Neuropharmacology 61 (2011) 355e363

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Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Serotonin transporter and memory

Alfredo Meneses a, *, Georgina Perez-Garcia a, Teresa Ponce-Lopez a, Ruth Tellez a, Carlos Castillo b
a
Depto. de Farmacobiología, CINVESTAV-IPN, Tenorios 235, Granjas Coapa, Mexico City 14330, Mexico
b
Escuela Superior de Medicina del IPN, Mexico City, Mexico

a r t i c l e i n f o a b s t r a c t

Article history: The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to
Received 1 October 2010 memory. Therefore, we made an attempt to summarize and discuss the available publications implicating
Received in revised form the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that
15 December 2010
Alzheimer’s disease and drugs of abuse like d-methamphetamine (METH) and (þ/)3,4-methyl-
Accepted 10 January 2011
enedioxymethamphetamine (MDMA, “ecstasy”) have been associated to decrements in the SERT
expression and memory deficits. Several reports have indicated that memory formation and amnesia
Keywords:
affected the SERT expression. The SERT expression seems to be a reliable neural marker related to
Serotonin
Transporter
memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular
Memory mechanisms associated to these changes are of great importance for investigation.
Amnesia This article is part of a Special Issue entitled ‘Serotonin: The New Wave’.
AD Ó 2011 Elsevier Ltd. All rights reserved.
Schizophrenia
Drugs
Autoshaping
Memory tasks
Rats
Humans

1. Introduction & learning” in the PuBmed resulted into only 77 publications of

In the last few years, serotonin (5-hydroxytryptamine, 5-HT) has
become one of the neurotransmission systems which engaged
growing interest in the area of learning and memory (for recent
reviews see e.g., Bert et al., 2008; Dayan and Huys, 2009; Eagle
et al., 2008; Francis, 2008; Gold, 2008; King et al., 2008;
Mendelsohn et al., 2009; Ogren et al., 2008; Perez-Garcia and
Meneses, 2008; Robbins and Roberts, 2007; Terry et al., 2008).
Evidence indicates that brain areas implicated in these cognitive
processes (Zola-Morgan and Squire, 1993) receive 5-HT pathways
(Jacobs and Azmitia, 1992; Steinbush, 1984), including the
prefrontal cortex, hippocampus, amygdala, etc (Meneses, 1999).
5-HT exerts its influence via 14 receptors, which have been char-
acterized genetically, pharmacologically and functionally (Fink and
Göthert, 2007; Hannon and Hoyer, 2008) and the reuptake of 5-HT
synaptic levels is regulated by 5-HT transporter “SERT” (see e.g.,
Hensler, 2006; Kalueff et al., 2010; Murphy et al., 2008). While the
number of publications about 5-HT receptors and memory is
growing, the wording “SERT & memory or serotonergic transporter
* Corresponding author. Tel.: þ52 55 54832869; fax: þ52 55 54832863.
E-mail address: ameneses@msn.com (A. Meneses).
which 7 are reviews (November, 2010) stressing out the limited
publication on this subject; but growing interest (see e.g., February,
3, 2011: 122 publications, including 14 reviews).
The SERT is localized on terminals of 5-HT neurons, ensures the
recapture of 5-HT and is the pharmacological target of selective
reuptake inhibitors (SSRIs) mainly used as antidepressants (Baudry
et al., 2010). The SERT has been implicated in diverse functions (e.g.,
neuroendocrine, sleep, body temperature, etc.) and diseases (e.g.,
obsessiveecompulsive disorder, depression, bipolar disorder,
motor abnormalities, etc.) (see e.g., Caligiuri and Buitenhuys, 2005;
Murphy et al., 2008). The SERT has been used as an index of
integrity of the axon terminals of brain serotonergic neurons
(Buchert et al., 2006). The lack of SERT in brain areas such as the
neocortex, hippocampus, amygdala and cingulate cortex has been
associated to lobus pallidus hyper-innervated and greater levels of
5-HT axonal markers (Selvaraj et al., 2009). 5-HT has been impli-
cated in Alzheimer’s disease (AD), for instance SERT expression was
decreased in patients with AD into several brain areas (see below).
In addition, pharmacological and genetic manipulations of the SERT
are known to modify memory performance in human and rodents
(see e.g., Chow et al., 2007; Meneses, 1999, 2002, 2007b; Monleón
et al., 2008; Savaskan et al., 2008). Emerging evidence indicates
that learning and memory modify the SERT expression. Hence,

0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropharm.2011.01.018
356 A. Meneses et al. / Neuropharmacology 61 (2011) 355e363
in this review an attempt was made to summarize and discuss
available evidence about the interaction between SERT and
memory, with focus on disorders such as AD as well as on phar-
macological and genetic manipulations of SERT. As the SERT
expression is affected by several drugs of abuse (e.g., metham-
phetamine, ecstasy), which seem to be associated to memory
deficits (see e.g., Chummun et al., 2010; McCann et al., 2008;
Thomasius et al., 2006 for reviews), hence the role of the SERT
expression in amnesia models induced by these drugs is also dis-
cussed. Although the focus of this review is the SERT, it should be
noted that AD is associated with changes in a variety of 5-HT
markers (see e.g., King et al., 2008; Meneses, 1999; Meneses and
Perez-Garcia, 2007; Terry et al., 2008) as in MDMA-induced 5-HT
neurotoxicity (see below).
2. Alzheimer’s disease and SERT
Probably the most known neurological alteration associated to
memory deficit is the AD. The most commonly recognized
symptom in the early stages of AD is memory loss, such as diffi-
culty in remembering recently learned facts. As the disease
advances, more symptoms arise like confusion, irritability and
aggression, mood swings, language breakdown, long-term
memory loss, and the general withdrawal of the sufferer as their
senses decline (Arnsten and van Dyck, 1997; Meltzer et al., 1998;
Michelsen et al., 2008). AD has also been related to the SERT (for
reviews see Arnsten and van Dyck, 1997; Azmitia and Whitaker-
Azmitia, 1997; Meltzer et al., 1998; Solodkin and van Hoesen,
1997; Smith and Lakoski, 1997; Michelsen et al., 2008). For
instance, the SERT expression is found to be decreased in patients
with AD into several brain areas such as hippocampus, frontal,
temporal and entorhinal cortices, putamen and dorsal raphe nuclei
(Arnsten and van Dyck, 1997; Azmitia and Whitaker-Azmitia, 1997;
Belcher et al., 2005; Lai et al., 2007; Solodkin and van Hoesen,
1997; Tejani-Butt et al., 1995; Terry et al., 2008). Serotonergic
dysfunction appears to be closely linked to the behavioral aspects
of AD (see Meltzer et al., 1998), including depression, aggressive
behavior and psychosis. Only scarce information is known about
AD, selective 5-HT reuptake inhibitors (SSRIs) and memory func-
tions or dysfunctions. It is known that administration of citalopram
to healthy subjects has no effect on the working memory (Rose
et al., 2006), however in patients with AD both fluoxetine and
sertraline have improved cognition (Lyketsos et al., 2000; Mowla
et al., 2007; Mossello et al., 2008; see also Wuwongse et al.,
2010). Moreover, Chow et al. (2007) have highlighted that some
SSRIs could modify AD through their effects on amyloid plaques
formation or hippocampal neurogenesis (see also Aboukhatwa
Table 1
Summary of data obtained in the autoshaping task in diverse laboratories.
Role of incentive salience, amygdala, opioid receptors and individual differences
Determining individual differences, role of dopamine system and addiction
Detecting expression of 5-HT1A and 5-HT2 receptors protein in hippocampus and cortex
Detecting differences between strains of dextroamphetamine (AMPH) intracranial
self-administration (ICSA) into the nucleus accumbens
Measuring noradrenalin and 5-HT release
Separating the contributions of the orbitofrontal and infralimbic cortex to memory
Studying operant learning in 5-HT1A and 5-HT1B receptor knockout mice
Determining the inhibitory role of hippocampus
Determining the basal forebrain involvement
Studying the participation of dopaminergic and glutamatergic receptors
Facilitatory effects of 5-HT6 receptor antagonists
Effects of the cholinesterase inhibitor physostigmine
Facilitatory effects of 5-HT6 receptor antagonists in other memory tasks
et al., 2010). Preclinical evidence showed that in a triple trans-
genic (expressing both plaques amyloid beta; Ab and neurofibril-
lary tangles) mouse model of AD (Noristani et al., 2010),
a significant increase in SERT fibres in the hippocampus CA1 in
a subfield-, strata- and age-specific manner, at 3 months (by 61%)
and at 18 months (by 74%). These results may indicate an associ-
ation (or link to) AD cognitive impairment and imbalanced sero-
tonergic neurotransmission. Recent experimental studies involving
healthy human volunteers have revealed that manipulations of the
central 5-HT system can produce quite specific changes in cogni-
tive functioning, independent of overt mood changes (see e.g.,
Schmitt et al., 2006). Dual inhibitors of acetylcholinesterase and
5-HT uptake has been tested in rodents and it has been proposed
as possible treatment of Alzheimer’s disease (Abe et al., 2003; see
also Mowla et al., 2007; Orjales et al., 2003; Toda et al., 2010).
Further investigation is necessary to clarify the interaction of the
SERT, memory and AD; however, preclinical pharmacological and
genetic manipulations of the SERT have already revealed signifi-
cant clues.
3. Pharmacological manipulation of SERT and memory
Pharmacological manipulations of the SERT has a long tradition
regarding memory (see Altman and Normile, 1988; Chow et al.,
2007; Flood and Cherkin, 1987; Meneses, 1999, 2002, 2007b;
Meneses and Hong, 1995; Monleón et al., 2008; Savaskan et al.,
2008). Thus, while pre-training administration of SSRIs has
shown to either improve (with some isolated exceptions), have no
effect on memory or undermine it, post-training administration of
SSRIs (e.g., fluoxetine, sertraline) has been demonstrated to
improve memory or no change (see Monleón et al., 2008; and also
Meneses, 2002). Of the available memory tasks (Lynch, 2002;
Myhrer, 2003; Peele and Vincent, 1989; Meneses and Perez-
Garcia, 2007) among those most used are: the water maze, novel
object recognition, passive avoidance, T-maze, stone-maze,
autoshaping (see e,g., Altman and Normile, 1988; Dere et al., 2007;
Ennaceur and Delacour, 1988; Flood and Cherkin, 1987; McAdam
et al., 2008; Meneses, 2003, 2007b; Meneses and Hong, 1995).
Chronic fluoxetine did not affect matching-to-place or reference-
memory performance in intact rats in the Morris water-maze task.
Surprisingly, chronic fluoxetine adversely affected recovery of
function on both tasks was in rats with dentate gyrus damage
(Keith et al., 2007). In contrast, chronically fluoxetine-injected rats
did not show any impairment relative to the saline controls in
either the acquisition or the retention phases of the water maze
(hippocampal-dependent task; but see Box 1), however they did
spent significantly less time exploring the novel object in the novel
Mahler and Berridge, 2009
Flagel et al., 2007, 2008, 2009
Tomie et al., 2003
Rodriguez et al., 2008
Tomie et al., 2004
Chudasama and Robbins, 2003
Pattij et al., 2003
Ito et al., 2005
Steckler et al., 1993
Dalley et al., 2005
Schreiber et al., 2006, 2007
Sparber, 2001
Hirst et al., 2006; Lieben et al., 2005;
King et al., 2004; Mitchell et al., 2006;
Schreiber et al., 2007; Woolley et al., 2003
 A. Meneses et al. / Neuropharmacology 61 (2011) 355e363
object recognition (NOR) task and needed more time to learn the
association between the conditional stimulus and the appetitive
unconditional stimulus in the appetitive Pavlovian-conditioning
task (according with Valluzzi and Chan, 2007 both tasks are
hippocampal-independent). Although this is consistent with the
evidence that fluoxetine pre-training administration impairs
memory (see e.g., Meneses, 2002; Monleón et al., 2008); it is
noteworthy that in the short-delay Pavlovian-conditioning task of
12 sessions, significant deficits on memory were observed in the
fluoxetine-treated groups only during the sessions 3e5 relative to
control animals (Valluzzi and Chan, 2007; see also Tellez et al.,
2008, 2010). These data suggest that SSRIs have a specific time-
window to have an impairment effect on memory consolidation. As
mentioned before, acute fluoxetine administration after memory
training improved the memory consolidation in a Pavlovian/
instrumental autoshaping (Meneses and Hong, 1995) or passive
avoidance task (Izquierdo et al., 2006; for review see Monleón et al.,
2008). These contradictory findings make it necessary to revise
very briefly the interaction among brain areas, neurotransmitters
systems, drug administration, cognitive and behavioral demand of
learning tasks and the extent of training (see Box 1).
Box 1. Types of memory and behavioral tasks
Memory may be defined according to its content or in rela-
tion to time and neurobiological basis: in the former case, as
declarative/explicit or non-declarative/implicit memory, and
regarding time, as short- or working, and long-term memory
(Meneses and Perez-Garcia, 2007; Meneses et al., 2010).
Explicit memory is related to hippocampus and implicit is
related to striatum (see e.g., Adamantidis and de Lecea, 2009;
Kandel, 2001). Accordingly, behavioral memory tasks have
been classified by implication, lesion studies, neurobiolog-
ical changes, etc. For instance, the Morris water maze (the
platform hidden and prove trials version) is the classical
example of memory hippocampus-dependent (Schenk and
Morris, 1985; D’Hooge and De Deyn, 2001; Gerlai, 2001).
Other memory tasks requiring of hippocampus include
passive avoidance (see e.g., Izquierdo et al., 1999), fear
conditioning (Albrechet-Souza et al., 2010) and Pavlovian/
instrumental autoshaping (Meneses, 2003; Meneses et al.,
2009, 2011; Tellez et al., 2010). However, overtrained
animals engage more striatum and less hippocampus on
behavioral tasks such as autoshaping, passive avoidance
(e.g., Meneses, 2003; Izquierdo et al., 2006; Tellez et al., 2010;
see also Talpos et al., 2010).
Autoshaping has been used to study diverse problems,
including brain areas mediating memory, neurotransmission
systems, addiction, genetic deletions, etc. (Table 1). Even
comparable effects to those observed in autoshaping have
reported in social recognition, Morris water maze, spatial
DNMTS, etc (Millan et al., 2004). Pavlovian/instrumental
autoshaping memory formation, resembles situations of self-
taught (Meneses et al., 2009) and recruit diverse neural
markers, including the SERT and 5-HT receptors expression in
brain areas such as dentate gyrus, hippocampal CA1, baso-
lateral amygdaloid nucleus and prefrontal cortex, striatum
(Perez-Garcia and Meneses, 2008; Tellez et al., 2010). Hipo-
campi of untrained vs. autoshaping trained control groups
showed hippocampal 315 up-regulated genes, including
dopamine D1 and D5, a-adrenergic1d, NMDA and AMPA
receptors; and 365 down-regulated: 5-HT2C,4,6,7; b-adrenergic,
etc (Perez-Garcia and Meneses, 2009a,b). Hippocampal
lesions impaired memory consolidation in diverse memory
tasks, including autoshaping (Good and Macphail, 1994; Hall
et al., 1996; Ito et al., 2005; Liy-Salmeron and Meneses, 2007,
2008; Meneses, 2007a,b; Reilly and Good, 1989; Richmond
357
and Colombo, 2002; Schreiber et al., 2007). Thus, Pavlovian/
instrumental autoshaping learning task is mediated by brain
areas involved in explicit and implicit memory (Perez-Garcia
and Meneses, 2008; Tellez et al., 2010). Certainly, habit and
autoshaping have been linked (see e.g., Correa, 2007; also
Fone, 2008; King et al., 2008), however it is important to
remember that the learning of explicit rules are used to learn
even a sequence of motor responses and once the behaviors
are repeated or well-learned, they become automatic and can
be called habits (see e.g., Izquierdo et al., 2006). This is
observable in diverse memory tasks, including the Morris
water maze, passive avoidance and autoshaping. Multiple
memory mechanisms can work in tandem to support perfor-
mance on an implicit memory task and even additional
contribution of explicit memory can be observed in neuro-
logically healthy individuals (Koenig et al., 2008) and during
acquisition of an implicit learning task. Thus, during memory
consolidation hippocampus is in charge and when perfor-
mance become asymptotic or “automatic”, engaging striatum
(and other areas including cortical ones). Instrumental
learning requires repeated protein synthesis in the nucleus
accumbens (Hernandez et al., 2002; Hernandez and Kelley,
2004) and takes time to become observable. For instance,
vehicle-treated rats begin to consistently respond on the
correct lever starting approximately on training day 4, and
their responses progressively increased over subsequent
sessions; in contrast, animals given post-trial high dose of
anisomycin (a protein inhibitor) show evidence of learning
until day 7, two days after drug treatment had ended, even-
tually reaching the control levels.
Moreover, while autoshaping memory is progressive (0
e120 h), mRNA 5-HT6 receptor expression is not modified; in
contrast, 5-HT1A or 5-HT7 receptors expression monotonically
augmented or declined in prefrontal cortex, hippocampus and
raphe nuclei, respectively. However, under autoshaping
memory facilitation (with the 5-HT6 receptor antagonist SB-
399885) or amnesic states a differential 5-HT6 receptor mRNA
expression is observed (Huerta-Rivas et al., 2010; Meneses
et al., 2007; Perez-Garcia and Meneses, 2009a,b; for recent
review see Meneses et al., 2011). The 5-HT6 receptor mRNA
a higher degree in prefrontal cortex, hippocampus and stria-
tum in the amnesic model of scopolamine, while in the dizo-
cilpine model increased it more in the striatum. Memory and
mRNA are reestablished by SB-399885 (Huerta-Rivas et al.,
2010). Similar complex changes are observed between 5-HT
receptors and cAMP (Perez-Garcia and Meneses, 2008). Con-
firming the interaction of time, memory tasks and neural
markers, evidence from rats overexpressing dorsomedial
striatum, but not dorsocentral striatum, 5-HT6 receptors
shows impaired performance in a simple operant learning
task (a striatum-dependent learning model), but not in the
hippocampus-dependent water-maze task (Mitchell et al.,
2007). This impairment effect was appreciable at the third
testing session or during the second extinction session of
(Mitchell et al., 2007). Hence, an important clarification about
“cognitive” (explicit) and “habit” (implicit) memory consists
of the timing of observation. This notion is important in the
context of investigation of potential memory and amnesia
markers and loci.
4. SSRI and models of amnesia
Some drugs induce memory impairments that resemble, in part,
those observed in disorders such as AD, schizophrenia or drugs
causing addiction; including cholinergic (e.g., scopolamine) and
glutamatergic (e.g., dizocilpine, ketamine) antagonists, drugs of
abuse (e.g., methamphetamine, ecstasy), protein synthesis inhibi-
tors (e.g., anisomycin), etc. Especially, the cholinergic or
358 A. Meneses et al. / Neuropharmacology 61 (2011) 355e363
glutamatergic antagonists represent partial models for amnesia
and they have been very useful in determining whether SSRIs
reverse or prevent memory deficits. For instance, repeated
administration of SSRIs such as fluvoxamine reverses the memory
deficit induced by phencyclidine (PCP) a N-methyl-D-aspartate
receptor antagonist in the NOR test (Hashimoto et al., 2007). Also,
citalopram reversed scopolamine-induced impairment of spatial
memory in the radial maze (Egashira et al., 2006). The post-training
administration of the 5-HT uptake facilitator tianeptine (Fattaccini
et al., 1990) enhanced memory consolidation, normalized the
impaired memory induced by scopolamine or dizocilpine, and it
partially reversed the memory deficit induced by TFMPP (5-HT1B/
1D/2Ae2C/7 agonist/antagonist) in the autoshaping Pavlovian/
instrumental learning task (Meneses, 2002). It should be noted that
glutamatergic antagonists such phencyclidine (PCP), ketamine and
MK801 (dizocilpine) are used to produce cognitive disturbances,
which are relevant to schizophrenia and memory deficits associ-
ated to this disease (see e.g., Neill et al., 2010; also Liy-Salmeron and
Meneses, 2008). Likewise, in pharmacological or pathological
amnesia models such as abuse of drugs, the SERT and amnesia have
been linked. Few studies in humans have reported a loss of the SERT
in methamphetamine (METH) users, likely since primates are far
less vulnerable to methamphetamine-induced 5-HT injury than to
dopamine injury (Easton and Marsden, 2006; Nordahl et al., 2003).
However, METH and (þ/)3,4-methylenedioxymethamphetamine
(MDMA, “ecstasy”), reduced brain SERT density, which was asso-
ciated to cognitive deficits (Herring et al., 2008; McCann et al.,
2008; Marshall et al., 2007; Scott et al., 2007). For instance, absti-
nent MDMA users with a history of using substantial MDMA (two
or more doses over a 3- to 12-h period) and age-, gender-, and
education-matched controls participated (McCann et al., 2008).
Subjects in a positron emission tomography study to measure the
dopamine transporter (DAT) and SERT binding [11C]WIN 35,428
and [11C]DASB. MDMA users displayed significant reductions in
SERT binding in multiple brain regions (dorsolateral prefrontal,
orbitofrontal and parietal cortices), but were not observed in
striatal DAT binding. Memory performance in the aggregate subject
population was correlated with SERT binding in brain regions
implicated in memory function and prior exposure to MDMA
significantly diminished the strength of this relationship. These
data are the first to directly relate memory performance to human
brain SERT density (McCann et al., 2008). Importantly, SERT-
immunoreactive fiber density is significantly reduced in the
hippocampus but not in the neocortex of MDMA users, suggesting
that the hippocampus may be particularly vulnerable to moderate
MDMA exposure during adolescence (Meyer et al., 2008).
Furthermore, MDMA use has been associated with impairments of
psychological well-being, verbal memory and altered serotonergic
functioning in a number of cross-sectional studies (Thomasius
et al., 2006). These authors have noted that reduced SERT avail-
ability might be a direct effect of heavy ecstasy use, since it partially
recovered when the current users reduced their MDMA consume.
Nonetheless, Thomasius et al. (2006) have observed that this
measure may not necessarily be a valid indicator of the number or
integrity of serotonergic neurons. Verbal memory of ex-ecstasy
users did not improve even after 2.5 or more years of abstinence,
therefore this effect may represent persistent functional conse-
quences of MDMA neurotoxicity; notwithstanding, pre-existing
group differences cannot be completely excluded. Likewise, both
semantic knowledge and retrieval are impaired in ecstasy users and
the verbal fluency deficit may be attributable to a disruption of
frontal-striatal circuits directly related with the 5-HT function as
well as a depletion of lexical-semantic stores mediated by temporal
structures (Fagundo et al., 2010). Apparently, during performance
of a response-inhibition GO/NOGO task using functional magnetic
resonance imaging, no performance deficits were evident in
ecstasy (slight) users (Roberts and Garavan, 2010). Nevertheless,
whether ecstasy is contributing to or arising from using it, a dys-
regulation in brain regions subserving cognitive function and
default-mode processes in current recreational drug users mirrored
effects previously observed for “harder” drugs of abuse (Roberts
and Garavan, 2010). Moreover, even though there is no clear
evidence supporting an interaction between harmful effects in
ecstasy users and age-related memory decline or mid-life depres-
sion (Schilt et al., 2010), certainly memory deficits and the SERT
expression seem to be related in AD (see above).
5. Genetic manipulation of SERT
The importance of SERT on memory is substantiated by the
result that SERT (/) rats with acute tryptophan depletion
showed impaired STM in the NOR task (Olivier et al., 2008). Inter-
estingly, Kalueff et al. (2010) revised several aspects of SERT (/)
mice and rats, including cognitive functions. For instance, in mice
no effects were observed on spatial working memory (open field
and elevated plus maze habituation) and Pavlovian-to-Instru-
mental transfer task; nonetheless, SERT deletion impaired spatial
reversal learning task. In the Morris water-maze SERT (/) rats
took longer to find the hidden platform. According to Kalueff et al.
(2010), the absence of the SERT slightly impairs hippocampus-
dependent spatial/object memory, in striking contrast with
improved amygdala-dependent emotional memory (e.g., fear
conditioning) in SERT (/) rodents.
6. Are SERT and memory related?
Regarding whether or not SERT is involved in memory forma-
tion and/or amnesia, recent evidence indicates that MDMA
pretreatment led to chronic unpredictable stress-induced learning
impairment in the Morris water maze and dramatic reductions of
the SERT protein in MDMA-treated animals (Cunningham et al.,
2009). In addition, autoshaping trained rats decreased cortical
SERT binding relative to untrained ones (Tellez et al., 2010).
Administration of amnesic doses of METH to trained and untrained
animals decreased the SERT binding in several areas including
hippocampus and cortex (see Fig. 1). Interestingly, in the trained
animals fluoxetine improved memory, increased SERT binding,
prevented the METH amnesic effect and reestablished the SERT
binding (Tellez et al., 2010). Thus, SERT expression might be
important for memory formation, amnesia and the reestablishment
of memory. Apparently memory consolidation, and in a major
degree, amnesia make the SERT vulnerable to the effects of METH.
On the other hand, there is the possibility that memory perfor-
mance and SERT expression are not related, since the effects of
drugs such as fluoxetine and METH on the SERT expression might
appear to be more of a pharmacological nature rather than related
to memory. METH produces amnesia in diverse memory tasks,
including NOR (Kalueff et al., 2010; Tellez et al., 2010), egocentric
learning in the Cincinnati water maze (Vorhees et al., 2010), water
maze (Camarasa et al., 2010; Yamazaki et al., 1995; but see Schröder
et al., 2003), passive avoidance (Jia et al., 2008; but see Timár et al.,
2003), fear conditioning (Balci et al., 2008) and conditioned taste
aversion (Harrod et al., 2010). Although these memory tasks have
different behavioral, cognitive and neural demand (see e.g., Box 1;
see also Meneses et al., 2011), METH mainly affects the memory.
Confirming the notion that METH acts on memory, recent evidence
shows that this drug in untrained animals slightly reduced SERT,
but when it produced amnesia in autoshaping trained rats a higher
reduction of the SERT expression occurred in specific regions,
including cortices (prefrontal, cingulate, perirhinal, entorhinal,
 A. Meneses et al. / Neuropharmacology 61 (2011) 355e363 359

Fig. 1. Distribution of SERT in rat brains after various experimental treatments as revealed by [3H]citalopram binding autoradiography. Representative Autoradiograms from control
untrained and trained treated animal, made of series of consecutive coronal sections, from rostral (top) to caudal (down). Optical density readings are represented from colors,
which were added following optical density readings and represent from (red) strong expression to weak (blue and purple). Strong (black) to weak (grey) binding. Distance: 200 m.
(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

etc.), lateral septum, hippocampus (dentate gyrus, CA1 and CA3
areas), basal ganglia (accumbens nucleus and caudate putamen),
amygdala (basolateral, basomedial nuclei and stria terminal), and
the dorsal and median raphe nuclei and the ventral tegmental area
(see Fig. 1). In short, while memory formation is accompanied by
a moderate and selective reduction, confirming the previous sug-
gesting that memory makes the SERT more liable to the effects of
METH (Tellez et al., 2010). Together with this, the use of substantial
MDMA doses is also associated with lasting decreases in human
brain SERT (McCann et al., 2008). Thus, drugs of abuse like METH
and MDMA provoked cognitive deficits and reduced human SERT
density (Marshall et al., 2007; Scott et al., 2007) in the dorsolateral
prefrontal, orbitofrontal and parietal cortices (McCann et al., 2008).
7. Possible mechanisms for SERT involvement
on memory and amnesia
A key step that determines the intensity and duration of mono-
amines signaling at synapses is the reuptake of the released 5-HT
into nerve terminals through the SERT. Thus, SERT mediates reup-
take of 5-HT into presynaptic terminals, fine-tunes serotonergic
neurotransmission and inactivates 5-HT. As a logical consequence,
a reduction of the SERT will reduce 5-HT clearance resulting in
persistently increased concentrations of synaptic 5-HT (see e.g.,
Hensler, 2006). Diverse mechanisms might be responsible for effects
of the 5-HT inhibitors, MDMA, METH and memory on the SERT,
including 5-HT or dopamine release, abnormal glutamatergic/
cholinergic function, redistribution of catecholamines from synaptic
vesicles to the cytosol, induction of reverse transport of transmitter
through plasma membrane uptake carriers, etc. (see e.g., Nakagawa
and Kaneko, 2008; Siegel et al., 2010; Sulzer et al., 2005). Recent
evidence (Tellez et al., 2008, 2010) clearly indicates to draw caution
about extrapolating conclusions derived from ex vivo studies to those
realized in vitro and vice versa. Taking this into account and
considering transient actions, it is reasonable to assume that reduced
SERT expression is accompanied with memory consolidation, which
might be related to a selective modulation of 5-HT concentration.
Indeed it has been found that memory modifies 5-HT release, for
example in the matching-to-sample task in pigeons which shows
that WM is accompanied by a prefrontal cortex but not a striatal
release of 5-HT (Karakuyu et al., 2007). In contrast, well-trained rats
in the radial maze showed hippocampal acetylcholine increased
levels during the waiting period and further increases during the
radial-maze performance, while 5-HT levels did not change during
the waiting period (Stancampiano et al., 1999). These authors
suggest that: (i) hippocampal acetylcholine could be involved in
attentional and cognitive functions underlying motivational
processes; (ii) 5-HT could be implicated in non-cognitive processes
(i.e. in the control of motor and feeding behavior) (Stancampiano
et al., 1999). It should be emphasized that, during the extinction
phase 5-HT, but not acetylcholine, release quickly declines (see
Stancampiano et al., 1999). This suggests that 5-HT release is
involved in memory formation. Further investigation is necessary to
clarify the issue of 5-HT release, SERT and memory, amnesia and
forgetting. While autoshaping memory formation was associated to
down regulation of the SERT expression, an increased SERT expres-
sion was associated to either facilitation of memory (i.e., fluoxetine
administration) or anti-amnesic actions (i.e., fluoxetine plus METH
administration) (Tellez et al., 2010). In contrast, the METH-induced
amnesia was associated to SERT down-regulation. Thus, it is possible
that higher/lower 5-HT levels are associated to lower/higher SERT
expression, respectively, which should affect 5-HT receptors sensi-
tivity and/or up/down regulation. This notion is supported by
pharmacological evidence indicating that the fluoxetine-facilitation
memory effects are reversed by selective 5-HT1A, 5-HT1B, 5-HT2Ae2C,
5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists (Meneses, 2002,
360 A. Meneses et al. / Neuropharmacology 61 (2011) 355e363
2007a,b; Meneses and Hong, 1995). Moreover, as already mentioned
the antidepressant tianeptine (which increases uptake of 5-HT in the
cortex and hippocampus; see Fattaccini et al., 1990; Kasper and
McEwen, 2008) also enhanced memory consolidation, which was
reversed by fluoxetine or 5-HT depletion.
Tianeptineefluoxetine co-administration had no effect on
memory consolidation; nevertheless, the acetylcholinesterase
inhibitor, phenserine, potentiated the subeffective tianeptine or
fluoxetine doses (Meneses, 2002). Collectively, these data strongly
suggest that endogenously 5-HT modulates, via uptake sites and 5-
HT1e7 receptors, memory consolidation; which is consistent with
the evidence that protein and/or mRNA expression of diverse 5-HT
receptors are involved in memory consolidation (see Box 1 and
Huerta-Rivas et al., 2010; Perez-Garcia and Meneses, 2008)
and receptors of other neurotransmission systems (Perez-Garcia
and Meneses, 2009a,b). Importantly, regulation of SERT function
can occur at the level of transcription, translation or post-trans-
lational (see Hensler, 2006), which are also part of the memory
signaling cascades (see e.g., Bailey and Kandel, 2008), including
cAMP, protein kinase C (PKC), the neurotrophin Brain-Derived
Neurotrophic Factor (BDNF), cAMP-responsive element binding
protein (CREB)-mediated gene expression and neurogenesis. Post-
translational modifications like phosphorylation of serine, threo-
nine, and tyrosine, neurotransmitter release, vesicle trafficking and
synaptosomal or synaptosomal-associated proteins, substrates of
a series of specific protein kinases and their counterparts, and
protein phosphatases play a major role in memory as well (Mansuy
and Shenolikar, 2006; Sunyer et al., 2008). In addition, memory and
METH reduce the SERT expression. Studies concerning these
underlying molecular mechanisms should also focus on the
expression of 5-HT receptors, CaMKII, as well as on the fact that
METH or MDMA may also down-regulate the SERT expression
(Zahniser and Doolen, 2001).
MDMA causes a redistribution of SERT from the cell surface to
the intracellular compartment by a mechanism independent of
phospho-p38-mitogen activated protein kinase activation (Kivell
et al., 2010). Certainly, more work is necessary to unraveling the
exact molecular mechanisms.
8. Serotonergic neurobiological changes and memory
Although the effects of pharmacological and genetic manipu-
lation of 5-HT receptors and SERT on memory have been studied
(see above), there are only a few publications exploring the
neurobiological changes associated to this monoamine on
mammalian species. For instance, Belcher et al. (2008) reported
that an effective dose of METH regimen attenuated the acute
hyperthermic response to the subsequent METH binge and pre-
vented the NOR impairments and SERT reductions in striatum,
hippocampus and perirhinal cortex that otherwise occur one week
after the METH binge. In addition, repeated treatment with ser-
traline (which has moderate affinity for the dopamine transporter)
reduced the SERT expression in the hippocampus and induced
a persistent antidepressant-like effect on forced-swim test (Zhao
et al., 2008). Further investigations are required to determine
precisely, whether the changes were due to altered Kd or V-max
values. Moreover, the molecular mechanisms of memory remain to
be fully established as well as the molecular mechanisms mediating
the effects of fluoxetine and METH on memory. In addition, it is
important to investigate the effects of METH on dopamine and/or
norepinephrine systems and their transporters. Behavioral and
pharmacological controls such as separate groups of drug-treated
trained rats and for LTM without confound of being tested for STM
while the drugs were on board. It is important to emphasize that
the serotonergic system seems to offer different mechanisms and
neural markers for the improvement (and impairment) of memory,
as revised here with the SERT. Nonetheless, in the passive avoid-
ance memory task, performance may be improved by physical
exercise, which decreases the 5-HT level for the hippocampus and
the expression of 5-HT1A receptors on the amygdala without
altering the transporter expression (Jen et al., 2008). Notably, in
healthy subjects high SERT binding in fronto-striatal regions is
associated with better performance on tasks involving executive
function and logical reasoning but not LTM (Madsen et al., 2010).
To conclude, the SERT expression is important for memory
formation, amnesia and in the reestablishment of memory.
Apparently, memory consolidation and, in major degree, amnesia
make the SERT more vulnerable. Emerging evidence also indicates
that memory formation and amnesia affect the SERT expression.
SERT seem to be reliable neural markers in the understanding of
memory mechanisms, its alterations and potential treatment.
Behavioral and cognitive demands exert differential and selective
influence over pre- and postsynaptic 5-HT markers which might be
exacerbated by amnesic states and/or aging but reversed by phar-
macological treatments.
In addition to the SERT, other 5-HT markers have been related to
memory formation and cognitive decline, hence some of them
might also be useful not only for diagnosis of cognitive decline but
also for understanding the pathological mechanisms as well as
a basis for development of therapeutics. The memory and molec-
ular mechanisms associated to these changes represent promise
steps of investigation.
Acknowledgments
This work was supported in part by CONACYT grant 80060. We
wish to express our thanks for the excellent comments and
suggestions made for two anonymous referees.
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