Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
Contents
lists
available
at
Neuroscience
and
Biobehavioral
Reviews
j o u
r n
a l
h
o m
e p a g e :
w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v
Review
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response
Paul
W.
Andrews
,
Aadil
Bharwani
,
Kyuwon
R.
Lee
,
Molly
Fox
,
Q1
J.
Anderson
Thomson
a
Department
of
Psychology,
Neuroscience
and
Behaviour,
McMaster
University,
1280
Main
Street
West,
Hamilton,
Ontario
L8S
4K1,
Canada
b
Department
of
Biological
Anthropology,
University
of
Cambridge,
Pembroke
Street,
Cambridge
CB2
3QY,
England,
United
Kingdom
Q2
c
Counseling
and
Psychological
Services,
University
of
Virginia
Student
Health,
Charlottesville,
VA,
USA
d
Institute
of
Law,
Psychiatry,
and
Public
Policy,
University
of
Virginia,
Charlottesville,
VA,
USA
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
4
September
2013
Received
in
revised
form
8
January
2015
Accepted
15
January
2015
Available
online
xxx
Keywords:
Analysis
Depression
Serotonin
Energy
regulation
Learning
Plasticity
Working
memory
Distraction
Hippocampus
Prefrontal
cortex
Hypothalamus
a
b
s
t
r
a
c
t
The
role
of
serotonin
in
depression
and
antidepressant
treatment
remains
unresolved
despite
decades
of
research.
In
this
paper,
we
make
three
major
claims.
First,
serotonin
transmission
is
elevated
in
mul-
tiple
depressive
phenotypes,
including
melancholia,
a
subtype
associated
with
sustained
cognition.
The
primary
challenge
to
this
first
claim
is
that
the
direct
pharmacological
effect
of
most
symptom-reducing
medications,
such
as
the
selective
serotonin
reuptake
inhibitors
(SSRIs),
is
to
increase
synaptic
serotonin.
The
second
claim,
which
is
crucial
to
resolving
this
paradox,
is
that
the
serotonergic
system
evolved
to
regulate
energy.
By
increasing
extracellular
serotonin,
SSRIs
disrupt
energy
homeostasis
and
often
worsen
symptoms
during
acute
treatment.
Our
third
claim
is
that
symptom
reduction
is
not
achieved
by
the
direct
pharmacological
properties
of
SSRIs,
but
by
the
brain’s
compensatory
responses
that
attempt
to
restore
energy
homeostasis.
These
responses
take
several
weeks
to
develop,
which
explains
why
SSRIs
have
a
therapeutic
delay.
We
demonstrate
the
utility
of
our
claims
by
examining
what
happens
in
animal
models
of
melancholia
and
during
acute
and
chronic
SSRI
treatment.
©
2015
Published
by
Elsevier
Ltd.
Contents
1.
Introduction
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00
2.
Serotonin
is
elevated
in
multiple
depressive
phenotypes
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2.1.
In
people
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2.1.1.
Polymorphism
in
the
SERT
gene
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00
2.1.2.
5-HIAA
levels
in
the
jugular
vein
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00
2.1.3.
Tryptophan
depletion
increases
DRN
activity
in
depressed
patients
taking
ADMs
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00
2.1.4.
Increased
preference
for
carbohydrates
in
depression
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2.1.5.
Tianeptine
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2.1.6.
Anxiety
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00
Abbreviations:
5-HT,
5-hydroxytryptamine
(serotonin);
DA,
dopamine;
NE,
norepinephrine;
ADM,
antidepressant
medication;
SSRIs,
selective
serotonin
reuptake
inhibitors;
SERT,
serotonin
transporter;
5-HIAA,
5-hydroxyindoleacetic
acid;
PFC,
prefrontal
cortex;
mPFCv,
ventral
part
of
the
rodent
medial
prefrontal
cortex;
DLPFC,
dorsolateral
prefrontal
cortex;
VLPFC,
ventrolateral
prefrontal
cortex;
DRN,
dorsal
raphe
nucleus;
PET,
positron
emission
tomography;
ATP,
adenosine
triphosphate;
BDNF,
brain-derived
neurotrophic
factor;
NET,
norepinephrine
transporter;
DAT,
dopamine
transporter.
∗ Corresponding
author.
Tel.:
+1
905
525
9140x20820;
fax:
+1
9055296225.
address:
(P.W.
Andrews).
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
0149-7634/©
2015
Published
by
Elsevier
Ltd.
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Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
2
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
2.2.
In
non-human
animal
models
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Stressor
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Genetic
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Lesion
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Summary
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3.
The
energy
regulation
function
of
the
serotonergic
system
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3.1.
Overview
of
the
serotonergic
system
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3.2.
The
evolution
of
serotonin
in
mitochondria
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00
3.3.
The
mitochondrial
functions
of
serotonin
.
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00
3.4.
What
is
the
function
of
the
serotonergic
system?
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00
3.4.1.
Serotonin
and
energy
regulation .
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.
00
3.4.2.
The
homeostatic
equilibrium
level
of
serotonin
transmission
is
increased
in
situations
requiring
a
rebalancing
of
metabolically
expensive
processes
.
.
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00
4.
The
homeostatic
response
to
SSRIs
and
symptom
reduction
.
.
.
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.
.
00
4.1.
Acute
SSRI
treatment
disrupts
energy
homeostasis
.
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.
00
4.2.
The
brain’s
compensatory
responses
to
SSRI
treatment
.
.
.
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.
00
4.3.
The
mechanisms
of
symptom
reduction
.
.
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.
00
4.4.
Symptom
reduction
is
a
temporary
overshoot
of
the
homeostatic
equilibrium
.
.
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.
00
4.5.
The
effects
of
SSRIs
during
recalibration
of
serotonin
transmission
.
.
.
.
.
.
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.
00
5.
What
is
serotonin
doing
in
melancholia?
.
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.
00
5.1.
Energy
is
reallocated
to
cognition
in
melancholia .
.
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.
00
5.2.
The
situational
triggers
of
the
melancholic
state
.
.
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.
00
5.3.
Serotonin
coordinates
the
mechanisms
promoting
rumination
.
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00
5.3.1.
The
amygdala
and
orienting
attention
to
the
problem
that
triggered
the
episode
.
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00
5.3.2.
The
nucleus
accumbens
and
anhedonia
.
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00
5.3.3.
The
hypothalamus
reallocates
energy
to
rumination
.
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00
5.3.4.
The
hippocampus
and
the
allocation
of
working
memory
.
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00
5.3.5.
The
lateral
PFC
promotes
distraction-resistance
.
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.
00
5.4.
The
effects
of
ADMs
on
the
melancholic
energy
allocation
pattern
.
.
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00
6.
Conclusion
and
future
directions
.
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00
Acknowledgments .
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.
00
Appendix
A
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00
References
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.
00
1.
Introduction
Depression
is
a
heterogeneous
suite
of
states
characterized
Q3
by
sad
mood
and
anhedonia
(an
inability
to
experience
pleasure)
Depressive
states
share
some
genes
and
neurobiology
in
common,
but
they
otherwise
dif-
fer
in
symptom
and
etiology
For
instance,
depressive
symptoms
can
occur
in
response
to
infection
(called
sickness
behavior)
or
starvation
though
the
symptoms
are
not
con-
sidered
pathological
in
these
contexts
In
the
fifth
edition
of
the
Diagnostic
and
Statistical
Manual
for
Mental
Disorders
(DSM-5),
the
diagnostic
category
of
major
depression
envelops
some
of
the
symptomatic
heterogeneity
by
allowing
for
variability
in
weight,
sleeping,
and
psychomotor
activity
Episodes
of
major
depression
may
be
further
subdivided
into
more
precise
phenotypes.
Melancholia
(weight
loss,
insomnia,
and
agitation/retardation)
is
considered
by
many
to
be
the
“biological
core
of
depression”
46).
It
is
the
most
common
and
reliably
diagnosed
subtype,
often
accounting
for
50%
or
more
of
clinical
episodes
Melancholia
is
associated
with
height-
ened
hypothalamic-pituitary-adrenal
(HPA)
activity
(
which
is
a
physiological
indicator
of
stress
While
it
was
formerly
called
endogenous
depression,
melan-
cholia
is
in
fact
associated
with
stressful
life
events
that
are
often
serious
or
highly
private
in
nature
(
Atypical
depression
(weight
gain,
hypersomnia,
and
retardation)
is
the
other
major
subtype,
but
it
is
heterogeneous
and
not
well
understood
Despite
decades
of
research,
the
role
serotonin
plays
in
depres-
sive
phenotypes
has
not
been
conclusively
determined.
The
original
clue
that
monoamines
(serotonin,
norepinephrine,
and
dopamine)
were
involved
in
depression
came
from
two
serendipitous
dis-
coveries
(
First,
during
the
investigations
of
iproniazid
as
a
treatment
for
tuberculo-
sis
and
imipramine
as
a
treatment
for
schizophrenia,
clinicians
reported
that
these
drugs
could
reduce
depressive
symptoms.
An
effort
was
then
made
to
find
a
common
pharmacological
prop-
erty
that
could
explain
their
antidepressant
effect.
Eventually,
researchers
found
that
iproniazid
inhibits
the
enzymes
that
break-
down
the
monoamines,
while
imipramine
blocks
the
serotonin
transporter
(SERT)
and
the
norepinephrine
transporter
(NET).
Sec-
ond,
clinical
observations
suggested
that
reserpine,
a
drug
known
to
deplete
monoamines,
increased
depressive
symptoms.
These
find-
ings
appeared
to
solve
the
puzzle.
By
preventing
the
breakdown
of
norepinephrine
and
serotonin,
or
preventing
their
clearance
from
the
synapse,
iproniazid
and
imipramine
appeared
to
increase
forebrain
monoamine
levels.
The
monoamine-enhancing
effect
of
antidepressant
medications
(ADMs),
coupled
with
the
depression-
inducing
effects
of
reserpine,
suggested
that
depression
was
caused
by
reduced
monoamine
neurotransmission
(
Other
researchers
soon
suggested
that
serotonin
was
the
most
important
monoamine
(
Often
it
is
called
the
‘monoamine
hypothesis’
or
the
‘serotonin
hypothesis.’
We
refer
to
it
as
the
low
serotonin
hypothesis
because
it
proposes
a
particular
direction.
Researchers
then
focused
on
the
creation
of
drugs
that
could
increase
synaptic
serotonin
without
perturbing
other
monoamines
by
selectively
binding
to
the
serotonin
transporter
42
43
44
45
46
47
48
49
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
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
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P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
3
Table
1
The
symptoms
of
major
depression,
according
to
the
DSM-5.
Episodes
of
major
depression
can
have
melancholic
or
atypical
features.
Major
depression
Melancholic
subtype
Atypical
subtype
Sad
mood
Sad
mood
is
worse
in
the
morning
and
not
reactive
to
positive
events;
different
from
grief
or
loss
Sad
mood
is
reactive;
brightens
in
response
to
positive
events
Anhedonia
Anhedonia
Weight
loss
or
gain
Weight
loss
Weight
gain
Hypersomnia
or
insomnia
Insomnia
with
early
morning
waking
Hypersomnia
Psychomotor
agitation
or
retardation
Psychomotor
agitation
or
retardation
Leaden
paralysis
Fatigue
Excessive
feelings
of
worthlessness
or
guilt
Excessive
guilt
Difficulty
concentrating
Suicidal
ideation
Sensitivity
to
interpersonal
rejection
(SERT).
This
research
effort
was
successful,
and
the
selective
serotonin
reuptake
inhibitors
(SSRIs)
are
now
among
the
most
widely
prescribed
medications
(
However,
many
problems
with
the
low
serotonin
hypothesis
have
prompted
a
reassessment
of
serotonin’s
role
in
depression
(see
Although
the
idea
that
a
single
neurochemical
is
the
cause
of
depression
is
now
considered
simplistic,
the
low
serotonin
hypothesis
still
lies
at
the
foundation
of
most
research
on
depression
(
It
is
generally
thought
that
reduced
serotonin
transmission
is
one
of
the
more
distal
factors
in
the
neurological
chain
of
events
that
regulate
depressive
symp-
toms
(
The
fact
that
ketamine
(which
Box
1:
Problems
with
the
low
serotonin
hypothesis
There
has
been
no
direct
test
of
the
low
serotonin
hypothesis
in
humans
because
it
requires
invasive
techniques
(see
Section
Nevertheless,
several
findings
have
cast
doubt
on
the
low
serotonin
hypothesis.
1.
Some
drugs
that
block
serotonin
reuptake
(e.g.,
cocaine
and
amphetamine)
are
not
effective
in
treating
depression
2.
Researchers
and
historians
have
concluded
that
reserpine-
induced
depression
is
a
‘myth’
(
and
that
it
may
actually
have
antidepressant
properties
The
only
placebo
controlled,
randomized,
parallel
group
study
of
chronic
reserpine
treatment
in
anxious
or
depressed
people
showed
that
reserpine
had
an
antide-
pressant
effect
(
Indeed,
some
researchers
argued
that
reserpine
had
antidepressant
prop-
erties
and
it
was
used
in
the
1970s
and
1980s
to
manage
refractory
depression
3.
SSRIs
and
other
ADMs
increase
extracellular
serotonin
within
minutes
to
hours
of
the
first
dose
but
they
do
not
reduce
symptoms
until
after
several
weeks
of
continuous
treatment
This
pattern
is
called
the
therapeutic
delay.
4.
The
attempt
to
reduce
serotonin
through
tryptophan
deple-
tion
fails
to
trigger
depression
in
non-depressed
participants
5.
Neonatal
exposure
to
SSRIs
causes
depressive
symptoms
in
adult
rodents
6.
Genetic
downregulation
of
SERT,
which
increases
synaptic
serotonin,
is
associated
with
an
increase
in
depressive
symp-
toms
(
7.
Meta-analyses
of
published
and
unpublished
studies
show
that
ADMs
are
only
modestly
more
effective
than
placebo
at
reducing
depressive
symptoms
blocks
a
glutamate
receptor)
has
rapid
antidepressant
effects
lends
support
to
the
hypothesis
that
depressive
symptoms
are
more
proximally
controlled
by
glutamate
transmission
in
frontal
regions
(
Others
propose
serotonin
does
not
exert
any
regulatory
control
over
depressive
symptoms
(
Still
others
have
suggested
serotonin
transmission
is
elevated
in
depression
In
this
paper,
we
make
three
major
claims.
The
first
claim,
dis-
cussed
in
Section
that
serotonin
transmission
is
elevated
in
multiple
depressive
phenotypes,
including
melancholia,
infection,
and
starvation.
We
refer
to
this
as
the
high
serotonin
hypothesis.
What
constitutes
evidence
of
serotonin
transmission
is
the
key
to
the
evaluation
of
this
hypothesis.
Since
depression
is
a
per-
sistent
state,
reliable
indices
of
stable
serotonin
transmission
are
particularly
relevant.
The
5-HIAA/5-HT
ratio
is
the
most
reliable
index
of
stable
serotonin
transmission,
although
5-HIAA
is
also
used
While
the
literature
on
depressed
patients
is
necessarily
limited
due
to
the
methodological
diffi-
culties
measuring
serotonin
and
5-HIAA
in
the
human
brain,
the
most
pertinent
studies
support
the
high
serotonin
hypothesis.
In
non-human
animal
models
of
depression—where
these
indices
can
be
measured
more
readily—abundant
evidence
supports
the
high
serotonin
hypothesis.
The
primary
challenge
for
the
high
serotonin
hypothesis
is
explaining
how
ADMs,
nearly
all
of
which
rapidly
increase
extra-
cellular
serotonin,
reduce
depressive
symptoms.
Our
second
claim,
discussed
in
Section
crucial
to
resolving
this
paradox.
Specif-
ically,
we
argue
that
the
evolved
function
of
the
serotonergic
system
is
energy
regulation—which
we
define
as
the
coordination
of
metabolic
processes
with
the
storage,
mobilization,
distribution,
production
and
utilization
of
energetic
resources
to
meet
adaptive
demands
In
the
brain
and
throughout
the
body,
serotonin
is
homeostati-
cally
regulated
(
The
energy
regulation
hypothesis
predicts
that
the
homeostatic
equilibrium
level
of
serotonin
transmission
is
elevated
in
situations
that
require
limited
energetic
resources
to
be
reallocated
among
metabolically
expensive
processes:
growth,
reproduction,
physical
activity,
maintenance,
immune
function,
and
cognition.
there
is
a
stable
increase
in
serotonin
transmission
to
the
hypothalamus
in
both
positive
and
negative
mood
states
where
energy
must
be
reallocated
for
prolonged
periods
of
time.
Similarly,
the
effects
of
SSRIs
are
state-dependent.
Depending
on
the
context,
SSRIs
can
increase
or
decrease
anxi-
ety
(
motor
activity
(
anhedonia
(
and
neurotrophin
signaling
(
Thus,
serotonin
cannot
be
simply
described
as
an
‘upper’
or
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
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
165
166
167
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
4
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
Table
2
The
serotonergic
system
and
energy
regulation.
Processes
and
systems
regulated
by
serotonin
Production
of
adenosine
triphosphate
(ATP)
Oxidative
phosphorylation
(slow,
efficient)
Aerobic
glycolysis
(fast,
inefficient)
Energy
storage/mobilization
Insulin,
glucagon,
leptin
secretion
Distribution
of
energetic
resources
Vasoconstriction/vasodilation
Neuronal
activity
Activation/inhibition
Tissue
uptake
All
major
tissues
in
the
body
Metabolically
expensive
processes
Growth
Maintenance
Reproduction
Immune
function
Motor
activity
Cognition
a
‘downer’;
its
symptomatic
effects
depend
on
the
organism’s
state
(i.e.,
whether
it
is
infected,
starving,
satiated,
physically
exhausted,
sexually
exhausted,
etc.).
lists
the
symptoms
of
three
reliably
diagnosed
depressive
states:
sickness
behavior,
starvation
depression,
and
melancholia.
Each
involves
an
altered
balance
between
metabol-
ically
expensive
processes
In
sickness
behavior,
limited
energetic
resources
are
devoted
to
immune
function
at
the
expense
of
growth
and
reproduction.
In
starvation
depression,
energy
is
devoted
to
maintenance
functions
at
the
expense
of
growth,
reproduction,
and
immune
function.
In
melancholia,
there
is
an
upregulation
in
sustained
cognition
at
the
expense
of
growth
and
reproduction.
The
energy
regulation
hypothesis
suggests
serotonin
transmission
is
elevated
in
these
states
to
coordinate
tradeoffs
in
energy
allocation.
In
melancholia,
this
tradeoff
is
coordinated
by
serotonin
transmission
to
various
regions,
including
the
hypothal-
amus,
amygdala,
hippocampus
and
lateral
prefrontal
cortex
(PFC)
In
the
hippocampus
and
lateral
PFC,
the
processes
involved
in
sustained
cognition
are
energetically
expensive
and
can
only
be
sustained
with
aerobic
glycolysis
(the
generation
of
lactate
from
the
metabolism
of
glucose
stored
in
astrocytes).
Our
third
major
claim,
discussed
in
Section
that
the
direct
pharmacological
effects
of
SSRIs
are
not
responsible
for
symptom
reduction.
Rather,
by
rapidly
increasing
extracellular
serotonin,
Table
3
States
in
which
serotonin
transmission
to
the
hypothalamus
is
elevated.
Indices
of
elevated
serotonin
transmission
include
the
ratio
of
5-HIAA
to
serotonin
(5-HIAA/5-
HT),
extracellular
5-HIAA
(5-HIAA),
extracellular
serotonin
(5-HT),
and
activity
of
the
dorsal
raphe
nucleus
(DRN).
‘REM’:
rapid
eye
movement
sleep.
State
Index
References
Infection
5-HIAA/5-HT
Fasting/starvation
5-HIAA,
5-HT
Satiation
5-HIAA,
5-HT
Physical
exhaustion
5-HIAA,
5-HT
Sexual
exhaustion
5-HIAA,
5-HT
Awake
>
REM
DRN
activity
Female
>
male
5-HIAA/5-HT
Proestrus
5-HIAA/5-HT
Cold
>
warm
5-HIAA/5-HT
Fig.
1.
Graphical
representation
of
how
depressed
organisms
make
different
adaptive
trade-offs
in
allocating
limited
energetic
resources.
(The
numbers
are
hypo-
thetical
and
illustrative.)
Relative
to
normal
baseline:
infection
involves
upregulated
immune
function,
while
growth
and
reproduction
are
downregulated
(
in
starvation,
a
higher
proportion
of
ener-
getic
reserves
are
devoted
to
maintenance
(
while
growth,
reproduction,
and
immune
function
are
suppressed
melancholia
involves
an
increase
in
cognition
(Section
and
possibly
immune
function
(
while
growth
and
reproduction
are
down-
regulated
(
SSRIs
cause
a
disruption
in
energy
homeostasis
(the
state-dependent
balance
between
energetically
expensive
processes
that
existed
prior
to
medication),
and
a
worsening
of
symptoms.
For
instance,
in
melancholia,
serotonin
transmission
to
the
PFC
causes
an
increase
in
energetically
expensive
glutamatergic
activity
which
is
exacerbated
during
acute
SSRI
treatment
We
argue
that
symptom
reduction
is
due
to
the
compensatory
changes
made
by
the
brain’s
homeostatic
mechanisms
that
attempt
to
restore
energy
homeostasis
These
compensatory
changes
take
several
weeks
to
develop,
which
explains
why
symptoms
fail
to
alleviate
for
Fig.
2.
The
main
projection
regions
for
elevated
serotonin
transmission
in
rodent
models
of
melancholia
and
the
hypothesized
effects
on
symptoms
(see
Section
Increased
serotonin
trans-
mission
coordinates
multiple
processes
that
promote
sustained
processing
of
the
problem
that
triggered
the
episode:
(1)
Transmission
to
the
amygdala
directs
atten-
tion
to
the
problem
that
triggered
the
episode.
(2)
Transmission
to
the
hippocampus
promotes
changes
in
synaptic
plasticity
involved
in
allocating
working
memory
to
the
triggering
problem,
and
reducing
BDNF
signaling.
(3)
Transmission
to
the
lateral
PFC
is
involved
in
processing
of
the
problem
and
promoting
the
resistance
to
dis-
tracting
stimuli.
(4)
Transmission
to
the
nucleus
accumbens
produces
anhedonia,
which
reduces
the
interest
in
attending
to
alternative
stimuli.
(5)
Transmission
to
the
hypothalamus
downregulates
other
energetically
expensive
processes
(growth,
reproduction)
that
could
draw
limited
resources
away
from
processing
of
the
prob-
lem,
which
probably
contributes
to
many
psychomotor
symptoms
(e.g.,
reduced
eating
and
sexual
activity,
social
withdrawal,
lethargy).
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
201
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
5
Table
4
Energy
consumption
of
different
tissues
in
humans
sheep
as
well
as
the
uptake
of
serotonin
(
metabolism
of
serotonin
these
tissues.
Region
Energy
consumption
Serotonin
Humans
(W/kg)
Sheep
(QO
2
)
5-HT
uptake
in
mice
(ng/g)
5-HIAA
in
rats
(ng/g)
Heart
32.3
–
295
155
Kidney
23.3
27.5
66.3
106
Liver
12.2
8.5
97
50
Gastrointestinal
tract
–
7.7
419
Lungs
6.7
5.4
778
754
Skeletal
muscle
0.5
–
24
–
Spleen
–
6.9
941
165
Skin
0.3
–
18.3
–
Brain
11.2
19.7
10.7
785
several
weeks
after
the
initiation
of
SSRI
treatment
(the
therapeutic
delay).
In
Section
show
how
these
claims
help
explain
what
is
happening
in
non-human
animal
models
of
melancholia
and
dur-
ing
acute
and
chronic
treatment
with
SSRIs.
We
conclude
with
implications
and
suggestions
for
future
research.
2.
Serotonin
is
elevated
in
multiple
depressive
phenotypes
It
is
currently
impossible
to
measure
5-HT
in
the
living
human
brain
because
it
requires
invasive
techniques
Moreover,
serotonin
cannot
cross
the
blood
brain
barrier
so
peripheral
measures
do
not
accurately
reflect
brain
levels.
Some
studies
use
molecular
in
vivo
neuroimaging
techniques
to
attempt
to
infer
changes
in
endogenous
serotonin
levels
These
techniques
can
measure
dynamic
changes
in
neurotrans-
mission
induced
by
pharmacological
or
physiological
challenges
if
radiotracers
measuring
monoamine
receptor
or
transporter
den-
sity
are
sensitive
to
changes
in
endogenous
monoamine
levels
(
This
has
been
successfully
applied
to
the
dopaminergic
system
where
such
ligands
are
available
(
However,
none
of
the
ligands
currently
avail-
able
for
the
serotonin
transporter
and
its
receptors
are
reliable
in
imaging
endogenous
serotonin
levels
Thus,
current
neuroimaging
techniques
cannot
reliably
measure
endogenous
serotonin
levels.
In
non-human
animals,
invasive
techniques
(cyclic
voltam-
metry,
microdialysis)
can
be
used,
but
most
only
measure
extra-
cellular
neurotransmitter
concentrations
Extracellular
concentrations
are
a
poor
index
of
serotonin
transmis-
sion,
which
ideally
requires
the
ability
to
measure
the
rate
at
which
serotonin
is
released
into
the
synapse.
Extracellular
concentrations
Fig.
3.
Hypothetical
serotonin
and
glutamate
patterns
in
projection
regions
(e.g.,
the
lateral
PFC)
over
the
course
of
depression
and
SSRI
treatment.
(A)
Equilibrium
serotonin
and
glutamate
transmission
in
the
non-depressed
state.
(B)
Equilibrium
transmission
of
serotonin
and
glutamate
in
the
depressed
state.
Indirect
evidence
in
humans
suggests
that
the
equilibrium
transmission
of
serotonin
is
elevated
and
this
is
supported
by
abundant
evidence
in
multiple
non-human
animal
models
(e.g.,
One
effect
of
sustained
serotonin
transmission
is
to
activate
cortical
networks,
which
are
primarily
glutamatergic
(
Current
research
suggests
depression
is
associated
with
elevated
glutamatergic
activity
in
many
regions
(C)
During
acute
SSRI
treatment,
blockade
of
the
serotonin
transporter
(SERT)
shifts
the
balance
of
serotonin
into
the
extracellular
compartment.
Extracellular
serotonin
is
therefore
perturbed
above
the
depressed
equilibrium.
Since
SERT
blockade
mimics
the
effects
of
a
sustained
increase
in
serotonin
transmission,
glutamatergic
activity
rises
above
the
depressed
equilibrium
symptoms
often
worsen
(D)
Over
prolonged
(chronic)
SSRI
treatment,
the
brain’s
homeostatic
mechanisms
attempt
to
reverse
the
excess
glutamatergic
activity
by
inhibiting
the
synthesis
of
serotonin,
which
eventually
brings
extracellular
serotonin
back
to
the
depressed
equilibrium
and
tonically
activating
the
5-HT
1A
heteroreceptor
These
homeostatic
responses
reduce
glutamatergic
activity
and
produce
the
antidepressant
response.
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
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
6
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
reflect:
(1)
the
rate
at
which
serotonin
is
released
into
the
synapse
(transmission);
and
(2)
the
rate
at
which
it
is
cleared
from
the
synapse.
Thus,
synaptic
serotonin
can
accrete
without
an
increase
in
serotonin
transmission
(e.g.,
if
SERT
functioning
is
downregu-
lated).
Conversely,
synaptic
serotonin
concentrations
can
decline
despite
elevated
transmission
if
the
rate
of
clearance
is
faster.
Single-unit
recording
techniques
allow
researchers
to
measure
the
rate
of
neuronal
firing
of
individual
neurons,
which
should
gen-
erally
correspond
to
the
rate
of
synaptic
release.
But
neurons
in
midbrain
nuclei
may
release
several
neurotransmitters,
so
single-
unit
recordings
must
be
used
in
conjunction
with
other
techniques
(e.g.,
voltammetry)
to
determine
the
rate
and
type
of
neurotrans-
mitters
that
are
released
In
short,
it
is
often
impractical
to
directly
measure
the
rate
serotonin
is
released
into
the
synapse.
To
deal
with
these
difficulties,
researchers
have
attempted
to
identify
indices
of
sustained
serotonin
transmission
(
This
research
is
particularly
relevant
because
depression
is
more
persistent
than
many
other
emotional
states.
different
indices
of
serotonin
transmis-
sion
to
the
amygdala,
nucleus
accumbens,
and
hypothalamus
in
response
to
electrical
stimulation
of
neurons
in
the
dorsal
raphe
nucleus
(DRN),
which
is
the
primary
source
of
serotonergic
neurons
projecting
to
forebrain
regions.
The
5-HIAA/5-HT
ratio
was
the
only
index
sensitive
to
the
duration
and
frequency
of
electrical
stimu-
lation.
The
effect
was
driven
by
an
increase
in
5-HIAA,
although
there
was
a
non-significant
decrease
in
serotonin.
Consequently,
the
5-HIAA/5-HT
ratio
is
the
most
reliable
index
of
sustained
sero-
tonin
transmission,
although
5-HIAA
can
also
be
used
(
In
the
absence
of
information
on
the
5-HIAA/5-HT
ratio
or
5-
HIAA
levels,
we
rely
on
the
extracellular
concentration
of
serotonin
despite
its
limitations.
2.1.
In
people
We
are
unaware
of
any
evidence
attempting
to
assess
serotonin
transmission
in
humans
during
starvation
depression
or
sickness
behavior.
However,
several
lines
of
evidence
suggest
that
serotonin
transmission
is
elevated
in
patients
with
major
depression.
2.1.1.
Polymorphism
in
the
SERT
gene
The
polymorphism
in
the
promoter
region
of
the
SERT
gene
has
two
major
variants:
the
short
(s)
and
the
long
(l)
alleles
(
The
polymorphism
has
transcriptional
and
functional
consequences,
with
the
s-allele
resulting
in
lower
densities
of
trans-
porter
mRNA
and
protein,
and
slower
clearance
of
serotonin
from
the
synaptic
cleft
By
reducing
serotonin
reup-
take,
the
s-allele
keeps
extracellular
levels
of
serotonin
higher
than
the
l-allele.
Consistent
with
the
high
serotonin
hypothesis,
the
s-
allele
is
associated
with
a
slightly
increased
risk
of
depression
in
response
to
stressors
2.1.2.
5-HIAA
levels
in
the
jugular
vein
The
level
of
5-HIAA
in
the
cerebrospinal
fluid
is
an
unreliable
indicator
of
brain
serotonin
transmission
because
it
is
contami-
nated
by
peripheral
sources
(
However,
the
level
of
5-HIAA
in
the
jugular
vein
is
less
contaminated
because
this
vein
directly
drains
blood
from
the
brain.
In
an
important
study,
a
group
of
Australian
researchers
found
that,
relative
to
non-depressed
con-
trols,
there
was
a
higher
overflow
of
5-HIAA
in
the
jugular
veins
of
human
subjects
who
met
DSM-IV
criteria
for
major
depression
5-HIAA
overflow
decreased
over
12
weeks
of
treatment
with
an
SSRI.
Finally,
among
the
depressed
patients,
5-
HIAA
overflow
was
2.4
times
greater
for
carriers
of
the
s-allele
of
the
serotonin
transporter
polymorphism
than
for
those
who
were
homozygous
for
the
l-allele.
The
authors
concluded
that
the
pat-
tern
of
results
“appear
to
run
counter
to
.
.
.the
conventional
view
that
[major
depression]
is
caused
by
a
relative
reduction
in
brain
monoaminergic
neuronal
activity”
42).
This
study
provides
converging
evidence
of
increased
serotonin
trans-
mission
in
the
brains
of
depressed
patients.
2.1.3.
Tryptophan
depletion
increases
DRN
activity
in
depressed
patients
taking
ADMs
While
tryptophan
depletion
does
not
trigger
depressive
symp-
toms
in
non-depressed
people
it
does
trigger
depressive
symptoms
in
remitted
patients
who
have
currently
or
previously
used
serotonergic
ADMs
In
such
patients,
it
does
not
suppress
DRN
activity,
as
the
low
serotonin
hypothesis
predicts.
Rather,
it
activates
the
DRN
which
is
consistent
with
the
high
serotonin
hypothesis.
Perhaps
tryptophan
depletion
causes
a
local
decrease
in
serotonin
around
the
DRN,
deactivating
the
5-HT
1A
autoreceptor
and
disinhibiting
serotonin
transmission
to
forebrain
regions.
2.1.4.
Increased
preference
for
carbohydrates
in
depression
The
high
serotonin
hypothesis
is
also
supported
less
directly
by
the
increased
preference
depressed
patients
have
for
carbohydrate
over
fat
and
protein
This
preference
for
carbo-
hydrate
rich
food
is
consistent
across
depressed
patients,
regardless
of
the
individual
variability
in
appetite
(i.e.,
increased
or
decreased
appetite).
Moreover,
the
intensity
of
this
preference
correlates
to
the
severity
of
depression
(
The
relative
increase
in
carbohydrates
intake
causes
brain
sero-
tonin
levels
to
increase
(
Upon
carbohydrate
intake,
insulin
levels
increase,
stimulating
the
uptake
of
large
neutral
amino
acids
(LNAAs)—including
valine,
leucine,
and
isoleucine—into
skeletal
muscle
and
out
of
the
bloodstream.
The
exception
is
tryptophan,
which
is
not
taken
up
into
the
skeletal
muscle
along
with
other
LNAAs
because
it
is
the
only
amino
acid
that
binds
to
serum
albumin.
Thus,
while
most
of
the
other
LNAAs
are
in
the
form
of
free
plasma
amino
acids—and
so
readily
taken
up
into
the
muscle
tissue—approximately
80–90%
of
circulating
tryptophan
is
normally
bound
to
serum
albumin
(
until
tryptophan
is
released
during
the
perfusion
of
brain
capillaries.
All
LNAAs
are
in
competition
for
transport
across
the
blood
brain
barrier,
and
by
increasing
the
tryptophan:LNAA
ratio
in
the
blood,
carbohydrates
enhance
the
transport
of
tryptophan
into
brain
tissue
(
Since
tryptophan
is
a
crucial
precursor
of
serotonin,
this
can
increase
serotonin
levels
in
the
brain.
The
low
serotonin
hypothesis
proposes
that
individuals
are
craving
carbohydrates
to
improve
mood
and
seek
relief
in
depres-
sive
symptoms
by
increasing
serotonin
(
However,
if
this
were
true,
then
a
prolonged
increase
in
carbo-
hydrate
intake
should
be
an
effective
treatment
for
depression
by
increasing
the
available
amount
of
serotonin.
Thus,
the
symptoms
of
depressed
patients
on
high
carbohydrate
diets
should
ameliorate
over
time
relative
to
depressed
patients
on
low
carbohydrate
diets.
However,
high
carbohydrate
diets
appear
to
increase
depressive
symptoms
rather
than
reduce
them
More-
over,
in
a
3-week
dietary
intervention,
depressed
patients
with
a
restricted
intake
of
sucrose
and
caffeine,
which
also
increases
extra-
cellular
serotonin
(
experienced
a
persistent
amelioration
in
depressive
symptoms
(
Thus,
it
seems
more
plausible
that
“the
consumption
of
sweet
carbohydrates
may
contribute
to
the
development
and/or
234
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358
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
7
maintenance
of
emotional
distress”
164).
2.1.5.
Tianeptine
The
fact
that
the
antidepressant
tianeptine
has
reuptake-
enhancing
properties
is
consistent
with
the
high
serotonin
hypothesis.
Its
efficacy
in
reducing
depressive
symptoms,
both
short
term
and
long
term,
is
comparable
to
other
ADMs
(
However,
as
with
other
ADMs,
there
is
a
therapeu-
tic
delay
(
Moreover,
the
mechanism
by
which
tianeptine
reduces
symptoms
is
unclear
Despite
its
reuptake-enhancing
properties,
neither
acute
nor
chronic
treatment
with
tianeptine
causes
actual
extracellular
serotonin
levels
to
fall
in
rodents
2.1.6.
Anxiety
Depression
and
anxiety
tend
to
co-occur
Among
people
satisfying
the
current
criteria
for
social
anxi-
ety
disorder,
for
instance,
the
rates
of
major
depression
range
from
36
to
58%.
Conversely,
among
those
with
major
depression,
the
rates
of
social
anxiety
range
from
20
to
45%.
If
subclinical
symptoms
were
to
be
included,
the
rates
of
co-occurrence
would
be
higher.
While
depression
is
co-morbid
with
many
conditions,
the
associ-
ation
with
anxiety
is
unique
because
multiple
studies
of
human
twins
have
found
that
depression
and
anxiety
have
virtually
iden-
tical
genetic
architectures
(
We
should
therefore
expect
that
genetic
variants
in
the
serotonergic
system
should
affect
the
risk
of
depression
and
anxiety
in
the
same
direc-
tion.
Indeed,
the
s-allele
in
the
serotonin
transporter
polymorphism
is
associated
with
an
increased
risk
of
anxiety
as
well
as
depression
in
humans
(
Further
evidence
that
depression
and
anxiety
bear
the
same
direction
of
association
with
serotonin
comes
from
another
inter-
nal
jugular
venous
sampling
study
from
the
Australian
group
They
found
a
4-fold
increase
in
5-HIAA
in
patients
diagnosed
with
panic
disorder
compared
to
healthy
subjects.
They
also
found
a
strong
positive
correlation
between
5-HIAA
and
the
severity
of
symptoms,
as
well
as
reduced
5-HIAA
with
chronic
SSRI
administration.
The
authors
suggested
that
the
increase
in
whole
brain
serotonin
turnover
in
patients
with
panic
disorder
“most
likely
derived
not
from
impaired
serotonin
reuptake,
but
from
increased
firing
in
serotonergic
midbrain
raphe
neurons
pro-
jecting
to
both
subcortical
brain
regions
and
the
cerebral
cortex”
(p.
295).
Indeed,
many
researchers
consider
anxiety
to
be
a
state
of
ele-
vated
serotonin
transmission
(
2.2.
In
non-human
animal
models
Further
support
for
the
high
serotonin
hypothesis
is
garnered
from
non-human
animal
models
of
depression,
including
stressor,
genetic,
and
lesion
models.
2.2.1.
Stressor
models
2.2.1.1.
Starvation.
Starvation
triggers
depressive
symptoms
in
humans
(
During
periods
of
fasting
and
starvation,
extracellular
5-HIAA
and
serotonin
increase
in
the
hypothalamus
During
prolonged
star-
vation,
the
ability
to
synthesize
serotonin
could
be
reduced
by
a
lack
of
dietary
tryptophan.
However,
the
metabolism
of
muscle
tissue
could
liberate
tryptophan
to
replace
declining
serotonin
lev-
els.
In
arctic
charr,
serotonin
declined
in
the
telencephalon
under
four
weeks
of
starvation,
but
the
5-HIAA/5-HT
ratio
was
unal-
tered
(
Since
body
weight
declined
by
nearly
20%,
we
suggest
that
muscle
metabolism
during
starvation
helps
maintain
serotonin
transmission.
To
help
maintain
extracellular
serotonin
levels,
the
starving
brain
also
appears
to
downregulate
the
density
of
the
serotonin
transporter
(
2.2.1.2.
Infection
and
immune
challenge.
Infection
also
triggers
depressive
symptoms
(
During
immune
challenge,
the
5-HIAA/5-HT
ratio
is
elevated
in
the
hypothalamus
(
and
remains
elevated
while
the
organism
is
sick
The
5-HIAA/5-HT
ratio
is
elevated
in
the
hippocampus
as
well
By
themselves,
pyrogenic
cytokines
also
increase
serotonin
transmission.
IL-1

has
been
found
to
increase
5-HIAA
in
the
PFC,
nucleus
accumbens
and
hippocampus
while
IL-6
has
been
found
to
increase
the
5-HIAA/5-HT
ratio
in
the
brain
stem,
hypothalamus
and
striatum
2.2.1.3.
Inescapable
shock.
Inescapable
shock
is
a
common
rodent
model
of
depression,
and
it
increases
extracellular
serotonin
in
the
medial
PFC
ventral
hippocampus
and
dor-
sal
periaqueductal
gray
basolateral
amygdala
(
and
nucleus
accumbens
(
Inescapable
shock
also
increases
the
activity
of
serotonergic
neu-
rons,
as
indexed
by
c-Fos
expression
suggesting
that
the
increase
in
extracellular
serotonin
is
caused
by
an
increase
in
transmission.
Since
the
5-HIAA/5-HT
ratio
is
our
main
index
of
serotonin
transmission,
it
is
perhaps
more
telling
that
inescapable
shock
increases
this
ratio
across
many
regions,
including
the
locus
coeruleus,
brain
stem,
thalamus,
hypothalamus,
striatum,
frontal
cortex,
and
hippocampus
2.2.1.4.
Chronic
social
defeat.
In
rats,
chronic
social
defeat
has
been
found
to
increase
extracellular
serotonin
in
the
DRN
(
5-HIAA
levels
in
the
amygdala
and
hippocampus,
and
the
5-HIAA/5-HT
ratio
in
the
midbrain
and
hypothalamus
(
In
mice,
chronic
social
defeat
has
been
found
to
increase
the
5-HIAA/5-HT
ratio
in
the
hypothalamus
and
hip-
pocampus
(
2.2.1.5.
Chronic
mild
stress.
In
chronic
mild
stress,
serotonin
trans-
mission
(as
indexed
by
5-HIAA
or
the
5-HIAA/5-HT
ratio)
is
elevated
in
many
regions,
including
the
PFC,
hypothalamus,
hippocampus,
and
amygdala
2.2.1.6.
Chronic
restraint
stress.
Chronic
restraint
stress
also
shows
evidence
of
elevated
serotonin
transmission
in
some
regions,
although
there
are
also
many
null
effects
(
The
mixed
evidence
is
probably
due
to
the
fact
that
rodents
are
more
likely
to
habituate
to
chronic
restraint
than
other
models,
thereby
lessening
its
depressogenic
impact
(
2.2.1.7.
Maternal
separation
and
social
isolation.
Some
depression
models
involve
examining
how
rodents
respond
to
a
stressor
after
having
been
raised
apart
from
their
mothers
or
in
social
isolation.
In
a
study
using
this
paradigm,
there
were
no
differences
in
serotonin
transmission
between
maternally
separated
rats
and
control
rats
at
baseline
(
However,
after
exposure
to
a
restraint
stressor,
the
maternally
separated
rats
had
a
higher
5-HIAA/5-HT
ratio
in
the
frontal
cortex
and
hypothalamus,
and
5-HIAA
levels
were
elevated
in
the
frontal
cortex
and
hippocampus.
Brush-tailed
rats
(Octodon
degus)
raised
in
social
isolation
show
increased
innervation
of
serotonergic
fibers
to
the
infralimbic
region
of
the
mPFC
Hooded
Lister
rats
raised
in
social
isolation
also
showed
an
increase
in
serotonin
release
(as
359
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Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
8
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
measured
by
voltammetry
and
microdialysis)
in
the
frontal
cor-
tex
in
response
to
KCl
and
fenfluramine
(
and
an
increase
in
extracellular
serotonin
in
the
nucleus
accumbens
in
response
to
a
conditioned
stress
paradigm
2.2.1.8.
Neonatal
SSRI
exposure.
Interestingly,
neonatal
exposure
to
SSRIs
is
a
model
of
depression
that
is
also
consistent
with
the
high
serotonin
hypothesis.
Adult
rats
exposed
to
SSRIs
as
neonates
show
increased
serotonin
transmission
(indexed
by
the
5-HIAA/5-
HT
ratio)
in
the
hypothalamus
(
and
exhibit
a
depressive
behavioral
profile
2.2.2.
Genetic
models
2.2.2.1.
The
Flinders
Sensitive
Line.
In
the
Flinders
Sensitive
Line
rat,
a
breed
that
exhibits
many
depressive
symptoms
sero-
tonin
and
5-HIAA
levels
are
elevated
in
the
PFC,
hippocampus
and
other
regions
relative
to
control
rats
(
2.2.2.2.
The
congenital
learned
helplessness
breed.
We
have
been
unable
to
find
any
evidence
on
serotonin
transmission
in
rats
bred
for
congenital
learned
helplessness.
We
predict
that
the
5-
HIAA/5-HT
ratio
will
be
elevated
in
multiple
regions,
particularly
the
hypothalamus,
PFC
and
hippocampus.
2.2.2.3.
SERT
and
5-HT
1A
knockouts.
Rodents
that
have
had
the
genes
for
SERT
or
the
5-HT
1A
receptor
knocked
out
express
higher
levels
of
depressive
symptoms
(
Consistent
with
the
high
serotonin
hypothesis,
5-HT
1A
knockouts
were
found
to
have
higher
5-HIAA
levels
in
multiple
brain
regions,
including
the
olfactory
bulb,
subs-
tantia
nigra,
thalamus,
locus
coeruleus,
and
the
dorsal
and
medial
raphe
nuclei
While
there
are
differences
in
the
levels
of
serotonin
and
5-HIAA
in
SERT
knockout
mice
and
SERT
knockout
rats
the
ratio
of
5-HIAA/5-HT
is
ele-
vated
in
multiple
brain
regions
in
both
species
(
2.2.3.
Lesion
models
2.2.3.1.
Olfactory
bulbectomy.
Olfactory
bulbectomy
is
the
only
model
of
depression
to
show
reduced
a
5-HIAA/5-HT
ratio
in
multi-
ple
brain
regions
(
This
is
because
olfactory
bulbectomy
causes
DRN
neurons
to
degenerate
so
there
is
less
capacity
to
transmit
serotonin
However,
it
is
possible
that
the
remaining
DRN
neurons
transmit
serotonin
at
a
heightened
rate,
which
would
be
consistent
with
the
high
sero-
tonin
hypothesis.
Indeed,
there
is
an
increase
in
the
innervation
of
serotonin
fibers
and
the
synthesis
of
serotonin
in
cortical
and
limbic
regions
following
olfactory
bulbectomy
2.2.3.2.
Lesion
of
the
DRN.
Lesion
of
the
DRN
is
not
a
model
of
depression,
which
is
problematic
for
the
low
serotonin
hypothesis.
For
instance,
rats
with
electrolytic
lesion
of
the
DRN
were
less
anhe-
donic
(assessed
by
intake
of
a
sucrose
solution)
than
sham-operated
controls
(
Given
the
state-dependent
effects
of
serotonin,
we
do
not
expect
DRN
lesion
to
have
simple
effects
on
depressive
symptoms.
But
DRN
lesion
should
inhibit
the
production
of
depressive
symptoms
in
response
to
depressogenic
stressors.
Indeed,
DRN
lesion
inhibits
the
development
of
depres-
sive
symptoms
in
the
inescapable
shock,
chronic
social
defeat,
and
chronic
mild
stress
models
(
2.3.
Summary
In
humans,
the
strongest
evidence
that
serotonin
transmis-
sion
is
elevated
in
depression
and
anxiety
comes
from
the
jugular
sampling
studies
of
5-HIAA,
which
is
a
commonly
used
index
of
sustained
serotonin
transmission.
This
is
strongly
supported
by
the
numerous
studies
in
non-human
animal
models
demonstrating
elevations
in
5-HIAA/5-HT,
5-HIAA,
and
even
extracellular
sero-
tonin
in
many
brain
regions.
The
principle
challenge
to
the
high
serotonin
hypothesis
is
the
fact
that
the
direct
pharmacological
properties
of
most
antidepres-
sants
increase
extracellular
serotonin,
most
commonly
by
SERT
blockade.
We
argue
that
this
puzzle
cannot
be
resolved
without
understanding
the
evolved
function
of
the
serotonergic
system,
to
which
we
now
turn.
3.
The
energy
regulation
function
of
the
serotonergic
system
In
this
section
of
the
paper,
we
propose
a
novel
hypothesis
for
the
evolved
function
of
the
serotonergic
system,
which
includes
serotonin,
its
receptors,
SERT,
and
other
components
that
help
reg-
ulate
serotonin
or
its
effects.
Our
hypothesis
owes
much
to
the
research
of
Efrain
Azmitia
on
the
evolution
of
serotonin
(
One
of
our
novel
contributions
is
to
explicitly
identify
the
evolution
of
the
mitochondrion
as
the
likely
point
on
the
tree
of
life
where
serotonin
evolved.
This
key
fact
helped
shape
our
energy
regulation
hypothesis
for
the
serotonergic
system.
3.1.
Overview
of
the
serotonergic
system
In
the
brain,
the
dorsal
raphe
nucleus
(DRN)
is
the
main
source
of
serotonergic
neurons
that
project
to
forebrain
regions
(
Tryptophan
is
the
crucial
precursor
used
to
synthesize
serotonin.
Animals
cannot
synthesize
tryptophan,
so
they
must
acquire
it
from
their
diet
(
and
it
goes
through
three
main
metabolic
pathways:
(1)
protein
synthesis;
(2)
the
kynure-
nine
pathway;
and
(3)
the
serotonin
pathway.
Of
the
tryptophan
not
used
in
protein
synthesis,
99%
goes
down
the
kynurenine
pathway
(
The
remaining
1%
is
con-
verted
to
serotonin
in
two
steps.
First,
tryptophan
is
converted
to
5-hydroxytryptophan
by
tryptophan
hydroxylase.
Second,
5-
hydroxytryptophan
is
converted
to
serotonin
by
aromatic
l-amino
acid
decarboxylase
(AADC).
There
are
no
enzymes
for
breaking
down
serotonin
in
the
extracellular
space
so
it
must
be
transported
inside
the
cell.
Most
extracellular
serotonin
is
transported
into
the
pre-synaptic
neuron
by
SERT
(
Serotonin
is
primarily
broken
down
to
5-HIAA
by
the
monoamine
oxidase
A
(MAO-A)
enzyme,
which
is
located
in
mitochondria.
SERT
is
widely
expressed
throughout
the
body
In
the
periphery,
SERT
is
commonly
expressed
in
many
organs
that
take
up
serotonin
from
the
bloodstream
Several
aspects
of
the
serotonergic
system
contribute
to
the
abil-
ity
to
produce
diverse
state-dependent
effects.
First,
the
DRN
has
several
anatomically
distinct
subdivisions
(
which
can
cause
differential
transmission
to
forebrain
regions.
For
instance,
activation
of
the
caudal
and
dorsal
DRN
has
anxiogenic
effects,
while
activation
of
the
ventrolateral
DRN/ventrolateral
periaqueductal
gray
has
anxiolytic
effects
(
Second,
the
large
number
of
serotonin
receptors
arguably
gives
the
serotonergic
system
greater
regulatory
flexibility
than
any
other
neurotransmitter
system
in
the
brain.
There
are
14
sero-
tonin
receptors
that
fall
into
seven
classes
(
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595
Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
9
The
5-HT
1
and
5-HT
5
classes
are
inhibitory,
while
the
5-
HT
2
,
5-HT
3
,
5-HT
4
,
5-HT
6
and
5-HT
7
classes
are
excitatory.
Multiple
serotonin
receptor
types
are
commonly
co-expressed
on
a
variety
of
cells
throughout
the
brain
and
the
periphery
Serotonin
receptors
can
also
form
homodimers
and
heterodimers,
the
functional
consequences
of
which
are
not
fully
understood
The
complex
control
that
can
be
achieved
with
the
diversity
of
receptor
function
supports
the
role
of
the
serotonin
system
in
energy
regulation.
Third,
the
temporal
firing
patterns
of
serotonergic
neurons
may
have
different
postsynaptic
effects.
For
instance,
prolonged
expo-
sure
to
serotonin
(but
not
other
neurotransmitters)
can
cause
phasically
firing
neurons
to
transition
to
a
repetitive,
prolonged
(tonic)
firing
pattern
A
sustained
increase
in
serotonin
transmission
has
a
similar
excitatory
effect
on
cortical
networks
in
the
PFC
(
5-HT
2A
receptors
mediate
the
tonic
increase
in
glutamatergic
activity
while
5-HT
2A/2C
receptors
mediate
the
tonic
increase
in
motorneuron
activity
3.2.
The
evolution
of
serotonin
in
mitochondria
It
is
very
likely
that
serotonin
evolved
in
mitochondria
or
their
immediate
ancestors.
First,
serotonin
is
found
in
plants,
animals,
and
fungi,
so
the
latest
it
could
have
evolved
was
in
the
unicellular
eukaryotic
precursor
to
multicellular
organisms,
which
is
about
one
billion
years
ago
Second,
the
synthesis
of
serotonin
requires
oxygen
which
is
also
important
in
mito-
chondrial
function.
Third,
MAO-A
is
localized
to
the
inner
surface
of
the
outer
mitochondrial
membrane
which
suggests
a
mitochondrial
origin
because
serotonin
must
be
inside
the
mitochondrion
to
be
metabolized.
Indeed,
the
mitochondrion
may
be
the
most
common
intracellular
location
of
serotonin
(
and
at
least
some
mitochondria
contain
the
enzymes
for
synthesizing
serotonin
Surprisingly,
the
genes
for
the
synthesizing
enzymes
are
not
located
in
the
mitochondrial
genome
(
but
in
the
nuclear
genome
How
could
serotonin
evolve
in
mitochondria
if
the
genes
for
the
synthe-
sizing
enzymes
are
not
located
in
the
mitochondrial
genome?
Of
particular
importance
is
AADC,
which
catalyzes
the
final
step.
AADC
belongs
to
a
class
of
enzymes
called
pyridoxal
phos-
phate
(PLP)-dependent
carboxylase
enzymes
Mitochondria
and
PLP-dependent
carboxylases
have
a
common
phylogenetic
origin.
Mitochondria
evolved
approximately
2
billion
years
ago
from
an
␣-proteobacterium
that
formed
an
endosymbi-
otic
relationship
with
an
ill-defined
larger
bacterium
(
Similarly,
PLP-dependent
carboxylases
evolved
from
␣-
proteobacteria
(
Thus,
AADC
evolved
from
the
PLP-dependent
carboxylase
precursor,
proba-
bly
in
the
mitochondrion.
As
mitochondria
evolved
and
became
more
integrated
with
the
endosymbiotic
host,
some
mitochondrial
genes
were
lost,
and
some
were
transferred
to
the
nuclear
genome
During
this
process,
the
AADC
gene
was
transferred
to
the
nuclear
genome
and
deleted
from
the
mitochondrial
genome
(
3.3.
The
mitochondrial
functions
of
serotonin
What
does
serotonin
do
in
mitochondria?
Serotonin
increases
the
potential
across
the
inner
mitochondrial
membrane,
although
the
precise
mechanisms
by
which
this
is
achieved
are
unknown
(
Serotonin
may
affect
mitochondrial
function
as
the
precursor
to
melatonin.
Mitochondria
have
the
enzymes
that
convert
serotonin
to
melatonin,
and
melatonin
increases
the
efficiency
of
energy
production
by
accelerating
electron
transport
(
Electron
transport
generates
reactive
oxygen
and
nitrogen
species
that
can
damage
the
mitochondrion
and
other
cel-
lular
structures
and
serotonin
and
melatonin
both
have
powerful
antioxidant
properties
(
3.4.
What
is
the
function
of
the
serotonergic
system?
The
serotonergic
system
affects
so
many
processes
that
some
researchers
despair
of
ever
identifying
a
unifying
function.
Based
on
the
foregoing,
serotonin
probably
evolved
first
to
regulate
mito-
chondrial
activity.
This
function
could,
in
principle,
affect
every
major
system,
organ,
and
metabolic
process
in
the
body.
Moreover,
it
is
so
important
that
it
is
highly
likely
that
any
subsequent
func-
tions
of
the
serotonergic
system
were
at
least
consistent
with
this
original
function,
and
probably
facilitate
it
(for
a
similar
point,
see
Mitochondria
face
adaptive
challenges
within
multicellular
organisms,
and
the
serotonergic
system
could
have
evolved
to
solve
these
problems.
Multicellular
organisms
are
composed
of
special-
ized
cells
with
different
functions
that
respond
to
environmental
contingencies,
and
these
responses
depend
on
ATP
produced
by
mitochondria
(or
glycolysis
in
the
cytosol).
Multicellular
organisms
must
therefore
coordinate
the
distribution
of
important
energetic
resources
(glucose,
fatty
acids,
amino
acids)
throughout
the
organ-
ism
with
regional
mitochondrial
activity
patterns.
We
propose
that
the
serotonergic
system
evolved
to
promote
energy
regulation,
which
we
define
as
the
coordination
of
metabolic
processes
with
the
distribution
and
utilization
of
limited
energetic
resources
to
meet
adaptive
demands.
Other
prominent
hypotheses
for
serotonin
propose
that
it
evolved
to
promote
homeostasis
or
phenotypic
plasticity
While
it
is
undeniable
that
serotonin
can
affect
homeostasis
and
phenotypic
plasticity,
this
is
true
of
all
biochemicals:
it
makes
little
sense
to
single
out
the
serotonergic
system
for
these
functions.
However,
the
seroto-
nergic
system
is
unique
in
that
it
can
simultaneously
coordinate
the
production,
storage,
mobilization,
distribution,
and
utilization
of
energy.
Arguably,
no
other
biochemical
system
in
the
body
can
do
this.
3.4.1.
Serotonin
and
energy
regulation
3.4.1.1.
Glucose
metabolism.
Serotonin
regulates
the
two
major
metabolic
pathways
for
generating
ATP
from
glucose.
In
addition
to
affecting
electron
transport
in
mitochondria
(oxidative
phosphory-
lation),
serotonin
can
upregulate
or
downregulate
the
production
of
ATP
from
glucose
in
the
cytosol
from
glycolysis
(
This
process
is
often
called
aerobic
glycolysis
because
it
can
take
place
in
the
presence
of
oxygen,
even
though
it
does
not
use
oxy-
gen.
Oxidative
phosphorylation
is
more
efficient
because
it
extracts
more
molecules
of
ATP
from
every
molecule
of
glucose,
but
aerobic
glycolysis
is
rapid
and
generates
ATP
at
a
faster
rate
than
oxida-
tive
phosphorylation
(
In
addition
to
being
faster,
glycolysis
may
produce
less
reactive
oxygen
species
that
can
harm
the
cell
or
the
mitochondrion
(
In
the
brain,
aerobic
glycolysis
involves
the
breakdown
of
glycogen
stored
in
astrocytes,
which
then
transport
the
endproduct
(lactate)
to
neurons
that
preferentially
use
it
as
a
fuel
source
(
In
astrocytes,
serotonin
regulates
aerobic
glycolysis
through
the
5-HT
1A
heteroreceptor
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Please
cite
this
article
in
press
as:
Andrews,
P.W.,
et
al.,
Is
serotonin
an
upper
or
a
downer?
The
evolution
of
the
serotonergic
system
and
its
role
in
depression
and
the
antidepressant
response.
Neurosci.
Biobehav.
Rev.
(2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.01.018
ARTICLE IN PRESS
G Model
NBR
2124
1–25
10
P.W.
Andrews
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
xxx
(2015)
xxx–xxx
3.4.1.2.
Blood
glucose
homeostasis.
Serotonin
has
bidirectional
con-
trol
over
glucose
homeostasis
in
the
bloodstream
by
regulating
glucagon
and
insulin
secretion
from
pancreatic
cells
(
3.4.1.3.
Lipid
storage
and
metabolism.
Serotonin
also
has
bidirec-
tional
control
over
the
homeostatic
regulation
of
stores
of
body
fat
through
the
leptin
signaling
pathways
involved
in
lipid
metabolism
3.4.1.4.
The
vascular
system.
Serotonin
also
exerts
control
over
the
vascular
system.
While
mainly
known
for
its
vasoconstrictive
prop-
erties,
serotonin
is
also
a
vasodilator
(
which
gives
it
bidirectional
control
over
the
distribution
of
energetic
resources.
Serotonin
also
regulates
vascular
networks
in
plants
and
future
research
should
test
whether
serotonin
has
a
similar
function
in
fungal
hyphae.
3.4.1.5.
Neuronal
activity.
Neurons
are
major
consumers
of
energy
in
the
brain,
and
serotonin
exerts
complex
bidirectional
effects
on
neuronal
growth,
differentiation,
and
death
(
Moreover,
inhibitory
and
excitatory
serotonin
receptors
are
often
co-expressed
on
cholinergic,
glutamatergic,
GABAergic,
dopami-
nergic,
and
motor
neurons,
so
serotonin
also
has
bidirectional
control
over
neuronal
activity
3.4.1.6.
Organ
function.
Many
organs
have
large
energetic
demands,
and
serotonin
is
either
produced
or
taken
up
from
the
bloodstream
by
every
major
organ
in
the
body
(
Indeed,
the
uptake
of
serotonin
in
lung
tissue,
platelet
cells,
and
chromaffin
granules
of
the
adrenal
medulla
is
positively
correlated
with
the
level
of
ATP
production
in
those
tissues
(
3.4.1.7.
Metabolically
expensive
processes.
Serotonin
also
controls
the
expenditure
of
energy
by
regulating
metabolically
expensive
processes—growth,
development,
reproduction,
immune
function,
and
the
stress
response
(
probably
by
affecting
hypothalamic
function.
The
hypothalamus
regulates
the
timing
and
coordination
of
these
processes
(
and
it
con-
tains
some
of
the
highest
concentrations
of
serotonin
in
the
brain
Important
metabolic
processes
are
disturbed
when
serotonin
transmission
is
disrupted.
For
instance,
monoamine
transmis-
sion
to
the
hypothalamus
is
completely
inhibited
in
REM
sleep
During
this
time,
important
physiological
parameters
also
become
less
regulated—blood
pressure,
heart
rate,
breathing
and
body
temperature
Despite
this,
the
brain’s
total
energy
consumption
during
REM
sleep
is
nearly
the
same
level
as
during
the
awake
state
Similarly,
Kanarik
and
colleagues
have
found
that
serotonergic
lesions
induced
by
the
neurotoxin
para-
chloroamphetamine
trigger
a
compensatory
response
28
days
later
in
which
cytochrome
oxidase
c
expression
was
increased
in
mul-
tiple
regions
of
the
rat
brain
(
Together,
both
lines
of
evidence
suggest
serotonin
increases
the
energetic
efficiency
of
metabolic
processes.
3.4.2.
The
homeostatic
equilibrium
level
of
serotonin
transmission
is
increased
in
situations
requiring
a
rebalancing
of
metabolically
expensive
processes
Based
on
the
foregoing,
we
propose
that
the
homeostatic
equi-
librium
level
of
serotonin
transmission
increases
in
situations
that
require
a
shift
in
the
balance
of
metabolically
expensive
processes
to
adaptively
respond
to
environmental
contingencies.
The
hypo-
thalamus
should
be
a
common
site
of
increased
transmission
due
to
its
role
in
coordinating
these
processes.
In
a
recent
study,
muscle
glycogen
levels
were
depleted
by
82–90%
in
adult
male
rats
during
exhaustive
exercise,
while
brain
glycogen
levels
decreased
by
50–64%.
During
recovery,
glycogen
reserves
were
replenished
through
a
supercompensatory
response
Interestingly,
during
exercise
there
is
an
increase
in
serotonin
transmission
to
the
hypothalamus
and
other
brain
regions
Another
study
found
that
sero-
tonin
levels
in
the
lateral
hypothalamus
increase
during
exercise
and
return
to
baseline
during
recovery
which
mirrors
what
happens
to
glycogen
levels.
Indeed,
ele-
vated
serotonin
levels
during
exercise
are
associated
with
fatigue
an
indicator
of
energetic
stress.
We
suggest
that
serotonin
is
elevated
during
exercise
because
the
fall
in
glyco-
gen
forces
a
reprioritization
in
energy
allocation.
During
recovery,
serotonin
levels
fall
as
glycogen
is
replenished
and
allocation
pat-
terns
normalize.
The
association
with
energetic
stress
is
not
limited
to
negative
situations.
Male
rats
become
unresponsive
to
new
mating
opportu-
nities
for
nearly
two
days
after
about
3.5
h
of
ad
libitum
copulation
with
successive
estrous
females
(
The
most
likely
reason
for
the
unresponsiveness
is
the
depletion
of
viable
sperm.
Since
spermatogenesis
is
energetically
expensive
(
sperm
depleted
males
must
devote
less
energy
to
mating
effort
and
devote
more
to
sper-
matogenesis.
During
the
period
of
sexual
exhaustion,
serotonin
is
elevated
in
the
hypothalamus
and
returns
to
baseline
as
sex-
ual
responsiveness
resumes
Consistent
with
the
role
of
serotonin
in
rebalanc-
ing
metabolically
expensive
processes,
elevated
serotonin
levels
in
the
hypothalamus
promote
spermatogenesis
inhibit
mating
behavior
In
short,
the
effects
of
enhanced
serotonin
transmission
are
state-dependent.
Physical
exhaustion,
sexual
exhaustion,
and
many
other
states
show
evidence
of
enhanced
serotonin
trans-
mission
yet
their
symptom
profiles
differ
in
important
ways.
Under
the
energy
regulation
hypothesis,
state-dependence
is
expected
because
situational
demands
determine
how
energy
should
be
adaptively
reallocated.
State-dependence
can
explain
some
inconsistent
findings.
Homberg
and
colleagues
have
shown
that
the
serotonergic
system
affects
rodents’
cognitive
flexibility,
including
reversal
learning,
attentional
set
shifting,
the
ability
to
form
and
update
represen-
tations
of
stimulus-reward
or
response-reward
contingencies,
the
inhibition
of
inappropriate
responses,
and
the
ability
to
post-
pone
immediate
reward
for
a
larger
delayed
reward
(
They
argue
that
the
serotonergic
system
integrates
past
learning
with
incoming
information
from
the
environment
to
regulate
attention,
focusing
on
the
processing
of
stimuli
most
relevant
to
the
organism’s
survival
and
reproduc-
tion
(‘vigilance
behavior’).
Their
hypothesis
is
consistent
with
a
larger
body
of
evidence
implicating
the
serotonergic
system
in
learning
and
memory
systems
However,
the
direction
of
association
is
unclear,
with
some
studies
reporting
a
positive
association
between
cognitive
flexibility
and
serotonin
transmission,
and
other
studies
reporting
a
negative
association
The
bidirectional
findings
are
explicable
by
the
hypothesis
that
the
serotonergic
system
is
part
of
the
adap-
tive
energy-regulation
machinery
that
balances
cognition
with
other
metabolically
expensive
processes—growth,
maintenance,
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