression [81,127] and SAD [128] but
were noted in the RBCs of hibernating black bears without reference to metabolic depression as the
[54], confirm that energy-saving mechanisms are common underlying mechanism, which can explain
in operation during hibernation in bears. Alterations the similarities in the presentation of hibernation
in intracellular Ca2+ function [111–113] and de- and depression. The hibernation model of depres-
creased Na+–Li+countertransport activity in RBC sion was abandoned, as it could not withstand the
membranes have been reported in bipolar patients criticism that large animals do not hibernate
[114,115]. The common mood-stabilizing mecha- [129], which has proven invalid [30,33,54]. The
nism of certain antiepileptics is voltage-dependent mitochondrial dysfunction hypothesis of depression
Na+channel inhibition [116,117] and lithium affects was proposed recently on the basis of (a) decreased
mood disorders by altering the transport kinetics of levels of phosphocreatine, which were observed in
the NA+À/L+ countertransport system [118] and Ca++ the left frontal lobes of patients with bipolar
homeostasis [119] . Lithium also suppresses hiber- depression by using magnetic resonance spectros-
nation in the Turkish hamster [120], normalizes sys- copy (31P-MRS) [130] (b) decreased expression of
temic immune system activation associated with nuclear messenger-RNA, coding for mitochondrial
depression [66,67], stabilizes fluctuation in the proteins, in the hippocampus and frontal lobes of
activities of different signaling systems through brains from subjects with bipolar disorders [131],
multiple sites of action [121,122], and desynchro- (c) altered brain phospholipid abnormalities and
nizes the oscillators [123] decoupling of which are their inhibitory effects on mitochondrial functions
associated with disturbances of the body’s natural [6,132], and (d) other studies involving the intra-
rhythms during mood disorders [124]. cellular process that regulates energy production.
The proposed metabolic depression theory explains
the above state-dependent phenomena that pro-
Discussion duce ‘‘hypometabolism’’ during the depressive
phase of bipolar disorder [130].
Metabolic depression is a well-coordinated process It is proposed here that according to the meta-
of different systems and pathways associated with bolic depression theory of depression, future stud-
transcription factors and differential gene expres- ies would confirm ‘‘hypometabolism’’ during the
sion. Initiated in response to stressors for energy depressed phase and ‘‘hypermetabolism’’ during
preservation (conservation/savings) and survival the hypomanic/manic phase of mood disorders as
of the organism, it is observed in organisms ranging cyclical, state-dependent phenomena. Polymor-
from worms and otala lactae to bears and, accord- phisms in different genes will be identified, which
ing to this theory, to humans during major depres- predispose individuals with a certain genotype or
sion. It has been proposed [18] and further endophenotype to react to environmental stressors
elaborated here that a form of metabolic depres- with ‘‘hypometabolism’’ [130], ‘‘functional shift’’
sion is responsible for the lack of energy, fatigue, [133], ‘‘conservation-withdrawal’’ [134,135] and
lack of interest in the environment, and sleep and alternating states between ‘‘hypermetabolism’’
eating disturbances associated with major depres- (flight/fight) and ‘‘hypometabolism’’ (withdrawal
sion. The way humans perceive cognitively, evalu- or freeze process) or mixed states.
ate, describe, explain, and react to the above Major depression with atypical features may be
vegetative signs and main characteristics of (a) a prodromal state to major depression with

6. 834 Tsiouris
melancholic features, (b) a separate state influ- sion and to preserve the sense of well-being and
enced by extremes in environmental temperatures ability to function.
and sunlight or, (c) the type of depression to
which individuals with anxiety disorders are
mostly predisposed. It appears that in such indi- Cortisol hypersecretion, metabolic
viduals with certain temperamental and personal- depression, and psychotic process
ity characteristics, the metabolic depression
process is not fully coordinated or there is resis- Some individuals have high cortisol baseline secre-
tance from the individual’s cognitive process to tion due to genetic factors and/or to stress during
‘‘give up’’ or ‘‘let it go,’’ which at times triggers the pre/postnatal period of development. Shyness
the fear of dying and panic attacks, bringing the in young children was associated with elevated
person to the emergency room for work-up for rates of baseline cortisol [140], which demon-
different medical disorders. Treatment with anti- strated heritability and a relationship of cortisol
depressants and antianxiety medication at this levels with social stress and lack of social recogni-
point or elimination of the environmental stress- tion [141]. Chronically high-average cortisol levels
ors disrupts or reverses the process of metabolic were associated with anxiety and withdrawal in
depression and reverses the symptoms of depres- adults with trait of anxiety and impaired social
sion, which could be considered another level of functioning [142,143]. High baseline morning corti-
an adaptive process [136]. It has also been ob- sol is associated with a twofold increase in the risk
served that people with anxiety disorders and for onset of major depression within one year in
depression with atypical features often develop adolescents identified as at high-risk for depression
bipolar disorder. Their bipolarity may be due to [144], and high evening cortisol levels in adoles-
a vigorous attempt by the individual to prevent cents with depression have been found to predict
entrance into major depression with melancholic chronic depression [145], recurrence of depres-
features, by remaining in the state of major sion, and future suicide attempts [146]. Also, dexa-
depression with atypical features and accumulat- methasone non-suppression has been associated
ing further weight (pre-hibernation) or escaping with both negative and cognitive symptoms in chil-
from it by entering into a hypomanic/manic state dren with learning disabilities [147].
(flight/fight response). It is worth noting that food Further increase of cortisol secretion secondary
availability in a relatively warm environment dis- to metabolic depression during major depression in
rupts the process of metabolic depression and en- such individuals can produce a trophic shift of
trance into deep hibernation in black and brown dopamine fibers away from pyramidal cells and into
bears living in different parts of the world, keep- interneurons [148,149]. These individuals can be
ing them in a state of pre-hibernation. vulnerable to developing reversible psychotic
The underlying mechanism for panic attacks or symptoms during depressive and manic episodes.
switching to hypomanic/manic state appears to The significant neurocognitive impairments across
be the following: Lack of energy due to the initia- a wide range of measures reported in bipolar pa-
tion of the metabolic depression process and nega- tients [150] and the similarities that were observed
tive cognitive evaluation of self-worth in in neuropsychological dysfunction between pa-
individuals with anxiety disorders and other yet tients with psychotic depression and schizophrenia
undefined temperamental and personality charac- [151] support this explanation.
teristics invoke fear of annihilation and over-stim- The role of metabolic depression in schizophre-
ulation of the central nucleus of the amygdala nia is unknown, but the prodromal symptoms of
(CNA) and over-secretion of corticotropin-releasing schizophrenia (increased anxiety, impaired func-
factor (CRF) [137,138]. This activation of CNA in tioning at different levels, withdrawal, lack of en-
concert with the bed nucleus of the stria termi- ergy, anhedonia, avolition, lack of interest in the
nales (BNST), the principal regulator of the locus outside world, decreased communication, preoccu-
ceruleus (LC) [139], through their excitatory pro- pation with body function and negative thoughts),
jections which contain CRF, stimulates the LC to in- which are similar to the symptoms of major depres-
crease norepinephrine production and reverses the sion [152] and the observed hypometabolism in first
process of metabolic depression. Panic attacks, episode psychosis and ultra high-risk individuals
psychomotor agitation, or sudden switches from [153] suggest activation of the metabolic depres-
depressed to hypomanic or manic phase can result sion process at the initial phase of schizophrenia.
from such attempts of the affected individual to Elevated baseline levels of cortisol [154–156]
resist or reverse the process of metabolic depres- and neurocognitive deficits [157] due to structural

7. Metabolic depression in hibernation and major depression 835
brain abnormalities [158] have been associated states should elucidate the neurobiological process
with increased risk for conversion to Axis I psy- of affective and possibly psychotic disorders.
chotic disorders. Psychosocial stress in vulnerable The hope is that understanding the etiology of
individuals [159] is perceived by the amygdala as the neurological finding of major depression and
a threat to survival of the organism due to the mood disorders in general, with or without psy-
inability to respond with flight or fight from lack chotic features, will enhance the development of
of energy due to the metabolic depression process. new preventive and treatment strategies, which
This threat for survival produces activation of the can be tested in the proposed animal model and
central or the basolateral nucleus of the hippocam- possibly change the psychosocial aspects and the
pus [160]. The activation of these hippocampus nu- stigma that is associated with these devastating
clei, combined with further increase of cortisol psychiatric disorders.
secondary to metabolic depression, can lead to tro-
phic shift of dopamine fibers into interneurons
[148,149] and might culminate in an increased Acknowledgments
excitatory drive to individual GABA-ergic cells at
the anterior cingulated cortex [161]. Dopaminergic The author thanks Lawrence Black for reference
inhibitory input to these GABA-ergic cells increases assistance, Maureen Marlow for editorial com-
[162] through this process, forcing the GABA-ergic ments/suggestions and Valerie Mazza for technical
cells to fail in their attempt to provide adequate assistance. This study was partially supported by
inhibitory modulation to pyramidal neurons. This the New York State Office of Mental Retardation
activity possibly precipitates the development of and Developmental Disabilities.
non-reversible psychotic symptoms in response to
stressors in fully withdrawn, isolated and anxious
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