Neuroscience and Biobehavioral Reviews 139 (2022) 104729

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

The role of serotonin in declarative memory: A systematic review of animal

and human research
Rebecca Coray a, b, *, Boris B. Quednow a, b
a
Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital Zurich, University of
Zurich, Switzerland
b
Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Switzerland

A R T I C L E I N F O A B S T R A C T

Keywords: The serotonergic system is involved in diverse cognitive functions including memory. Of particular importance to
Serotonin daily life are declarative memories that contain information about personal experiences, general facts, and
5-HT events. Several psychiatric or neurological diseases, such as depression, attention-deficit-hyperactivity disorder
Declarative memory
(ADHD), and dementia, show alterations in serotonergic signalling and attendant memory disorders. Never­
Learning
Encoding
theless, understanding serotonergic neurotransmission and its influence on memory remained a challenge until
Consolidation today. In this systematic review, we summarize recent psychopharmacological studies in animals and humans
Recognition from a psychological memory perspective, in consideration of task-specific requirements. This approach has the
Fear conditioning advantage that comparisons between serotonin (5-HT)-related neurochemical mechanisms and manipulations
are each addressing specific mnemonic circuits. We conclude that applications of the same 5-HT-related treat­
ments can differentially affect unrelated tasks of declarative memories. Moreover, the analysis of specific
mnemonic phases (e.g., encoding vs. consolidation) reveals opposing impacts of increased or decreased 5-HT
tones, with low 5-HT supporting spatial encoding but impairing the consolidation of objects and verbal mem­
ories. Promising targets for protein synthesis-dependent consolidation enhancements include 5-HT4 receptor
agonists and 5-HT6 receptor antagonists, with the latter being of special interest for the treatment of age-related
decline. Further implications are pointed out as base for the development of novel therapeutic targets for
memory impairment of neuropsychiatric disorders.

1. Introduction decisive contribution of 5-HT to memory formation by increasing the

The neurotransmitter 5-HT is involved in a wide variety of brain
functions and behaviours. This includes the control of physiological
activities, such as sleep, stress response, cardiovascular and endocrine
functions, the modulation of reward, emotions, mood, and behaviors
such as anger, aggression, appetite, pain, sexuality, as well as neuro­
psychological processes like perception, attention, and memory (Bac­
qué-Cazenave et al., 2020). Indeed, this broad spectrum of contributions
and the anatomical fact that 5-HT axons in the central nervous system
innervate almost every brain region, led to the claim, that – in terms of
brain functions – 5-HT “is at once implicated in virtually everything, but
responsible for nothing” (Jacobs and Fornal, 1995).
The specific serotonergic participation in learning and memory was
first demonstrated by Eric Kandel in the 1970 s. He demonstrated the
level of cyclic adenosine 3’,5’-monophosphate (cAMP) in the sensory
neurons of Aplysia (Cedar and Schwartz, 1972). This in turn activates
the cAMP-dependent protein kinase, which facilitates synaptic trans­
mission in terms of sensitization (Brunelli et al., 1976) and, after
repeated stimulations, induces protein synthesis-dependent long-term
potentiation (LTP) of synaptic strength (Schacher et al., 1988). Since
then, the participation of 5-HT in memory processes has frequently been
subject of research and up until today, the 5-HT system is considered as
interesting target in the development of therapeutic applications to treat
human memory disorders (Buhot et al., 2000; Chakraborty et al., 2019;
Meneses, 2013). In addition, dysregulations of the serotonergic system
have been associated with drug addiction and the development of
declarative drug memories that maintain addictive behaviors such as
drug-seeking behavior. Serotonergic treatments therefore may offer

* Correspondence to: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University
Hospital Zurich, University of Zurich, Lenggstrasse 31, CH-8032 Zurich, Switzerland.
E-mail address: rebecca.coray@bli.uzh.ch (R. Coray).

https://doi.org/10.1016/j.neubiorev.2022.104729
Received 11 February 2022; Received in revised form 13 May 2022; Accepted 6 June 2022
Available online 9 June 2022
0149-7634/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
R. Coray and B.B. Quednow
great potential to addiction treatments via attenuation and extinction of
otherwise resistant drug memories (Müller, 2013; Müller and Homberg,
2015).
There already exist some reviews about 5-HT and memory (Meneses,
2015; Perez-Garcia and Meneses, 2008; Zhang and Stackman, 2015a,
Van Goethem et al., 2015). Nevertheless, a systematic review with a
focus on the serotonergic involvement in the modulation of different
phases of declarative memories (encoding, consolidation, retrieval) is
lacking to date. This overview will thus be grouped into different types
of declarative memories to provide a framework that combines knowl­
edge from cognitive psychology and neuropharmacology. This focus on
serotonergic modulation of neuronal circuits required for a specific
memory process may provide a basis for deriving new hypotheses that
will inspire future research and development of therapeutic targets for
disorders of the brain involving memory impairment.
1.1. Anatomy of the serotonergic system
Despite its diverse involvement, the ability to synthesize 5-HT is
limited to just a few neurons; these account for less than 0.1% of neurons
in the mammalian brain (Okaty et al., 2019). The cell bodies of sero­
tonergic neurons are forming clusters in the brain stem, called raphe
nuclei, and their long and fine graded axons are widely branched
throughout the central nervous system. Of particular interest in this
review are ascending projections stemming from the dorsal raphe (DR;
B6 and B7) and the median raphe nuclei (MR; B5 and B8).
The rostral DR (B7) mainly projects to the extended amygdala,
striatum, cerebral cortex, and substantia nigra, whereas neurons of the
caudal DR (B6) innervate the (ventral) hippocampus, locus coeruleus
and entorhinal cortex. MR axons are targeting predominantly midline
structures, including the septo-hippocampal system, (dorsal) hippo­
campus, tegmental nucleus, interpeduncular nucleus, hypothalamus,
and lateral habenula (Hornung, 2003; Jacobs and Azmitia, 1992; Vertes
et al., 1999). Raphe projections are topographically organized and
adding the complexity of serotonergic forebrain projections, can be
further subdivided based on neuronal density, morphology,
co-transmission of other neurotransmitters, genetic signatures, electro­
physiological properties and projection areas (Okaty et al., 2019; Ren
et al., 2019). The axonal shapes of 5-HT vary according to function and
target regions, with MR arising axons beeing characterized by large
beaded varicosities (type M axons) while DR axons are predominantly
very fine with small, pleomorphic varicosities (type D axons) (Kosofsky
and Molliver, 1987). Type M fibres were shown to form direct synaptic
contacts, for example to hippocampal GABAergic interneurons (Papp
et al., 1999; Varga et al., 2009) in contrast to type D fibres which mainly
innervate cortical regions by volume transmission via extra-synaptic
serotonin-containing vesicle release (del Cid-Pellitero and Garzón,
2011).
5-HT receptors (5-HTRs) are classified into seven types, 5-HT1
through 5-HT7. The majority of 5-HTRs are postsynaptic with the
exception of 5-HT1ARs and 5-HT1BRs that additionally function as pre­
synaptic autoreceptors. Except 5-HT3Rs, which are ionotropic, all 5-
HTRs are coupled to G-proteins. This remarkable diversity within the
5-HT system enables to carry a variety of information and might
represent the morphological substratum of the diverse processes
modulated by 5-HT (Luchetti et al., 2020).
1.2. Declarative memories and their underlying substrates and
mechanisms
Declarative memory refers to the acquisition and retrieval of facts,
events, and episodes allowing the remembered material to be compared
and contrasted (Squire, 2004). Representations of declarative memories
can be accessed flexibly, enabling logical inferences and generalization
of experience. One prominent characterization of declarative memory is
that it can be decomposed into episodic and semantic memory, a key
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
distinction offered by Tulving in 1972 (Tulving, 1972). An episodic
memory trace usually binds together multiple situational aspects of a
unique personal experience, such as the time, place, or the social
context. In contrast, semantic memory incorporates memory for generic,
context-free knowledge which is acquired over multiple occasions and is
therefore partly dissociable from the episodic memory system. However,
in terms of the underlying neuronal substrates, these forms of memory
are closely related and recruit very similar brain structures during their
formation – at least in a healthy brain (Ryan et al., 2008). (See also Duff
et al., 2020 for a comprehensive review about the episodic vs. semantic
memory interdependence and distinction).
Declarative memories have extensively been studied in cases of
human amnesia (Squire and Zola, 1998). Out of this context, this term
originally refers to memories that can be consciously and verbally
stated. Another line of research investigated mnemonic functions of
animals in hippocampal-dependent learning and provided additional
insights in fundamental mechanisms of declarative memories across
species (Eichenbaum, 2000; Eichenbaum et al., 1992). As some
phenomenological aspects of the definition of human declarative
memory are not transferable to animal models (e.g. linguistic-based
behavioral markers of recollection), a more anatomically and biologi­
cally based framework was established to promote translational
research. In this framework, a functional organization of the declarative
memory system was proposed, that considered the medial temporal lobe
as a relational processing system whereas parallel “what”, “where” and
“when” information is integrated within the hippocampus to represent
events in the spatio-temporal context in which they occurred (Dere
et al., 2008; Eichenbaum, 2001). The consolidation of information into a
persistent trace relies on the prefrontal cortex areas in addition, which
also supports the recombination and transfer of experiences to novel
events in service of successful behavior (Preston and Eichenbaum, 2013;
Zeithamova et al., 2012). This definition encompasses the domain of
spatial memory (Buzsáki, 2002; Eichenbaum and Cohen, 2014; Has­
selmo and Stern, 2014), trace conditioning (Connor and Gould, 2016),
and contextual fear conditioning (Anagnostaras et al., 2001), since those
tasks were shown to critically rely on hippocampal system during
memory formation.
In the following, we will first review animal studies investigating
spatial memory, object memory, and contextual fear memory, while
each section is grouped according to effects of lowering and enhancing
5-HT levels and then summarizes the literature on specific 5-HTRs.
Subsequently, we will focus on human studies that employed verbal or
visual learning tasks, keeping the same structure for grouping seroto­
nergic manipulations as in the animal section.
2. Method
This systematic review was conducted according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)
statement (Page et al., 2021).
2.1. Study eligibility
For an extensive search of literature, we first defined search-terms
describing forms of learning that address declarative memories in
humans and mammals. Behavioral tasks assessing declarative memories
had to fulfill following criteria: the acquisition and storage of the
memory is reliant on brain structures of the medial temporal lobe, and
further, encoding, consolidation, and retrieval are critical steps of
memory processing (Eichenbaum, 2001). Matching task in humans are
verbal or visual tasks including the formation of associations between
pairs of stimuli or spatial locations, contextual fear conditioning, and
pattern or object recognition. Corresponding tasks in animals are novel
object recognition, spatial learning tasks (e.g. reference learning),
contextual fear conditioning, trace conditioning.
R. Coray and B.B. Quednow
2.2. Literature search
Two different search terms were used to identify human and animal
studies:
1. For human studies, we restricted our search to healthy participants
and searched PubMed (all years, 101 results, 21.3.2022) and Embase (all
years, 36 results, 21.3.2022) using following search strategy: ((serotonin
OR 5-HT OR serotonergic)("declarative memory" OR "episodic memory"
OR "semantic memory" OR "verbal memory" OR "verbal learning" OR
"visual memory" OR "contextual fear conditioning" OR "spatial memory"
OR "spatial learning" OR "associative learning" OR "long-term memory"
OR "pattern recognition" OR "object recognition")(placebo OR acute OR
challenge OR depletion)) NOT (review) NOT (disease). A filter to select
only studies with humans was applied for both databases.
2. This search strategy was slightly adapted to obtain equivalent
studies for non-human species: ((serotonin OR 5-HT OR serotonergic)
("declarative memory" OR "episodic memory" OR "semantic memory"
OR "object recognition" OR "object memory" OR "visual memory" OR
"contextual fear conditioning" OR "trace conditioning" OR "spatial
memory" OR "spatial learning" OR "associative learning" OR "long-term
memory")(placebo OR vehicle OR acute OR challenge OR depletion OR
deficiency)(animal)) NOT (review) NOT (model of schizophrenia) NOT
(model of depression) NOT (model of anxiety) NOT (disease). Like for
humans, PubMed (all years, 191 results, 21.3.2022) and Embase (all
years, 103 results, 22.3.2022) have been searched. No additional filters
were applied. Since for humans the terms "deficiency", "vehicle", and
"trace conditioning" did not yield any additional matching results, they
were omitted from the search term.
2.3. Inclusion criteria
Studies were identified which matched our definition of declarative
memories and then grouped according to population, intervention types,
underlying serotonergic mechanisms of actions and form of memory
before summarization.
Fig. 1. PRISMA flow diagram, based on inclusion and exclusion criteria.
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
3. Animal studies
3.1. Spatial learning and memory
Spatial learning involves the memorization of landmarks along a
route in a cognitive map and their flexible representation during navi­
gation (Tolman, 1948). To evaluate rodent spatial memory, maze
learning tasks are widely used. One of the most popular is the Morris
water maze (MWM), which assesses hippocampus-dependent reference
learning when the animals must search for a hidden platform to escape
the maze. It also has a hippocampal independent variant, using a visible
platform, that assesses cue learning.
3.1.1. Lowering or depleting 5-HT centrally and globally
Common approaches for lowering central 5-HT include nutritional
restrictions and chemical agents. Dietary 5-HT deprivation, for instance,
is carried out by substituting nutrition with a drink that contains a
mixture of large neutral amino acids but lacks the 5-HT precursor L-
tryptophan (TRP). This prevents 5-HT production in brainstem neurons
and results in a short-term and reversible reduction of cerebral 5-HT
(Hood et al., 2005; Van Donkelaar et al., 2011; Young et al., 1989).
Investigations on spatial memory indicated, that acute or chronic (~40
days) nutritional TRP restriction does not affect task performance in the
MWM (Lieben et al., 2004; Liu et al., 2013; Uchida et al., 2007) and also
not in a radial arm maze (Stancampiano et al., 1997). In line with this,
neither the chemical induced attenuation of 5-HT synthesis by the spe­
cific and irreversible tryptophan hydroxylase inhibitor p-chlor­
ophenylalanine (PCPA; 300 mg/kg single injection or 400
mg/kg/day×3) nor the serotonergic neurotoxin 5,7-dihydroxytrypt­
amine (5,7-DHT; 150 μg), which selectively destroys 5-HT axons, had
any effect on performance in hippocampus-dependent maze learning
tasks (Lehmann et al., 2000; Majlessi et al., 2003; Nilsson et al., 1988;
Richter-Levin and Segal, 1989). Thus, hippocampal-dependent allo­
centric spatial memory was not affected across several studies as well as
different procedures applied for central 5-HT depletion.
R. Coray and B.B. Quednow
Contrasting results were obtained after repeated 3,4-methylene­
dioxy-N-methylamphetamine (MDMA) intoxication. Although acutely
given MDMA stimulates the release of 5-HT, its repeated administration
within a short time frame inhibits 5-HT synthesis and therefore provokes
5-HT depletion (Lyles and Cadet, 2003). Such a regimen (15 mg/kg x 4
doses MDMA in one day) caused deficits in the Cincinnati water maze
and, to a lesser extent, long-term impairments in an MWM reversal
learning task (Able et al., 2006).1
We briefly mention some factors that may account to those contra­
dictory outcomes between MDMA and other 5-HT depletion methods.
The Cincinnati water maze, which involves egocentric route-based
learning, as well as the MWM reversal learning task are both sug­
gested to rely on the striatum (Braun et al., 2015; Castañé Anna et al.,
2010). By contrast, allocentric learning in the MWM reference memory
version is assumed to mainly rely on the dorsal hippocampus (Miyoshi
et al., 2012; Morris et al., 1982). Able et al. (2006) reported a decrease of
dopamine (DA) in the striatum indicating a contribution of dopami­
nergic interactions in MDMA-induced egocentric spatial memory im­
pairments. A similar pattern was found in adult rodents receiving
chronical MDMA treatment during development (Williams et al., 2003).
In a further egocentric spatial navigation task, facilitated task acquisi­
tion after selective striatal 5-HT depletion (using 5,7 DHT; 25 μg) was
observed and this effect was abolished by DA antagonists (SCH-23 390
or spiperone) (Anguiano-Rodríguez et al., 2007). This implies that the
deterioration in spatial performance may be mediated by a concomitant
influence on striatal DA tone following MDMA-induced 5-HT depletion
with egocentric learning being more severely affected.
3.1.2. 5-HT depletion in selective regions
Selective depletion of 5-HT from the medial septum (MS)/diagonal
band of the brocca or from the hippocampus facilitated spatial task
acquisition in the Morris water maze (Gutiérrez-Guzmán et al., 2011,
2017; Hernández-Pérez et al., 2015). For this, 5,7-DHT was injected into
the target region and in addition, hippocampal electroencephalography
(EEG) was measured during task performance. Improved spatial task
acquisition was accompanied by earlier expression of dominant high
frequency theta oscillations during training and increased theta
coupling coherence between the MS-hippocampus and the
MS-mammillary nuclei. Theta oscillations are critical for spatial cogni­
tion, serving the integration of information from separate functional
units during mnemonic processes (Korotkova et al., 2018). Accordingly,
in a state of low central 5-HT, facilitated communication between
task-involved regions could promote information processing. Indeed,
spatial encoding was improved, primarily during the initial phase of
learning, as expressed in behaviour (Gutiérrez-Guzmán et al., 2011,
2017). Hippocampal theta involvement was thereby specific for spatial
reference memory necessitating the use of cognitive maps, whereas cue
learning remained unaffected (Olvera-Cortés et al., 2002).
However, when depleting 5-HT from the supra-mammillary nucleus
(SUM), inefficient MWM performance was evident. Hippocampal high-
frequency theta was abolished during MWM training and facilitated
MS-hippocampal theta coherence was absent in SUM lesioned animals
(Hernández-Pérez et al., 2015). A participation of the SUM in retention
of spatial reference memory was suggested (Aranda et al., 2008; Shahidi
et al., 2004). Based on those findings, the authors proposed changes in
theta frequency as an operating mechanism by which the hippocampus
switches between acquisition and retrieval states. In this respect,
encoding of environmental information is supposed to be mainly per­
formed by the dorsal (in animals) or posterior (in humans) hippocam­
pus, which in turn is strongly innervated by MR originating, beaded type
M serotonergic axons (Freund et al., 1990; Wilson and Molliver, 1991).
1
MDMA studies with mice are omitted in this review given that MDMA is
mainly neurotoxic for the dopamine system instead of the 5-HT system in mice,
which is in contrast to other species (Logan et al., 1988).
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Moreover, suppression of theta, regulation of hippocampal ripple os­
cillations as well as memory consolidation were demonstrated to be
crucially modulated by MR 5-HT neuronal activation (Wang et al.,
2015).
3.1.3. Enhancement of 5-HT globally
Acutely administered selective serotonin reuptake inhibitors (SSRIs)
block 5-HT reuptake and increase its levels in the extracellular space
(Walker, 2013). Regarding spatial memory, SSRI administration was
robustly associated with performance deteriorations. Acute dosage with
citalopram (10 and 20 mg/kg) before MWM training caused spatial
reference memory deficits (Mutlu et al., 2011) and pretraining cit­
alopram (5 and 10 mg/kg) impaired long-term retention in the Y-maze
test (Bridoux et al., 2013). Further, a dose-dependency in the effects of
SSRI on maze-learning was revealed. Accordingly, MWM acquisition
and navigation were impaired after pretraining treatment with cit­
alopram (4 and 8 mg/kg), fluoxetine (8 and 16 mg/kg) or alaproclate
(7.5 and 20 mg/kg), whereby lower doses had no impact (Majlessi and
Naghdi, 2002; Riekkinen et al., 1991). The distinction between acute
and chronic administration does not seem to be necessarily important, as
a consistent effect was still replicated after 4 weeks of fluoxetine (0.7
mg/kg per day) treatment (Ampuero et al., 2013).
3.1.4. 5-HT1A/1BR
The 5-HT1AR is one of the most studied serotonergic receptors to date
(e.g., Glikmann-Johnston et al., 2015). There exists strong evidence for
5-HT1AR involvement in spatial memory. When animals had to perform
an Atlantis Water maze, pro-cognitive effects during encoding were
found after dosing with a selective and silent 5-HT1AR antagonist
(WAY-101 405; 1, 3, 10 mg/kg) (Hirst et al., 2008). In another study,
however, the 5-HT1AR antagonists NAD-299 (0.05, 0.15, 0.5 and 1.5
mg/kg) and WAY-100 635 (0.3 and 1 mg/kg) failed to alter MWM
performance (Lüttgen et al., 2005).
Agonistic 5-HT1AR ligands yielded mixed and dose-dependent re­
sults. As such, spatial memory was enhanced following a low dose of 8-
OH-DPAT (0.3 mg/kg) but deteriorated after a high dose of 8-OH-DPAT
(1.0 mg/kg) (Haider et al., 2012). Dose dependent impairments were
also found in other rat strains (Lüttgen et al., 2005). The selective
infusion of 8-OH-DPAT (0.5 μg) into the MS worsened MWM perfor­
mance (Bertrand et al., 2000) but deficits were reversed by injecting
WAY-100 635 at the same site. Interestingly, the variation of the time­
points when infusing 8-OH-DPAT into the MS (pre-training,
post-training, 2 h after training, before probe-trial) unveils, that
5-HT1AR of the MS contribute to a 5-HT-mediated mechanism involved
in encoding and in consolidation, but not retrieval of spatial
hippocampal-dependent knowledge. Specifically, 8-OH-DPAT infusion
into the MS hindered encoding and the protein synthesis-dependent,
late-phase consolidation processes (Koenig et al., 2008). The effect
was suggested to be mediated through an 8-OH-DPAT-induced hyper­
polarisation of cholinergic and/or GABAergic and/or glutamatergic
neurons in the MS-hippocampal neuronal pathway (Bertrand et al.,
2000; Koenig et al., 2011).
Consequences of persistent alterations in 5-HT1AR expression were
investigated in transgenetic mouse models. 5HT1AR – knockout (KO)
mice exhibited spatial memory impairments but intriguingly, this was
only obtained in tasks requiring the integrity of hippocampal functions
(Sarnyai et al., 2000). As contributing factors, the absence of 5-HT1A
autoreceptors (Wolff et al., 2004) and/or long-term developmental
plastic adaptions such as altered hippocampal CA1 GABAergic trans­
mission (Sarnyai et al., 2000) were suggested. Spatial performance of
5-HT1AR KO seems to be age-dependent, since deficits were obvious in
young adult (3 months) but not older (22 months) 5-HT1AR KO mice.
This is possibly attributable to an age associated compensation of
reduced cholinergic activity by the 5-HT1AR KO mutation (Wolff et al.,
2004). Likewise, elevations of hippocampal acetylcholine after acute
dosage of WAY-101 405 (10 mg/kg) have been reported (Hirst et al.,
R. Coray and B.B. Quednow
2008).
Overexpression of 5-HT1AR did not affect spatial learning. 8-OH-
DPAT (0.3 mg/kg) administration in transgenetic mice, however,
resulted in a higher sensitivity for MWM task failures. Those might be
mediated by the surplus of postsynaptic heteroreceptors in projection
areas of 5-HT neurons such as the hippocampus and outer cortical layers
(Bert et al., 2009).
There are only two studies on 5-HT1BRs and their role in spatial
memory. Both investigations observed improved long-term performance
in 5-HT1BR KO mice which was specifically evident in the hippocampus-
dependent reference version of the MWM, but not in the cue-guided
visual version (Buhot et al., 2003; Malleret et al., 1999). This effect
was stronger at increased task complexity and even persisted with older
age. Those findings indicate pro-cognitive influences of 5-HT1BR genetic
deletion on spatial memory and even a protective effect on age-related
hippocampal-dependent memory decline.
3.1.5. 5-HT2AR
Activation of 5-HT2ARs was associated with impaired spatial memory
encoding and retrieval. Acute dosing with the 5-HT2AR agonist TCB-2 (1
mg/kg) before the probe trial delayed the initiation of spatial search
behavior, which is required to escape the MWM in the reference version,
without affecting cue memory. In addition, those findings were
accompanied by diminished long-term stability of hippocampal CA1
place fields especially for the novel environment, but not for pre-existing
place cell firing maps. Those effects were prevented by the 5-HT2AR
antagonist MDL 11 939 (0.5 mg/kg) (Zhang et al., 2017). Similar find­
ings were obtained using the 5-HT2AR agonistic acting substance psilo­
cin, which impaired encoding in the Carousel maze (1 and 4 mg/kg) and
retrieval in the MWM (4 mg/kg) after previous drugfree acquisition
(Rambousek et al., 2014). Blockade of hippocampal CA1 5HT2A/2 CRs by
ritanserin (4 μg) improved learning in spatial version of MWM. Ac­
cording to the authors, ritanserin might act on GABA interneurons and
disinhibit cholinergic transmission and/or prevent 5-HT induced inhi­
bition on CA1 pyramidal neurons (Naghdi and Harooni, 2005). In line
with this finding, no navigational deficits were found in 5-HT2AR KO
mice in several spatial memory tasks (Morici et al., 2015).
3.1.6. 5-HT3R
The blockade of hippocampal CA1 pyramidal neuron 5HT3Rs by
granisetron (0.25 μg) caused impairments in the MWM (Naghdi and
Harooni, 2005). Another investigation, however, found spatial naviga­
tion being improved after application of the 5-HT3R antagonist ondan­
setron (doses between 100 and 1000 μg/kg) (Stäubli and Xu, 1995).
3.1.7. 5-HT4R
There is one investigation on 5-HT4R signalling providing evidence
for a bidirectional impact on memory formation. Accordingly, the
agonist BIMU8 (30 mg/kg) enhanced plasticity on the Schaffer collat­
erals and improved performance in an MWM. The specific antagonist
GR125487 (10 mg/kg), on the other hand, impaired synaptic potentia­
tion and in consequence, spatial memory was attenuated (Teixeira et al.,
2018).
3.1.8. 5-HT6R
5-HT6R antagonists produced beneficial effects on spatial learning
(Da Silva Costa et al., 2008: SB-27 104 610 mg/kg; Rogers and Hagan,
2001: SB-271 046-A or SB-357 134-A, 10 mg/kg). Acute dosage pro­
longed the retention MWM reference memory (Rogers and Hagan, 2001)
and further, improved acquisition and consolidation of spatial recogni­
tion in the Y-maze in young adult mice. In addition, 5-HT6R antagonism
counteracted age-related consolidation deficits of spatial recognition
memory in older mice (18–21 months) (Da Silva Costa et al., 2008; Foley
et al., 2004). In another examination, Long-Evans rats (2 years old) were
tested in a clinical trial-like design. For this, a “patient population” was
created by increasing the difficulty of the task step-by-step. In this,
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
sub-chronic treatment (13 days) with the 5-HT6R antagonist RO-4 368
554 (3 mg/kg per day) did not yield any effects on spatial cognition
(Gyertyán et al., 2020). Nevertheless, another investigation pinpointed
the cognition-enhancing effects of the 5-HT6R antagonist (SB-27 104
610 or 20 mg/kg per day for 40 days) on the acquisition and recall of a
spatial learning task following chronic drug administration in a popu­
lation of aged rats (Foley et al., 2004). Together, 5-HT6R antagonists
might still be an interesting target for cognitive enhancement and
memory improvement especially in some age-related dysfunctions.
3.1.9. 5-HT7R
In 5-HT7R KO mice, long-term memory formation, memory consol­
idation, and memory retrieval of a Barnes maze were unaffected, sug­
gesting that this receptor is not critical for spatial memory in general.
However, 5-HT7R KO mice were less efficient in accommodating to
changes in spatial arrangement as evident in reversal learning. When
changing the location of the escape hole, 5-HT7R KO mice displayed
perseverative behavior. Therefore, a role for the 5-HT7R in the adjust­
ment of neuronal networks to changes in environments was suggested.
In line with this, the ability to perform a switch from a striatal-
dependent egocentric cognitive strategy towards a hippocampus-
dependent allocentric cognitive strategy while solving a spatial task
was reduced (Roberts et al., 2004; Sarkisyan and Hedlund, 2009).
3.2. Summary
In general, global lowering of 5-HT levels did not affect spatial
learning except when using MDMA as depleting agent. Sub-chronic
MDMA administration might particularly affect spatial tasks whose
performance is additionally modulated by the striatal DA tonus. Global
enhancement of 5-HT by SSRIs worsened spatial performance. Inter­
estingly, the serotonergic tonus in the SUM might be important for
memory consolidation. By contrast, high levels of 5-HT in the MS
hampered encoding/consolidation but low levels supported encoding.
MS 5-HT levels were additionally related to increases in theta frequency
and coherence suggesting a role for 5-HT as hippocampal theta modu­
lator. Studies investigating specific receptors revealed mostly conflicting
results, but acute administration of 5-HT6R antagonists might improve
spatial learning performance.
3.3. Object recognition
Novel object recognition is usually assessed by letting the animal
deeply explore two objects (sample session) and afterwards, replacing
one object with a new object (test session). Rodents have a natural pro­
clivity to explore novel, non-threatening objects and therefore, the time
spent exploring the new object in comparison to the old object is
considered as valid measurement for novelty recognition (Cohen and
Stackman, 2015). Although the hippocampus and amygdala were once
thought to be critical contributors to object recognition memory, recent
systematic studies have revealed the greater importance of temporal
cortical areas, with particular emphasis on perirhinal cortex. While the
hippocampus clearly contributes to the performance of object recogni­
tion tasks under certain, as yet not fully understood conditions, it does
not appear to be required for the familiarity-based recognition of object
information per se (Winters et al., 2008).
3.3.1. Lowering or depleting 5-HT globally
In contrast to in spatial learning, global cerebral serotonin deficiency
was quite consistently related to object recognition impairments. A
bunch of evidence using acute TRP depletion observed object recogni­
tion impairments, that have been evident 2 – 6 h after the first treatment
(Jans et al., 2007, 2009, 2010; Lieben et al., 2004, 2005a; Olivier et al.,
2008; Rutten et al., 2007; van Donkelaar et al., 2008). Similar findings
were obtained after 21 days of a TRP-free diet (Jenkins et al., 2010). In
addition, TRP depletion decreased 5-HT levels in brain structures that
R. Coray and B.B. Quednow
incorporate a crucial role in memory, such as the hippocampus and the
frontal cortex (Jans et al., 2007; Jenkins et al., 2010; Olivier et al.,
2008). The observed effects of TRP depletion were even more pro­
nounced in rodents with pre-existing abnormal 5-HT function (Olivier
et al., 2008). Importantly, sex and estrous cycle phase were demon­
strated to influence the behavioral response to TRP depletion whereby
females in pro-estrus/estrus exhibited the strongest object recognition
deficits after acute TRP depletion (Jans et al., 2007). Notably, a possible
strain dependence of animals in TRP effects was suggested as well (Jans
et al., 2010).
Those findings were not obtained in two examinations using other
chemical agents for cerebral 5-HT depletion. One study applied a sub­
cutaneous p-chloroamphetamine (PCA) regimen (5 mg/kg) and tested
animals in an object recognition task one week later. Object recognition
remained intact, even though SERT binding in the hippocampus and
perirhinal cortex was decreased in depleted animals (Belcher et al.,
2005). In another investigation repeated MDMA treatment (15 mg/kg x
4 doses in one day) produced substantial reductions of 5-HT and 5-HIAA
concentrations in the whole brain including the hippocampus and the
prefrontal cortex. Nonetheless, object recognition performance was not
impaired (Able et al., 2006). By contrast, (Morley et al., 2001) compared
a high dose MDMA regimen (4 ×5 mg/kg, over 4 h on each of 2
consecutive days) with a moderate dose regime of MDMA (1 ×5 mg/kg
on each of 2 consecutive days). Animals were then tested in a novel
object recognition task 14 weeks after drug administration. After 15 min
retention, deficits were evident in the high dose group. The authors of
this study considered neurotoxic effects due to the high MDMA dosage as
an explanatory factor.
Object recognition was also impaired in a hypo-serotonergic mouse
model (Pet1KO) at delayed recalls (90 min and 2 h). Measurements of
field excitatory postsynaptic potential (fEPSP) at Schaffer collaterals
during task performance revealed exaggerated LTP mechanisms in
Pet1KO mice compared to a control group. Increases in fEPSP ampli­
tudes were observed directly after training and were even strikingly
larger after 5 h. To note, no alterations in hippocampal theta or gamma
oscillations were found in this study. Further, novel object recognition
deficits have been restored by increasing global 5-HT levels through
repeated administration of a combination of 5-HTP (10 mg/kg) and
benserazide (20 mg/kg) while training and before testing. Accordingly,
the non-specific strengthening of synapses after object recognition
acquisition in the CA1 region may occlude the correct formation of
object memory traces, which emphasizes that serotonergic inhibitory
control over the hippocampal formation is fundamental to normal object
memory functions during consolidation. In a subsequent examination of
the same experimental setting, the authors demonstrated that neural
activity of the MR is required for encoding/consolidation but not recall
of object memory. This was shown by selective blockade of either MR of
DR activity with reversible designer drugs (DREADDs) induced chemo­
genetic inhibition during task performance (Fernandez et al., 2017).
Overall, a bunch of evidence reliably related acute lowering of 5-HT
levels by TRP depletion, but not more direct 5-HT depletion methods, to
object recognition impairments. We will briefly mention some possible
reasons for the discrepancies reported beyond depletion regimens. In
this, strain specific variations might play a role. For example, Able et al.
(2006) and Belcher et al. (2005) used Sprague-Dawley rats for their
examinations. In contrast to other strains (e.g. Morley et al., 2001),
Sprague-Dawley rats have been found to be less vulnerable to 5-HT
associated object recognition deficits before (Jans et al., 2010). More­
over, Able et al. (2006) used a rather short retention time (1 h),
compared to other studies (e.g. Lieben et al., 2004, 2005b [4 h, 24 h];
Rutten et al., 2007 [3 h]; Jans et al., 2009 [2 h, 4 h, 6 h]). This pinpoints
a role of 5-HT specifically in late phase consolidation processes.
3.3.2. Enhancement of 5-HT globally
In line with the experimental findings on spatial learning, the acute
increase of central 5-HT tonus by SSRI treatment resulted in worse
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
object recognition performance. In this regard, fluoxetine (10 mg/kg)
was demonstrated to increase the extracellular 5-HT concentrations, e.g.
in the medial prefrontal cortex (mPFC), and impaired performance of
mice in the object recognition 24 h post-administration (Castañé et al.,
2015; Flores-Burgess et al., 2019).
3.3.3. 5-HT1A/1BR
A role of 5-HT1ARs in object recognition was pointed out. In this
regard, the treatment with 5-HT1AR antagonists (WAY-101 405: 1.0–10
mg/kg or WAY-100 635: 1.0 mg/kg) prolonged memory span in object
recognition up to 48 h (Hirst et al., 2008; Pitsikas et al., 2003). These
promoting effects were observed regardless of the time of administra­
tion, which took place either before the acquisition, storage, or retrieval.
Accordingly, 5-HT1AR antagonists likely restore time-related object
recognition deficits overall and not specific to memory phases (Pitsikas
et al., 2003). To determine the unique contribution of 5-HT1A autor­
eceptors and heteroreceptors on object recognition, Van Goethem et al.
(2015) used ‘biased agonists’ which preferentially activate only one of
those subtypes. They challenged mechanisms of hippocampal pattern
separation with an object-in-context recognition version of object
recognition. The results described a bell-shaped dose response curve for
both agents. Activation of postsynaptic 5-HT1A heteroreceptors (with
F15599) positively affected object recognition at a midrange dose (0.04
mg/kg), whereas higher and lower doses tended to impair performance.
Activation of 5-HT1A autoreceptors in raphe (with F13714) impaired
object recognition at concentrations of 0.0025 or 0.01 mg/kg, with no
effects at other doses. Together, those findings indicate that object
recognition performance might benefit from activation of 5-HT1A het­
eroreceptors (Van Goethem et al., 2015). On the contrary, the genetic
deletion of 5-HT1BRs did not change object recognition performance
(Malleret et al., 1999).
3.3.4. 5-HT2A/2 CR
Systemic 5-HT2AR activation (TCB-2; 1.0 mg/kg) enhanced the
consolidation of object memory. The strongest impact on object recog­
nition performance was reported when the agent was given directly after
object memory acquisition. Pre-treatment with a 5-HT2AR antagonist
(MDL 11 939) diminished this effect. Since memory consolidation in its
initial stages is thought to start right after learning, this finding suggests
that TCB-2 likely strengthened the nascent object memory (Stackman
et al., 2013). In line with this, activation of 5-HT2AR was associated with
increases of extracellular glutamate efflux and facilitated induction of
synaptic plasticity (Zhang et al., 2016).
The ability to remember the spatial context or the temporal order of
objects was demonstrated to rely more heavily on the hippocampus than
the usually applied simple object recognition procedure (Balderas et al.,
2008; Forwood et al., 2005). To challenge hippocampal functions as
such, animals were trained to remember object-in-context combination
or the temporal-order-of objects, that necessitate the recollection of
conjunctive ‘what’ or ‘when’ and ‘which context’ representations at test.
Specific and retrieval associated deficits for object-in-context recogni­
tion were found after the selective blockade of 5-HT2ARs (MDL 11 939)
in the mPFC (Bekinschtein et al., 2013) and the same findings were
obtained in 5-HT2AR KO mice (Barre et al., 2016; Morici et al., 2015),
whereas the conventionally applied object recognition procedure
remained unimpaired (see also Castañé et al., 2015). Their role in
retrieval-related deficits was supposed to be mediated by imbalances of
5-HT concentrations in the mPFC. A detrimental excess of 5-HT is likely
due to increased 5-HT1AR activation, as observed in the absence of
5-HT2AR signalling (Castañé et al., 2015; Morici et al., 2015).
Prefrontal-hippocampal circuit are essential for the encoding and
retrieval of declarative memories, and the specific role of 5-HT2ARs
herein was further pinpointed. Bekinschtein et al. (2013) injected rats
either ipsilateral, contralateral, or bilateral with the 5-HT2AR antagonist
MDL 11 939 in the mPFC and/or muscimol in the hippocampus. They
found that both, the 5-HT2ARs in the mPFC and 5-HT2AR activity in the
R. Coray and B.B. Quednow
hippocampus are necessary for the correct solution of the
object-in-context task. In addition, contralateral infusion of both agents
resulted in performance deficits, whereas ipsilateral infusions, which
leave the more dominant interactions between the mPFC and the hip­
pocampus intact (Churchwell and Kesner, 2011), had no impact.
Crucially, the restauration of object-in-context recognition performance
in 5-HT2AR KO mice was possible using a viral gene-delivery approach.
After the re-expression of 5-HT2ARs at presynaptic sites in the medi­
odorsal thalamus, no more differences to wild-type mice have been
evident (Barre et al., 2016). Morici et al. (2015) demonstrated a role for
mPFC 5-HT2ARs in the selection of the correct memory trace during
retrieval. Together, these findings strikingly suggest a necessary
engagement of 5-HT2ARs in prefrontal-hippocampal circuits, incorpo­
rating a role specific to the retrieval of contextual elements in episodic
memories.
Pro-cognitive effects in object recognition were also demonstrated
after selective blockade of 5-HT2 CRs. Specifically, SB 242 084 (0.63, 2.5
and 10 mg/kg) prolonged object recognition memory duration up to 24
h (Bertaina-Anglade et al., 2011).
3.3.5. 5-HT4R
Systemic activation of 5-HT4Rs yielded beneficial effects on object
memory. In general, 5-HT4Rs have been shown to improve acquisition
and consolidation in several mnemonic domains (e.g. Hagena and
Manahan-Vaughan, 2017), which also applies to object recognition
tasks. Acute and sub-chronic activation (14 days) of the 5-HT4R with the
partial agonist RS-67 333 extended memory traces in the novel object
recognition task. This was suggested to result from a functional inter­
action between the cholinergic and serotonergic system, which is
mediated by the nucleus basalis magnocellularis (NBM). Regarding this,
the local intra-NBM infusion of RS-67 333 enhanced the acquisition and
the consolidation of place recognition memory but did not affect recall.
These effects were reversed by pre-treatment with the selective 5-HT4R
antagonist RS-39 604 (Orsetti et al., 2003; Quiedeville et al., 2015).
3.3.6. 5-HT6R
Evidence of 5-HT6R on object recognition revealed mixed results, but
quite a bunch of studies reported prolongations of object memory after
treatments with 5-HT6R ligands. Acute dosage with 5-HT6R antagonists
(Ro 04–6790 and SB-271 046; both: 10 mg/kg) shortly before, or
directly after the object recognition sample session, improved object
memory acquisition and/or consolidation and prolonged the duration of
the memory (up to 4 h). No effects were evident when the administration
took place before the test session (Kendall et al., 2011; King et al., 2004,
2009). Similar findings where obtained after 14 days sub-chronic
antagonistic treatments (Mitchell et al., 2009: Ro4368554 [5 mg/kg];
Quiedeville et al., 2015: SB-271 046 [10 mg/kg]). In addition,
Ro4368554 (3 mg/kg or 10 mg/kg) was able to reverse object recog­
nition retention deficits within 1 h delay in a serotonergic deficiency
model (TRP-restriction regimen) (Lieben et al., 2005a). Those beneficial
effects on object recognition were suggested to be mediated via MR
innervated brain regions. Accordingly, the selective lesioning of the MR
– but not the DR – completely abolished the effects of a 5-HT6R antag­
onist (Ro 04–679 010 mg/kg) (King et al., 2009). However, it is worth
mentioning that together, the abovementioned enhancing effects on
retention were rather short-lived and absent with longer inter-trial in­
tervals (up to 24 h) (Gyertyán et al., 2020; Lieben et al., 2005b) or
non-evident within a very short inter-trial time interval (1 min)(Woolley
et al., 2003).
At first glance, it might be paradoxical, that agonistic ligands such as
E-6801 (5 or 10 mg/kg) and EMD-386 088 (10 mg/kg) were shown to
enhance object recognition memory as well. This was true, even when
given together with sub-effective dose of the 5-HT6R antagonist SB-271
046. The closer inspection on this phenomenon revealed distinct con­
tributions of agonistic and antagonistic agents to object recognition. One
plausible explanation is, that agonists directly amplify the action of 5-
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
HT6Rs on glutamatergic and/or cholinergic neurones whereas antago­
nists attenuate active serotonergic input to upstream inhibitory
GABAergic neurones, which in turn disinhibit glutamate and/or
acetylcholine release. Thus, both agents may elevate glutamate and/or
acetylcholine release and augment object memory albeit via distinct
mechanisms of action (Kendall et al., 2011).
3.3.7. 5-HT7R
A role in novelty detection for 5-HT7Rs was indicated. Accordingly,
both pharmacological blockade (SB-269 970; 10–15 mg/kg) and genetic
inactivation resulted in a lack of behavioral response to novel objects
and novel environments without altering habituation behavior. In
addition, the tendency to actively seek novelty was inversely correlated
with 5-HT7R gene expression in pivotal areas for information trafficking,
such as thalamo-cortical projection areas and the dorsal hippocampus
(Ballaz et al., 2007; Sarkisyan and Hedlund, 2009). On the other hand,
5-HT7R activation LP-211 (0.25 mg kg-1) improved the consolidation of
chamber-shape memories after the sample session. This was evident in
the subsequent novelty-preference test where ameliorated chamber
recognition memory was observed that persisted up to 24 h (Beaudet
et al., 2017).
3.4. Summary
Global 5-HT lowering or elevation impaired object memory, except
in two studies where MDMA or PCA, respectively, was administered to
achieve central depletion. 5-HT1AR and 5-HT2 CR antagonists prolonged
the memory of the object unspecific to any memory phase. 5-HT2AR, 5-
HT4R and possibly 5-HT7R agonists as well as 5-HT6R ligands enhanced
its acquisition and/or consolidation. Concordantly, blockade of 5-
HT2ARs worsened object memory and underlined the involvement of 5-
HT2ARs in hippocampal - prefrontal circuits as modulators of synaptic
plasticity and memory consolidation.
3.5. Contextual fear conditioning
Contextual fear conditioning can be described as a type of associative
learning that involves a strong emotional arousal due to the sudden
application of a painful stimulus in a specific spatial context. Contextual
fear conditioning accounts for an episodic-like memory in its extended
definition, since successful learning and retrieval can be inferred from
behavioral expressions referring to the content (what), place (where),
and temporal context (sequence of events) (Pause et al., 2013). It re­
quires the normal function of the hippocampus, where the contextual
element is stored, and the amygdala. Cued fear conditioning instead
builds an associative memory between a tone and fear, it requires
normal function of the amygdala only (Kim and Fanselow, 1992). While
the former is dependent on a specific context (place) as a conditioned
stimulus for fear induction, the latter is context-independent in the sense
that the cuing stimulus triggers fear behaviour no matter where it is
perceived.
3.5.1. Lowering or depleting 5-HT globally
Some studies obtained contextual fear conditioning impairments
after acute central 5-HT depletion that were evident in reduced freezing
behavior of rodents at the test session. It was thereby irrelevant, whether
5,7-DHT (25 mg/kg) (Matsumoto et al., 2004) or TRP dietary restriction
(Uchida et al., 2007) was applied as depleting compound. Contextual
fear conditioning deficits were apparent 2 h, 24 h, and 3 weeks after
acquisition. No behavioral alterations have been obtained during
training and 30 min afterwards at the first test session, indicating that
5-HT deficiency did not affect contextual fear conditioning acquisition
or baseline anxiety levels. Crucially, animals did also not differ in a cued
fear conditioning paradigm, where – as mentioned above - the
hippocampal-dependent processing of the contextual component is
lacking (Uchida et al., 2007). Taken together, those findings suggest that
R. Coray and B.B. Quednow
acute central 5-HT deficiency might impair the hippocampal-dependent,
but not the amygdala-dependent, processes that are involved in the
consolidation of contextual fear memory.
Contrasting results were obtained in mice with a constitutive lack of
central 5-HT. Such mice were generated, for example, by a region-
specific conditional KO of the transcription factor Lmx1B and conse­
quently, those mice are lacking essentially all central 5-HT neurons and
5-HT levels are decreased to a level of < 10%. Another approach is the
targeted inactivation of the neuronal tryptophan hydroxylase-2 (Tph2)
gene. Such Tph2 null mutant (Tph2 − /− ) mice lack the capability to
synthesize 5-HT specifically in the brain (Gutknecht et al., 2009). Both
variants of genetic manipulations in mice provoked greatly enhanced
contextual fear memory. Tph2 − /− mice displayed a faster acquisition
of conditioned fear, as well as enhanced contextual representation of the
fear memory, but normal functional extinction of the context (Gutknecht
et al., 2015; Waider et al., 2019). In conditional KO mice, exaggerated
contextual fear memory was diminished after injecting 5-HT into the
lateral ventricles or by administration of the 5-HT1AR agonist 8-OH-D­
PAT (Dai et al., 2008). The examination of immediate-early gene
expression (c-Fos imaging) and electrophysiological recordings in the
dorsal hippocampus (dHip) of Tph2 − /− mice emphasized that lifelong
5-HT deficiency renders the dHip hyperexcitable in fear conditioning
(Waider et al., 2019). These observations are in accordance with the
finding of exaggerated LTP at Schaffer Collaterals after high-frequency
stimulation in the 5-HT deficient Pet1KO mouse model (Fernandez
et al., 2017). In this sense, exaggerated context-dependent fear memory
likely involves dysfunctional raphe-hippocampal 5-HT innervation,
which may result in the failure of 5-HT receptor-mediated inhibition of
hippocampal circuitries. Of note, female Tph2 − /− mice, in contrast to
males, displayed increased stress vulnerability and depression-like
behavior, suggesting additional sex-hormone-dependent interactions
between female and male behavioral responses to central 5-HT defi­
ciency (Gutknecht et al., 2015). In sum, the abovementioned results
support the view of a direct relationship between 5-HT levels and
contextual fear memory. However, whereas in the case of a chronic 5-HT
deficit since birth, contextual fear memory was exaggerated, the oppo­
site was true in case of an acutely induced deficit by 5-HT depletion,
which specifically deteriorated the storage of the contextual element in
the hippocampus. Yet, under both conditions, cued fear conditioning
remained unaffected (Fernandez et al., 2017; Uchida et al., 2007), this
was also true when using 5,7-DHT for central 5-HT deficiency induction
(Romano et al., 2006).
3.5.2. Enhancement of 5-HT globally
Acute or chronic SSRI treatment before contextual fear conditioning
training revealed mixed behavioral responses. Escitalopram 1 mg/kg
(but not 0.5 and 5 mg/kg) given 30 min before training increased
freezing time in the retention test 24 h after acquisition. However, when
escitalopram 1 mg/kg (but not 0.5 and 5 mg/kg) was administered the
next day after acquisition, 30 min before the test session, reduced
freezing time was evident. To elucidate the effect on memory consoli­
dation, escitalopram (5 mg/kg; but not 0.5 and 1 mg/kg) was given
immediately after the acquisition phase which induced augmentation of
freezing at the retention test held on next day. Of note, escitalopram did
not affect baseline freezing behavior at any dose tested. This demon­
strates that contextual fear conditioning is affected differently and dose-
sensitively by central 5-HT tonus depending on the mnemonic phase
(Montezinho et al., 2010). In another investigation, rodents were treated
sub-chronically (21 days; 7 mg/kg; 18 doses) after having been sub­
jected to contextual fear conditioning. Contextual fear conditioning
acquisition (over 3 days) took place in a box with the contextual element
being represented by a specific odour und using eyelid-shocks as an
unconditioned stimulus. Following three weeks of fluoxetine treatment
(7 mg/kg), they were re-exposed to the conditioning context. In this
investigation, SSRI treatment failed to abolish conditioned freezing to
contextual stimuli. However, fluoxetine treatment restored
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
electrophysiological baseline activity of fimbria-CA3 synaptic efficacy
and furthermore, when animals where re-exposed to the fear context
after successful extinction training, fear learning potentiation was sup­
pressed. This finding suggests a protective effect of fluoxetine on
conditioned fear and stress-induced disturbances of hippocampal plas­
ticity (Spennato et al., 2008).
3.5.3. 5-HT1A/1BR
During stressful conditions, protective functions of endogenous 5-HT
were shown, by decreasing the firing activity of hippocampal CA1 py­
ramidal neurons (McEwen and Magarinos, 1997). The 5-HT1AR antag­
onists WAY-100 635 (0.2 mg/kg) and WAY-100 135 (5 mg/kg)
abolished the decrease in firing frequency during conditioning, yet
without affecting contextual conditioning-induced freezing behavior at
retrieval (Tada et al., 2004). Congruently, the selective intra­
hippocampal activation of postsynaptic 5-HT1AR by injection of flesi­
noxan (3 μg) reduced the expression of conditioned fear (Li et al., 2006).
Moreover, the MR – hippocampal pathway was associated with reduced
fear responses evoked by contextual but not acoustic sensory stimuli.
This finding was obtained after selective 8-OH-DPAT microinjection into
the MR (1 μg/0.5 μl saline), which underlines the involvement of
5-HT1ARs during the process of memory formation of conditioning fear
associated with aversive contexts (Avanzi and Brandão, 2001).
The one investigation on 5-HT1BR KO mice revealed no alterations of
contextual fear conditioning compared to wild-type controls (Malleret
et al., 1999).
3.5.4. 5-HT2AR
Stimulation of 5HT2A was related to facilitated consolidation and
extinction of fear memories in a trace fear conditioning task. Trace fear
conditioning demands the CS and the US to be associated over a
stimulus-free interval known as the “trace” and are thereby thought to
be functionally and morphologically incorporated by hippocampal
neurons. It was found that post-conditioning activation of 5-HT2ARs by
TCB-2 (1 mg/kg) enhanced consolidation of the fear memory, whereas
post-conditioning blockade of 5-HT2ARs by MDL 11 939 (0.5 mg/kg)
yielded a tendency towards less freezing. Both ligands had no effects
when administered right before encoding or retrieval (Stackman et al.,
2013). 5-HT2AR activation induced facilitation in fear condition, was
further shown in cued and Pavlovian eyeblink conditioning, indicating
that 5-HT2AR activation is not specifically related to the contextual
element but to associative learning (Romano et al., 2006). In addition,
dosing animals with TCB-2 (1.0 mg/kg) before training facilitated the
extinction of the non-hippocampus-dependent cued delay fear memory
and by contrast, MDL 11 939 (0.5 mg/kg) delayed the recovery of
freezing in mice (Stackman et al., 2013). Taken together, reported
studies indicate a rather general role for 5-HT2AR in fear memory
consolidation and extinction. Nonetheless, it is conceivable that
5-HT2AR activation facilitates hippocampal glutamate transmission
(Zhang and Stackman, 2015b), thereby promoting the information
transmission and retention in mnemonic circuits in support of consoli­
dation including the hippocampus, lateral amygdala and mPFC.
3.5.5. 5-HT7R
In 5-HT7R KO mice, a specific impairment of contextual fear condi­
tioning was found, sparing other forms of learning such as spatial
learning, cued and operant conditioning (Roberts et al., 2004). The
dissociation between contextual-based learning and the cued fear con­
ditioning indicates, that more complex integrative learning mechanism
involving contextual processing, may rely on 5-HT7Rs. Dissociations
between spatial learning and contextual fear condition have been pre­
viously reported (Cho et al., 1998; Clark et al., 2008). This com­
plementing finding of Roberts et al. (2004) might indicate a deficit in
place learning that is distinct from spatial processing and navigation,
with 5-HT7Rs playing a role.
R. Coray and B.B. Quednow
3.6. Summary
Central or hippocampal 5-HT elevations may protect against hypersen­
sitivity to contextual fear learning in cases of innate 5-HT deficiency by
reducing pyramidal cell firing in the CA1 region. 5-HT2ARs exert hippo­
campus independent influences on contextual fear memory consolidation. 5-
HT7Rs may be involved in more complex processing of contextual elements.
Specifically, activation of 5-HT2ARs or inhibition of 5-HT7Rs appears to
facilitate contextual memory processes in a cortico-limbic circuit.
3.7. 5-HT and interactions with other neurotransmitters
Interactions between 5-HT and the cholinergic system have often
been addressed. The potential of serotonergic agents to change levels of
cholinergic transmission is of great interest for research on novel ther­
apeutic targets treating disorders such as age-related cognitive decline
or dementia (Lanctô et al., 2001).
It was demonstrated, that the combined cholinergic and serotonergic
denervation of the forebrain in rodents produces severe spatial memory
impairments, whereas 5-HT depletion alone had no effect (Lehmann
et al., 2000; Nilsson et al., 1988; Richter-Levin and Segal, 1989;
Richter-Levin et al., 1994). Further, the administration of the SSRI
alaproclate (20 mg/kg) together with scopolamine (0.8 mg/kg) or the
combination of 8-OH-DPAT and scopolamine at subthreshold doses (30
µg/kg and 100 µg/kg, respectively) likewise induced a far greater place
navigation deficit than scopolamine alone (Riekkinen et al., 1995,
1991). This entails, that changes in central 5-HT levels are capable to
magnify the functional defects induced by cholinergic blockade, leading
to a severe failure of spatial performance.
On the other hand, scopolamine induced deficits in contextual fear
conditioning and object recognition tasks where reversed by pretraining
administration of 5-HT1AR antagonists (WAY-101 405 [1 mg/kg];
Ro4368554 [10 mg/kg or 30 mg/kg]; WAY 100 635[1 mg/kg]; Ro 04–6790
[10 or 30 mg/kg]) (Hirst et al., 2008; Lieben et al., 2005a, b; Pitsikas et al.,
2003; Woolley et al., 2003). The memory improving effects were thereby
associated with increases in hippocampal acetylcholine levels (Hirst et al.,
2008). A possible underlying mechanism of action could involve opposite
interactions between 5-HT1AR antagonists and scopolamine at the level of
pyramidal hippocampal neurons. Accordingly, the blockade of hyper­
polarizing actions by endogenous 5-HT may compensate the loss of cholin­
ergic input, favouring the action of other excitatory neurotransmitters on
pyramidal cells (Carli et al., 1997; Pitsikas et al., 2003).
In a similar vein, scopolamine induced object recognition deficits
were counteracted by 5-HT6R ligands. The agonistic compound E-6801
(2.5 or 5 mg/kg) alone or in combination with subthreshold doses of the
antagonistic compounds EMD386088, as well as the antagonistic com­
pound Ro4368554 (3 mg/kg or 10 mg/kg) restored object recognition
performance (Kendall et al., 2011; Woolley et al., 2003). Furthermore,
the acute and prolonged (21-day) administration of both, the selective
5-HT6R agonist WAY-181 187 (1 and 3 mg/kg) and the antagonist
SB-745 427 (3 mg/kg) prevented memory impairments and alterations
in BDNF signaling induced by MK-801 in rats (Rychtyk et al., 2019).
4. Human studies
4.1. Verbal learning and memory
Verbal learning tests in humans usually consist of a list of words that
has to be memorized by the subject being tested. During the learning
phase, words are presented verbally or visually and immediately
retrieved afterwards, a procedure that is repeated several times (5 times
in general). This is followed by delayed recall procedures including the
recognition of words from a list. Delayed recalls are performed after the
presentation of an interference list (without recognition), after 2 h delay
and after 24 h delay (to assess protein-dependent long-term memory).
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The most popular tests following this procedure are the Rey Auditory
Verbal Learning Test (RAVLT) and the California Verbal Learning Test
(Strauss et al., 2006).
4.1.1. Lowering 5-HT globally
TRP depletion as a pharmacological 5-HT deficiency model in
humans, commonly results in impairments of declarative memory. In
verbal learning tests, the effects were most prominent at delayed recall,
with fewer words recollected after TRP depletion (Amin et al., 2006;
Borghans et al., 2017; Harrison et al., 2004; Klaassen et al., 1999;
McAllister-Williams et al., 2002; Riedel et al., 1999a, 1999b; Sambeth
et al., 2007, 2009; Schmitt et al., 2000). There are only two studies,
which at least partly, failed to replicate this finding (Evers et al., 2005;
Hughes et al., 2003). In another examination on verbal memory,
whereas prose paragraph had to be recalled, no verbal memory deficits
have been observed after using chronic fenfluramine (20 mg PO/day)
application for 5-HT depletion (Meador et al., 2008).
In contrast to verbal learning, immediate verbal recall was mostly
either unaffected (Harrison et al., 2004; Klaassen et al., 1999; Riedel
et al., 1999a, 1999b; Schmitt et al., 2000), or only females were found to
be impaired (Borghans et al., 2017; Helmbold et al., 2013; Mace et al.,
2008; Sambeth et al., 2007). The specific greater vulnerability of females
to the effects of TRP restriction likely involves interactions with estro­
gen. Evidence for this was provided by estrogen treatments in meno­
pausal woman, which leaded to augmented verbal memory performance
(Amin et al., 2006) and increased 5-HT turnover (Lippert et al., 1996).
Moreover, recovered depressed participants receiving a low-dose TRP
diet were more vulnerable to deteriorations in cognitive function. In this
study, impairments were specific to verbal short-term memory deficits,
without showing changes in word encoding, long-term memory, and
subjective mood (Hayward et al., 2005).
Regarding specific memory phases, a TRP depletion-related consol­
idation impairment was pointed out. Consolidation is a process
involving several stages (McGaugh, 2000), and in relation to TRP
depletion, mostly immediate consolidation, which begins as early as
during encoding up to 30 min after acquisition, was reduced (Harrison
et al., 2004; Riedel et al., 1999a, 1999b; van der Veen et al., 2006). EEG
measurements during a verbal learning task revealed alterations of the
N400 event-related potential component after acute TRP depletion,
which is consistent to consolidation deficits (Borghans et al., 2017). No
event-related potential changes were found at retrieval (McAllis­
ter-Williams et al., 2002). One study, applying task-based fMRI after
TRP depletion, observed attenuated neuronal activity in the right hip­
pocampus during encoding of a visual-verbal memory task. No brain
activity differences in comparison to a control group were detectable
during retrieval (van der Veen et al., 2006).
Effects of TRP depletion on word recognition were less consistent.
Recognition deficits were reported to be most pronounced after some
hours delay (Riedel et al., 1999a, 1999b; Rubinsztein et al., 2001;
Sambeth et al., 2007; Schmitt et al., 2000; van der Veen et al., 2006).
Evers et al. (2005) found increased reaction times in delayed visual word
recognition, however, other examinations failed to find differences in
comparison to control conditions (Borghans et al., 2017; Harrison et al.,
2004; Helmbold et al., 2013; Klaassen et al., 1999; Sambeth et al., 2009).
Interestingly, the cognitive effects of TRP depletion were differentially
affected by genotypes at the 5-HTTLPR polymorphism (ss vs. ll geno­
type). Regarding this, the ss genotypes showed deficits in an affective
verbal directed forgetting task after TRP depletion, in contrast to the ll
genotype group (Roiser et al., 2007).
4.1.2. Enhancement of 5-HT globally
Acute treatment with SSRIs, which causes a global increase in the
serotonergic tonus, had fairly inconsistent effects on verbal learning
across studies. Citalopram (10 mg IV) was found to improve long-term
recall and recognition in the RAVLT in female volunteers, without
R. Coray and B.B. Quednow
affecting immediate recall 15 min earlier. This finding is consistent with
studies suggesting reduced memory consolidation after TRP depletion,
thus indicating reciprocal effects of low and high 5-HT levels in long-
term memory processes in humans (Harmer et al., 2002). Yet, other
studies did not find group differences in verbal memory after acute
citalopram ingestion (20 mg oral) (Sambeth et al., 2015; Wingen et al.,
2007) or by contrast, they observed impaired verbal memory perfor­
mance (Heckman et al., 2019a). Chronic escitalopram treatment (10–20
mg/day) for 15 days did not affect visual-verbal memory, which was
tested on several days during this period (Wingen et al., 2006).
Acute administration of the serotonin and noradrenaline releaser
MDMA causes a strong increase of extracellular 5-HT and noradrenaline
levels by promoting non-exocytotic release of these neurotransmitters
from storage vesicles (Rothman et al., 2001). Acute MDMA worsens
verbal memory during the intoxication phase at immediate and delayed
recall (Haijen et al., 2018; Kuypers et al., 2013, 2016; Kuypers and
Ramaekers, 2005). The effects were strongest when MDMA was given
before encoding, but also present when MDMA was given before
retrieval (Doss et al., 2017). Verbal memory recognition scores were not
affected by acute MDMA intoxication (Kuypers et al., 2013; Kuypers and
Ramaekers, 2005; Van Wel et al., 2011), yet deficits have been obtained
in a pictorial recognition task (Kuypers et al., 2013). Some research
points towards a specific role of 5-HT2ARs in MDMA induced memory
impairments (Reneman et al., 2001; Van Wel et al., 2011).
4.1.3. 5-HT1AR
In male volunteers, the regional binding density of 5-HT1ARs ([11C]
WAY-100 635) was negatively associated with verbal memory perfor­
mance exclusively in the hippocampus. 5-HT1AR binding density in
other memory relevant regions (e.g. ant. cingulate cortex, PFC, temporal
cortex) was not related to verbal or visual memory. Further, the 5-HT1AR
agonist tandospirone (60 mg, but not 30 mg) selectively impaired verbal
memory in the RAVLT in several indices without affecting other cogni­
tive domains, such as working memory or the ability to inhibit cognitive
interference (Stroop task). The authors suggested a postsynaptically
mediated mechanism, which inhibits hippocampal pyramidal neurons
(Yasuno et al., 2003). In accordance, the combination of the 5-HT1AR
agonist pindolol (10 mg) and escitalopram (20 mg) exacerbated deficits
in immediate verbal memory recall (Wingen et al., 2007). Pindolol binds
at presynaptic 5-HT1A autoreceptors and hence, likely contributes to the
general 5-HT increase caused by escitalopram (Rasmussen et al., 2004).
4.1.4. 5-HT2AR
Psilocybin (10, 20 and 30 mg/70 kg) and LSD (100 micrograms) are
both acting as 5-HT2AR (and a weaker 5-HT1AR) agonists and their
application decreased the free recall of words in a verbal memory task.
This effect was dose-dependent for free recall and recognition, with the
lowest dose of psilocybin (10 mg/70 kg) and a lower dose of LSD (50
micrograms) having no effect on word recognition (Barrett et al., 2018).
Similarly, object recognition and recall were affected after LSD appli­
cation (100 micrograms) (Jarvik et al., 1955).
4.1.5. 5-HT4R
The memory enhancing effects of 5-HT4R agonism observed in ani­
mal studies could be demonstrated in humans as well. The 5-HT4R
agonist prucalopride (1 mg) increased recall of words in a verbal
learning task and increased the accuracy of recall and recognition of
words in an incidental emotional memory task. This successful trans­
lation from animal to human studies suggest 5-HT4R agonist as prom­
ising treatment for cognitive disturbances (Murphy et al., 2020a).
4.2. Summary
Central 5-HT deficits mainly impaired delayed recall in verbal
learning tasks, suggesting poor consolidation. But also, studies that
induced overstimulation of the 5-HT system through SSRI, 5-HT1AR
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Neuroscience and Biobehavioral Reviews 139 (2022) 104729
activation, or MDMA administration reported prominent deficits in
verbal memory overall. The effects of 5-HT2AR activation in humans
may not be easy to interpret given that the psychedelics commonly used
induced hallucinogenic effects which also affect attentional processes
(Vollenweider et al., 2007; Quednow et al., 2012). The 5-HT4R might be
an interesting candidate for enhancing cognitive performance.
5. Visuo-spatial learning and memory
5.1. Lowering 5-HT globally
A simple spatial learning task involved the pictorial presentation of a
house with nine windows, yet only four of those windows had a light
turned on. The memory for the positions of those illuminated windows
after a short delay was not different between an TRP depletion group
and controls, indicating no visuo-spatial learning alterations. To note,
reducing dopamine availability resulted in short-term memory impair­
ments in the same task (Harrison et al., 2004). Furthermore, no influ­
ence of TRP depletion was found on spatial pattern – location
recognition or in visuo-spatial learning tests from neurocognitive as­
sessments (Amin et al., 2006; Evers et al., 2005; Hughes et al., 2003;
Mace et al., 2008; Park et al., 1994; Rubinsztein et al., 2001; Scarnà
et al., 2005). In an object relocation task, ten objects were presented
shortly to participants in a square frame. Afterwards, the positions of the
objects were marked, and the objects had to be assigned to their previous
positions. In this specific task, TRP depletion was found cause perfor­
mance deficits in delayed recall taking place 4 h later. However, for the
same task, there was a separate condition, demanding the placement of a
set of new objects in their original position as accurately as possible,
without pre-marked dots. Interestingly, the TRP depletion group’s per­
formance was superior to controls in placing objects to their exact co­
ordinate position. According to the authors, the assignment of objects to
a relative position likely incorporates a verbal component, as opposed to
the remembrance of the more precise, metrical position of an object
whereas the metrical displacement to the correct position is measured
(Sambeth et al., 2009). Similarly, TRP depletion was found to augment
spatial pattern recognition (Scarnà et al., 2005).
5.1.1. Enhancement of 5-HT globally
Acute administration of the SSRI citalopram (20 mg) did not affect
spatial memory or visuo-spatial recognition, neither in a spatial test
based on object relocation, nor in a continuous pattern recognition test
(Heckman et al., 2019b; Park et al., 1994; Sambeth et al., 2015). In
accordance, no effects on memory outcomes, white matter plasticity
(measured by diffusion tensor imaging), or structural changes
(T1-weighted MRI data) were found after chronic escitalopram treat­
ment for 3 weeks (10 mg/day) during a visual face – object associate
relearning task (Vanicek et al., 2022). However, functional activation
changes while relearning were found from the right insula to both the
anterior cingulate and right angular gyrus in the same sample (Reed
et al., 2022). In contrast to these previous studies, the combined treat­
ment of citalopram (20 mg) together with anodal transcranial direct
current stimulation, entailed beneficial effects on short-term memory in
an object-location recognition task. This applied to both, younger and
older adults (Prehn et al., 2016).
Acute MDMA induced pronounced impairments of visuo-spatial
memory. Neither pretreatment with the 5-HT1AR antagonist pindolol
(20 mg) nor with the 5-HT2AR antagonist ketanserin (50 mg) prevented
or altered MDMA induced visuo-spatial memory impairments (Hasler
et al., 2009; Van Wel et al., 2011).
5.2. Summary
Interestingly, spatial memory for accurate placements might even
slightly benefit from 5-HT deficiency induced by TRP depletion. This
contrasts with the apparent impairments in verbal memory using the
R. Coray and B.B. Quednow
same psychopharmacological manipulation.
6. General discussion
6.1. Low global 5-HT
In the majority studies, TRP depletion induced deficits in human
verbal memory or object recognition in animals while sparing spatial
memory. Across species, females were more vulnerable to TRP
depletion-induced deficits, especially before ovulation when estrogen
levels are rising. To mention at this point are findings that document a
higher 5-HT synthesis overall in males than in females, which could
relate to the abovementioned finding (Chugani and Muzik, 2000). In
addition, conditions associated with less efficient 5-HT functions, such
as psychiatric disorders in humans or their mimicry in genetically
modified animals, enhanced the effect of TRP depletion (Alhaj et al.,
2012; Merens et al., 2008). TRP depletion was further associated with
slight increases in attentional processes and perceptual processing
(Schmitt et al., 2000), whereas dopamine depletion primarily affected
spatial working memory (Harrison et al., 2004). Concerning human
studies a contribution of lowered mood which negatively affects
Table 1
Main effects animal studies. Superscript arrow symbols refer to directions of effects found in the respective studies. ↑: memory improvement. ↓: memory deterioration.
→: no effect.
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memory performance has been discussed, but in most of the studies
showing memory effects after TRP depletion, mood was not altered
(Ruhé et al., 2007).
Evidence stands that partially segregated networks are recruited for
spatial navigation and object memories even though they all do account
as medial temporal lobe dependent memories (Chao et al., 2016; Hales
et al., 2014; Rauchs et al., 2008). Most interestingly, according to the
findings reviewed here, cognitive subroutines underlying spatial navi­
gation, object memories, and storage of the contextual element in
contextual fear conditioning, seem to be differentially affected by cen­
tral 5-HT deficiency. This suggests dissociable processes underlying
storage of objects and contexts as opposed to the formation of cognitive
maps during allocentric navigation. Research on such topics remained
sparse to date, especially with regard to 5-HT. The retrosplenial cortex
and the MS are critically involved in spatial navigation (Kubik et al.,
2012), yet storage of objects relies on extrahippocampal structures such
as the perirhinal cortex in particular (Burwell et al., 2004; Miranda and
Bekinschtein, 2018). Considering this, further research might take up
findings describing different molecular mechanisms in the respective
brain regions that process and store different types of information
(Mitchnick et al., 2015; Natale et al., 2020), and relate them to the 5-HT
R. Coray and B.B. Quednow
Table 2
Main effects human studies. Superscript arrow symbols refer to directions of effects found in the respective studies. ↑: memory improvement. ↓: memory deterioration.
→: no effect.
system. A further interesting topic to pursue are theta wave changes
found to occur after modulating 5-HT levels. For example, Kragel et al.
(2020) suggested that encoding and retrieval happens at different pha­
ses of hippocampal theta oscillations, an observation which may provide
indications why a lower central 5-HT tone supported encoding under
some conditions (e.g. spatial learning).
In addition, another intriguing issue to be addressed is the fact that 5-
HT might differently influence distinct forms of synaptic plasticity. In
this respect, it was found that various forms of LTP contribute to
different aspects of memory storage with theta frequency and CaMKII-
(calmodulin-dependent protein kinase) dependent LTP being particu­
larly necessary for spatial navigation (Bach et al., 1995; Rotenberg et al.,
1996). This was indicated by the observation, that CaMKII mutant mice
exhibit a selective loss of hippocampal LTP in the range of the theta
frequency and displayed impairments in spatial memory but not in
contextual memory storage (Bach et al., 1995; Silva et al., 1992).
Remarkably, TRP depletion-related results are consistent to in­
vestigations in recurrent MDMA users (human 5-HT lesion model).
Accordingly, MDMA-induced 5-HT deficiency was most pronounced in
the domain of verbal memory, but not in the visual domain (Bhattachary
and Powell, 2001; Burgess et al., 2011; Kalechstein et al., 2007; Qued­
now et al., 2006).
Some other mechanism of actions underlying TRP depletion than
purely serotonergic ones have been suggested (see van Donkelaar et al.,
2010 for an extensive review). One of the most debated is the possible
interaction between TRP depletion and the enzyme nitric oxide synthase
(NOS). Yet, NOS inhibitors have been demonstrated to severely impair
both, spatial learning and object recognition (Gocmez et al., 2015;
Majlessi et al., 2008; Pitsikas, 2015). It is therefore interesting that TRP
depletion consistently deteriorated object recognition, but not spatial
memory and navigation in animals. Two studies revealed very similar
findings in humans. This argues rather against NOS as a critical mediator
in TRP depletion induced object recognition deficits.(Tables 1 and 2).
Potential reasons for the contrasting effects between acute and
chronic 5-HT deficiency specifically in contextual fear conditioning can
just be discussed briefly here, as their elaboration would exceed the
scope of this review. 5-HT incorporates an influential role in circuit
formation and the refinement of neuronal connections during develop­
ment and therefore, alterations of the 5-HT system concomitant adap­
tations may have behavioral consequences (e.g. Daubert and Condron,
2010; Mosienko et al., 2014). Normally, MR – hippocampal 5-HT input
12
Neuroscience and Biobehavioral Reviews 139 (2022) 104729
modulates the output in dorsal and ventral hippocampus in opposite
directions, causing cell firing attenuation in the dorsal and facilitation in
the ventral segment (Mlinar and Corradetti, 2018). In response to
aversive stimuli, 5-HT level of dorsal hippocampus increases, serving
protective functions (Almada et al., 2013; Dai et al., 2008) and likely
counteract the consolidation of the contextual component in stressful
memories (Graeff et al., 1996; Maren et al., 2013). At the same time,
ventral hippocampal facilitation likely boosts the signal to its down­
stream targets, such the amygdala, that are involved in emotional
regulation (Mlinar and Corradetti, 2018; Ohmura et al., 2010; Twining
et al., 2020). The failure in retrieving fear-related contextual memory
occurs by not activating the subsequent fear circuit that induces freezing
behavior (Tada et al., 2004). Such a modulation was lacking in chron­
ically 5-HT deficient mice (Waider et al., 2019). Since innate anxiety
behaviors were reduced in chronic-5-HT deficient animals (Dai et al.,
2008; Mosienko et al., 2014), albeit inconsistently (Gutknecht et al.,
2015), exaggerated contextual fear conditioning is plausibly a conse­
quence of altered synaptic plasticity and circuitry in the hippocampus
resulting from lifelong 5-HT deficiency, and rather not due to a more
anxious phenotype. Abovementioned considerations pinpoint the MR as
crucial in fear-conditioning and this might further be a highly relevant
basis for exploring differences in terms of raphe nuclei and
material-specific consolidation (Lieben et al., 2006; Lin et al., 2021;
Netto et al., 2002).
6.2. High global 5-HT
Spatial navigation and object memories were both impaired after
either acute SSRI or acute MDMA treatment in animals, yet mixed effects
were obtained for contextual fear conditioning. Acute SSRI adminis­
tration in humans yielded inconsistent results so far. The global eleva­
tions in extracellular 5-HT concentrations trigger non-specific increases
in the activity of autoreceptors and heteroreceptors, which impede
efficient information processing (Fuller, 1995). Hence, resulting mem­
ory alterations might involve complex interactions and currently, it is
not known which receptors are indeed involved in the reduced memory
performance after elevation of 5-HT and whether different phases of
memory are affected differently.(Fig. 1).
R. Coray and B.B. Quednow
6.3. 5-HT receptors
For all forms of declarative memories investigated, procognitive ef­
fects of 5-HT1AR antagonists were demonstrated, while 5-HT1AR ago­
nists as well as changes in their expression profile yielded mixed results.
Improving effects on memory are likely mediated via stimulation of
postsynaptic receptors, yet overstimulation of the serotonergic system
might produce the opposite suggesting that associated pro-cognitive
effects may follow a bell-shaped function. There is further evidence
indicating that more efficient pattern separation in hippocampal CA1 is
accountable for improved memory due to increased inhibitory seroto­
nergic tone (Fernandez et al., 2017). 5-HT1AR interact with the cholin­
ergic and glutamatergic system and thus, might serve the treatment of
age-related cognitive disorders. Up until today, however, cognition
improving effects of 5-HT1AR partial agonists applied for treating
schizophrenia-related cognitive impairments in humans (e.g. buspirone
and tandospirone) has not been unambiguously demonstrated yet (Buoli
and Altamura, 2015).
Acute blockade of 5-HT2AR impaired recognition of objects in
context and reduced the conditioned response in contextual fear con­
ditioning, yet contrastingly, improved spatial reference memory
retrieval. Further investigations revealed that 5-HT2ARs in the mPFC
play an important role in controlling contextual retrieval of concurrent
memories by selecting the correct memory trace and suppressing com­
petitors in complex tasks. In rodents – but not in humans – 5-HT2AR
activation enhanced consolidation of object memory and contextual fear
memory as well as the reconsolidation of object memories in the peri­
rhinal cortex, especially when administered directly after learning,
while pre-training activation facilitated extinction of fear memories. In
spatial learning, however, agonistic ligands produced impairments.
Accordingly, effects of 5-HT2AR on declarative memories could differ
across mnemonic modalities. There is also an impairing side effect of
hallucinogenic agents on spatial navigation that merits consideration
(Zhang et al., 2017). Further studies with regard to possible
cognition-enhancing effects of 5-HT2 CR antagonists could certainly be
beneficial (Bertaina-Anglade et al., 2011).
Although the effects of 5-HT3R antagonism on spatial learning were
inconclusive in healthy animal populations, it may represent a potential
treatment for cholinergic dysfunction (Passani and Blandina, 1998).
Pro-cognitive effects on acquisition and/or consolidation were also
induced by 5-HT4R agonists and on the other hand, impairments were
observed when blocking this receptor. Positive effects also occurred in
humans, as evidenced by increased precision in recall and recognition of
verbal memory, concepting 5-HT4R agonists as a potential target for the
treatment of cognitive deficits (Murphy et al., 2020b).
5-HT6Rs constitute a further promising therapeutic objective
particularly for the prevention of age-related deficits due to its in­
teractions with the cholinergic system. Interestingly, both agonistic and
antagonistic ligands enhanced declarative memories in a similar vein,
yet via distinct neuronal mechanism of action (Kendall et al., 2011).
5-HT7R were of special relevance for the detection of novelty in
object recognition without having direct behavioral impacts in spatial
learning. Interestingly, KO models provided an example of dissociations
between egocentric and allocentric spatial learning strategies. Specific
deficits in contextual learning were uncovered, assumingly involving a
cognitive subroutine that is less important for egocentric spatial-
navigational processes with 5-HT7Rs playing a role (Sarkisyan and
Hedlund, 2009).
7. Conclusion
Taken together, the findings reviewed here indicate that acutely
lowered brain 5-HT tonus most likely impairs protein synthesis-
dependent consolidation in humans and rodents. Considering task-
related cognitive processes unveils material-specify for object-related
and verbal memory content being particularly affected. By contrast,
13
Neuroscience and Biobehavioral Reviews 139 (2022) 104729
spatial navigation might even benefit from low serotonergic tone in
support of encoding. Central and non-specific pharmacologically
induced 5-HT elevations may be beneficial for consolidation in some
cases, but further studies are clearly needed for clarification. 5-HT1AR
antagonists, 5-HT4R agonists, and 5-HT6R ligands might comprise
promising targets for declarative memory impairments.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgement
RC was supported by a grant of the Novartis Foundation for Medical-
Biological Research (#19C167).
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