NBR 416

NEUROSCIENCE AND
BIOBEHAVIORAL
REVIEWS

PERGAMON Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125

www.elsevier.com/locate/neubiorev
Review

5-HT system and cognition

A. Meneses*
Departamento de Farmacologı́a y Toxicologı́a, CINVESTAV-IPN, AP 22026, México D.F. 14000, Mexico
Received 22 January 1999; received in revised form 2 June 1999; accepted 23 September 1999

Abstract
The study of 5-hydroxytryptamine (5-HT) system has benefited from the identification, classification and cloning of multiple 5-HT
receptors (5-HT1 to 5-HT7). Growing evidence suggests that 5-HT is important in learning and memory and all its receptors might be
implicated in this. Actually, 5-HT pathways, 5-HT reuptake site/transporter complex and 5-HT receptors show regional distribution in
brain areas implicated in learning and memory. Likewise, the stimulation or blockade of presynaptic 5-HT1A, 5-HT1B, 5-HT2A/2C and 5-
HT3 receptors, postsynaptic 5-HT2B/2C and 5-HT4 receptors and 5-HT uptake/transporter sites modulate these processes. Available
evidence strongly suggests that the 5-HT system may be important in normal function, the treatment and/or pathogenesis of cognitive
disorders. Further investigation will help to specify the 5-HT system nature involvement in cognitive processes, pharmacotherapies,
their mechanisms and action sites and to determine under which conditions they could operate. In this regard, it is probable that
selective drugs with agonists, neutral antagonist, agonists or inverse agonist properties for 5-HT 1A, 5-HT1B/1D, 5-HT2A/2B/2C, 5-HT4 and 5-
HT7 receptors could constitute a new therapeutic opportunity for learning and memory alterations. q 1999 Elsevier Science Ltd. All
rights reserved.
Keywords: Learning; 5-HT receptors; Memory; Consolidation; Serotonin

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1111
2. 5-HT receptors occur in brain areas involved in learning and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1112
3. 5-HT1A receptors manipulation on behavioral cognitive tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1113
3.1. Pre- and post-synaptic 5-HT1A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
3.2. 5-HT1A receptors: agonism, inverse agonism and antagonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
3.3. 5-HT1A receptors co-localization with other 5-HT receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116
4. 5-HT1B/1D and 5-HT2A/2B/2C receptors manipulation on cognitive behavioral tests . . . . . . . . . . . . . . . . . . . . . . . . . .1116
5. 5-HT1B/1D receptors: agonism, inverse agonism and antagonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1116
6. 5-HT2A/2B/2C receptors: agonism or inverse agonism and antagonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1117
7. 5-HT3 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1117
8. 5-HT4 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1118
9. 5-HT1E, 5-HT1F, 5-HT5A/5B, 5-HT6, 5-HT7A/7B and 5-HTP receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1119
10. 5-HT uptake/transporter complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1119
11. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1120
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1120

1. Introduction ing field, with recent 5-HT receptor discoveries, their

Most preclinical studies indicate that the investigation on
serotonin (5-hydroxytryptamine, 5-HT) is a rapidly expand-
* Tel.: 152-5675-9075; fax: 152-5675-9168.
E-mail address: ameneses@df1.telmex.net.mx (A. Meneses)
0149-7634/99/$ - see front matter q 1999 Elsevier Science Ltd. All rights reserved.
PII: S0149-763 4(99)00067-6
possible functions and the new highly specific compound
synthesis. Growing evidence indicates that 5-HT system is
involved in learning and memory processes [78,79]. For
instance, a Medline search as [5-HT and memory] or
[5-HT and learning] produced 394 or 1512 articles. Reviews
concerning 5-HT drug effect on cognitive processes have
1112 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125

Table 1
5-HT Receptors or mRNA localized in brain areas involved in learning and memory and 5-HT changes observed during aging and Alzheimer’s disease ( " :
increased; # : decreased; ˆ : no change; nd: not determined)

5-HT Marker and Receptor Brain Area a Aging Alzheimer’s References

Disease

Raphe complex nd # [117]

5-HT release # # [42]
5-HT uptake/transporter # # [6,7,77–79,117,171]
5-HT1A Hippocampus (dentate gyrus, CA1, CA3), lateral #b #b [41,77,124]
septum, raphe n, entorhinal c, central amygdala
5-HT1B Globus pallidus, substantia nigra (pars reticula) nd # [41,75,77]
olivary pretectal n, dorsal subiculum, superior
colliculi (superficial layer)
5-HT1D Globus pallidus, substantia nigra, caudate- nd # [41,75,77]
putamen, n accumbens, frontal cortex
5-HT2A Claustrum, olfactory tubercle, frontal cortex, nd # [7,41]
neocortex (layer IV), raphe n
5-HT2B Cortex, amygdala, caudate, hypothalamus nd nd [9]
5-HT2C Choroid plexus, substantia nigra, globus pallidus, nd # [7,41]
neocortex (layer III), hippocampus (CA1, CA3),
raphe n
5-HT3 Amygdala (baso-lateral n), entorhinal cortex, nd ˆ [20]
hippocampus
5-HT3A/3B Amygdala, hippocampus nd nd [176]
5-HT4 Hippocampus (CA1), caudate, amygdala, colliculi nd # [29]
(superior layer)
5-HT5 Hippocampus, habenula nd nd
5-HT5B Habenula, hippocampus (CA1), raphe n nd nd
5-HT6 Piriform & prefrontal cortex, striatum, nd nd
hippocampus (CA1–CA3, dentate gyrus),
amygdala
5-HT7A Hippocampus, amygdala, cortex, raphe n #, ˆ nd [187,188]
5-HTP Hippocampus nd nd

a
Brain areas where 5-HT receptors or messenger RNA (mRNA) have been identified.
b
Both columns were taken form references cited to the right.

actually been published [5,13,16,20,29,41,46,63,76,78–
80,83,84,111,114,121,179,186]. Unfortunately, there is no
available work at present that offers a meaningful discussion
of 5-HT system involvement on cognitive processes. In
previous works [78,79], it was the intent to demonstrate
5-HT system involvement per se on physiological, patho-
physiological and therapeutic cognitive implications. In as
much as further findings seem to be consistent with this
contention, in the present work this line of argument is
reconsidered and extended. In addition, since 5-HT recep-
tors have been frequently associated with a function and/or a
disease, and considering that 5-HT is important for cogni-
tion and that all its receptors might be implicated, in this
work it was thought that it would be meaningful to look for
5-HT mechanisms mediating the learning and memory
normal functions and/or dysfunctions.
2. 5-HT receptors occur in brain areas involved in
learning and memory
Using receptor binding, transduction pathways coupled to
secondary messengers and functional activity ligands 5-HT
receptors have been identified into families and subtypes
(5-HT1A/1B/1D/1E/1F, 5-HT2A/2B/2C, 5-HT3A/3B, 5-HT4A/4B/4C/4D,
5-HT5A/5B, 5-HT6 and 5-HT7A/7B/7C/7D) [12,28,29,53,54,
115,116]. Similarly, 5-HT1A, 5-HT1B/1D, 5-HT2A/2B/2C,
5-HT3A/3B, 5-HT4A/4B, 5-HT5A/5B, 5-HT6, and 5-HT7 receptors
[1,3,28,29,53,54,106,115,132,176] have been localized so
far, in brain areas involved in learning and memory [135],
including the hippocampus, amygdala and cortex (Table 1,
Refs. [78,79,83] see Ref. [77], for review). Serotonergic
pathways and receptors seem also to be implicated in
brain areas involved in normal and dysfunctional cognitive
processes [165]. For instance, Alzheimer’s disease (AD)
apparently is associated with decrements in 5-HT markers
such as the raphe complex, the uptake/transporter complex
and in the number of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A,
5-HT2C and 5-HT4 receptors [77,79]. Schizophrenics and
AD patients showed highly significant correlations of
cortical 5-HT and 5-HIAA levels with cognitive impair-
ment [66]. In this context, it is important to mention that
different 5-HT mechanisms had been under investigation
as potential treatments for amnesia and AD [78].
 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125 1113

Table 2
Effects of 5-HT1A receptor agonists and antagonists on cognitive behavioral tests (aACQ: acquisition; CON: consolidation; RET: retention; " : facilitation; # :
impairment; ˆ : no change; nd: not determined; RAP: repeated-acquisition procedure; DCD: delayed conditional discrimination; EXT: extinction; DNMTS:
delayed nonmatch-to-sample task; DMTP: delayed-matching-to-position; DAT: delayed alternation task; AUTO: autoshaping; PA: passive avoidance; AA:
active avoidance; WM: water maze; RM: radial maze; PM: plus maze)

Behavioral Task Drug (mg/kg) ACQa CON RET References

Agonists
PA, AA 8-OH-DPAT (0.01–0.5) # #, ˆ # [93,141,144,145,150,152,178]
Buspirone (0.032–5.0) # nd # [151,153,155]
Ipsapirone (0.5–20.0) # nd # [154,156]
Gepirone (10.0) # nd nd [152]
PA Tandospirone (2.5) # ˆ nd [145]
AA (1.0) " # nd [149]
EXT, RAP 8-OH-DPAT (0.015–0.25) # " nd [138,158,169]
DMTP (0.003–1.0) ˆ, ", # nd nd [19,32,119]
Buspirone (0.01) ˆ nd nd [19,108]
Ipsapirone (2.5) nd nd ˆ [19,143]
DNMTS (2.5) nd nd ˆ [143]
8-OH-DPAT (0.2–0.5) ˆ nd ˆ, # [140]
RM (0.1–0.3,1.0) ", # nd nd [159,166]
PM (0.01) nd nd ˆ [144]
WM (0.003–0.25) ˆ, # ˆ # [14,15,59,108,168] a
Buspirone (0.032–5.0) # nd # [139]
DAT SR57746A (0.3–3.0) " nd " [170,185] b
RAP LY228729 (0.32–3.2) # nd nd [169]
RAP Buspirone (0.032–5.0) # nd # [139,158,169]
AUTO 8-OH-DPAT (0.015–0.062) ˆ, " ", ˆ ", ˆ [126,147,148]
Buspirone (1.0–5.0) nd # nd [146]
RAP, WM Ipsapirone (0.5–20.0) # nd # [154,157]
DCD Ipsapirone (0.5–20.0) # nd nd [142]
Antagonists
PA BMY7378 (1.0) ˆ nd nd [145]
PA, RAP NAN-190 (1.0–3.2) # nd nd [152,169]
DCD NAN-190 (0.1–3.0) ˆ, # nd nd [142]
DCD Flesinoxan (1.0) # nd nd [142]
DMTP NAN-190 (2.0) ˆ, # nd nd [153]
DMTP, RM WAY10063 (0.003–3.0) ˆ nd nd [32,166]
RAP p-MPPI (3.2 or 10.0) ˆ nd nd [170]
AUTO, PA WAY100135 (3.0–20.0) ˆ ˆ nd [87,167,179] [168] c
AUTO NAN-190 (0.5) nd ˆ nd [81]
S-UH-301 (0.3–3.0) nd ˆ nd [87]
WAY100635 (0.001–1.0) nd ˆ nd [87]

a
Intracerebral administration.
b
Aged rats.
c
Intrahippocampal administration.

3. 5-HT1A receptors manipulation on behavioral
cognitive tests
5-HT1A receptors have been the most extensively studied;
even though the available evidence is inconsistent (see
[78,79,84], for reviews), a few points have become clear
(Table 2). For instance, except for a facilitated learning
acquisition elicited by tandospirone, at 1.0 mg/kg, 5-HT1A
agonists had no effect or impaired learning acquisition
(ACQ), consolidation (CON) and retention (RET) in passive
(PA) and active avoidance (AA) tests. In the behavioral tests
used to measure memory, i.e. delayed-matching-to-position
(DMTP) or delayed nonmatch-to-sample task (DNMTS),
5-HT1A agonists had no effect, enhanced or impaired learn-
ing ACQ or CON. More significantly, the 5-HT1A receptor
agonists 8-OH-DPAT and SR 57746A, enhanced learning
acquisition, consolidation or retention in the behavioral
tasks of repeated-acquisition procedure (RAP), autoshaping
(AUTO), DMTP or radial maze (RM). Interestingly, SR
57746A improved ACQ and/or CON in aged rats
[170,185]. During learning acquisition or consolidation,
5-HT1A antagonists did not alter performance in the
DMTP, RM, RAP, PA and AUTO tasks. In contrast, the
partial 5-HT1A agonists BMY7378, NAN-190 and flesi-
noxan had no effect or impaired learning ACQ in the
behavioral tests of RAP, PA, AUTO, delayed conditional
discrimination (DCD) or DMTP. Notability, the 5-HT1A
receptor antagonists p-MPPI, WAY100135, S-UH-301 and
WAY100635 did not alter learning acquisition or consolida-
tion in the behavioral tests of PA, DMTP, RM, RAP or
1114 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125

Table 3
Effects of 5-HT1B/1D and 5-HT2A/2B/2C receptor agonists and antagonists on cognitive behavioral tests (ACQ: acquisition; CON: consolidation; RET: retention;
" : facilitation; # : impairment; ˆ : no change; nd: not determined. RAP: repeated-acquisition procedure; PA: passive avoidance; AA: active avoidance; WM:
water maze; RM: radial maze; DCD: delayed conditional discrimination; DNMTS: delayed nonmatch-to-sample task; DMTP: delayed-matching-to-position;
AUTO: autoshaping; CCNM: classically conditioned nictitating membrane; CR: conditioned response)

Behavioral Task Drug (mg/kg) ACQ CON RET References

Agonists
PA, RM, WM, DCD TFMPP (0.1–1.0) # nd nd [59,142,159,160]
PA mCPP (0.1–10.0) # nd nd [160]
LSD (0.1) # nd nd [41]
DOI (0.6–2.0) #, ˆ # ˆ [150,160]
DOB (0.1–2.0) # nd nd [167]
RM RU 24969 (0.3–3.0) # nd nd [96,159]
CP 93129 (0.3–3.0) # nd nd [161,173] a
CR TFMPP (1.25) " nd nd [46]
Quipazine (1.25) " nd nd [46]
AUTO TFMPP (0.1–10.0) nd # nd [85]
MCPP (0.1–10.0) nd # nd [85]
GR486611X (1.0–10.0) nd # nd [88]
Quipazine (5.0–10.0) nd # nd [79]
DOI (0.01–0.1) nd " nd [85]
1-NP (0.1–1.0) nd # nd [85]
WM DOI (0.1–0.25) ˆ nd nd [60]
CCNM LSD (0.001) " nd nd [46]
DOM (0.074) " nd nd [46]
Antagonists
PA Pirenperone (0.56–3.2) #, ˆ " " [5,167]
RP62203 (0.25–4.0) ˆ nd nd [161]
SR46349B (1.0–10.0) " nd nd [160]
SDZSER082 (0.1–1.0) " nd nd [160]
SB200646A (3.0–30) " nd nd [160]
Spiperone (0.3–3.0) " nd nd [160]
Ketanserin (0.56–5.0) # " nd [5,150]
DNMTS, CR, DCD (0.3–3.0) ˆ, # ", ˆ " [5,46,142,129,162]
CCNM, PA Ritanserin (0.3–20) # nd nd [46,78,130]
DNMTS Methiothepin (0.15) # nd nd [110,111,166]
Methysergide (3.0–15.0) ˆ nd " [111,166]
CR Spiperone (.0.2) ˆ nd nd [46]
AUTO Ketanserin (0.001–2.0) nd " nd [88]
Methiothepine (0.125–0.25) nd ˆ, " nd [79]
Mesulergine (0.2–0.4) nd ˆ, # nd [88]
Ritanserin (0.1–0.5) nd ˆ, " nd [88]
5-HT-moduline (50–500 mg i.c.v) a nd ˆ, " nd [88]
GR127935T (1.0–10) nd ˆ, #, " nd [88]
MDL100907 (0.1–3) nd ˆ nd [88]
SB200646A (2.0–40.0) nd ˆ nd [89]
CCNM BOL (1.66) # nd nd [46]
MDL11939 (0.2) # nd nd [46]
Pizotifen (2.5) # nd nd [46]

a
Intrahippocampal administration ( bintracerebral administration.)

AUTO. A further behavioral tests analysis revealed (Table
2) that the prototype 5-HT1A receptor agonist 8-OH-DPAT:
(i) at low doses (0.1–0.016 mg/kg) had no effect or
improved learning; (ii) when stimulated, presynaptic
5-HT1A receptors improved learning and/or reversed learn-
ing and memory deficits [87,168]; (iii) when stimulated,
postsynaptic 5-HT1A receptors impaired learning acquisition
and retrieval, but not consolidation, in aversive learning
(e.g. in PA) [90,179]; (iv) diminished exploration and
food intake behaviors [126,147,148,173], but did not alter
learning acquisition [84,126]; (v) the 5-HT1A receptor
antagonists WAY100135, WAY100635 and S-UH-301,
had no effect by themselves on learning consolidation (i.e.
they are silent, but see Refs. [128,133]); nevertheless, they
were able to reverse the induced effect by 8-OH-DPAT,
while p-chloroamphetamine (PCA) did not alter the silent
characteristic of 5-HT1A receptor antagonists; and (vi)
WAY 100635 had no effect by itself but blocked the
effects produced by 8-OH-DPAT in PA, spatial dis-
crimination, AUTO, DMTP and RM tests (Table 2,
 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
[49,87,119,168,179]). Notably, in the learning task of
AUTO [24,125] so far a large number of 5-HT mechanisms
of action have been explored (see Tables 2 and 3, and
text).
3.1. Pre- and post-synaptic 5-HT1A receptors
During different stages of passive avoidance training,
[ 3H]-5-HT specific binding is decreased, while MAO activ-
ity and 5-HIAA transport are increased from serotonergic
terminals [91]. Actually, the specific anatomical site where
5-HT acts (i.e. different effects depending on the type of
5-HT system or receptor located in brain areas under
study) determines 5-HT system’s role in cognitive
processes. For instance, 8-OH-DPAT injected systemically
impaired performance accuracy in DNMTP, while its
central infusion into median, but not dorsal, raphe nucleus
improved performance [127]. Pretraining 8-OH-DPAT
administered into the hippocampal (CA1) area impaired
performance accuracy [127] and spatial discrimination
acquisition [14,15,112]. In contrast, post-training CA1 infu-
sion of 8-OH-DPAT or NAN-190 (a partial 5-HT1A agonist)
into entorhinal cortex inhibited short- but not long-term
memory in an inhibitory avoidance task, while 8-OH-
DPAT intra-entorhinal infusion enhanced short-term
memory, but impaired long-term memory [56]. Neither
8-OH-DPAT nor NAN-190 by themselves had any effect
on retrieval of either short- or long-term memory when
given prior to testing [56]. Furthermore, post-training
intra-amygdala infusion of 8-OH-DPAT at low doses [69],
but not the 5-HT uptake inhibitor fluoxetine [55], produced
significant dose- and time-dependent retention deficits in a
PA task, while biphasic effects were induced by
WAY100635 (i.e. at 0.1 mg enhanced retention while at
10 mg impaired performance), but reversing the impairment
induced by 5-HT1A agonists. Within this framework, it is
noteworthy that electrophysiological studies [2] had showed
that ionophoretic 8-OH-DPAT intra-amygdala infusion
induced inhibitory and excitatory effects on neural activity,
which were blocked by different 5-HT1A and non-serotoner-
gic drugs. The same authors suggested that interneurons
seem to be involved in the mediation of 8-OH-DPAT-
induced effects and that 5-HT neurotransmission, at least
via 5-HT1A receptors, is involved in information processing
within the amygdala [2].
Extensive evidence indicates serotonergic regional
differences influences on cholinergic, GABAergic and
glutamatergic activity [1,16,25,94,107,121]. For instance,
5-HT1A auto- and/or hetero-receptors [11,16,19,33,35,
44,73,79,98,107,114,120] modulating serotonergic, choli-
nergic, glutamatergic and GABAergic systems in raphe
nuclei, amygdala, septum, hippocampus and neocortex
brain areas are strongly implicated in cognitive processes
[79]. 5-HT1A receptors are expressed by cholinergic neurons
in medial septum and diagonal band of Broca [65] and occur
as somatodendritic receptors in the hippocampus [57].
1115
Moreover, it is strongly supported by the following evidence
that 5-HT1A receptors may play a role in learning and
memory modulation: (i) serotonergic afferents from raphe
complex to cerebral cortex were significantly decreased in
AD [117]; (ii) inhibitory 5-HT autoreceptor undergo age-
dependent alterations [42]; (iii) 5-HT1A receptors decline in
rat cortex, hippocampus and cholinergic basal forebrain
nuclei during aging [97] and in post-mortem brains of AD
patients (Table 1); and (iv) significant decrements in affinity
for 5-HT1A receptors have been detected in frontal cortex,
hippocampus and amygdala across age [61] and age-depen-
dent differential regulation of G1 protein levels in aged
hippocampus [71].
Age-related loss of 5-HT attributable to disruptions of
5-HT1A receptors or changes in S-100b lead to the proposi-
tion that in the brains of AD patients, neurons are not dying,
but regressing to immature states induced by disruptions in
the 5-HT system and S-100b glial [7]. S-100b cortical is a
neurotrophic factor, whose release appears to be mediated
via 5-HT1A or 5-HT7 receptor stimulation on astrocyte [131].
S-100b excessive or insufficient activity may impair learning
consolidation [99]; treatment with 5-HT1A agonists in lesioned
adult animals increases S-100b release and promotes the over-
growth of serotonin terminals, suggesting that this effect is
more robustly expressed in a damaged brain [7,131].
3.2. 5-HT1A receptors: agonism, inverse agonism and
antagonism
Evidence that 5-HT1A receptors blockade ameliorated the
cognitive impairment induced by fornix transection [45] or
the NMDA antagonist dizocilpine [8] has led to the proposi-
tion that 5-HT1A receptors, together with cholinergic and
glutamatergic systems, could be modulating learning conso-
lidation in cognitively impaired animals. This has provided
support to the notion that 5-HT1A receptor antagonists may
be useful in the cognitive disorders treatment [13,20,29,79].
Nevertheless, contrary to this conclusion, there is evidence
showing that 8-OH-DPAT at low doses improved accuracy
in DMTP task, attenuated scopolamine-induced accuracy
impairment and, at higher doses, potentiated the impairment
[19]. Further, post-training administration of 8-OH-DPAT
and S-UH-301 reversed learning deficit induced by dizocil-
pine and scopolamine, whereas WAY100635 reversed only
the scopolamine effect [87]. Possibly, 5-HT1A autoreceptors
receive relatively little basal tone during learning consolida-
tion; notwithstanding, 5-HT1A receptor stimulation might be
able to reverse a poor retention [87] as a result of mediating
pathological and/or therapeutic, but not normal, mechan-
isms on cognitive processes. The reason why 5-HT1A
agonists [16,19,87,96,97,127] and antagonists [8,13–
15,25,31,34,49,50,59,60,108,109,112,119] may influence
both normal and altered cognitive processes is unclear at
present. Moreover, there is evidence that the 5-HT1A inverse
agonist SL88.0338-08 [18] facilitated the exploration
activity in an elevated plus-maze [43], and since exploration
1116 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
activity could be considered as a simple habituation learning
test [26], 5-HT1A inverse agonists could constitute a new
approach in cognitive malfunctions treatment. Future
experiments must be designed to investigate the mechanisms
and conditions concerning how and where 5-HT1A agonists,
inverse agonists or antagonists might operate.
3.3. 5-HT1A receptors co-localization with other 5-HT
receptors
5-HT1A receptors in hippocampus and cortex are
co-expressed in single neurons with 5-HT2A–2C and 5-HT4
receptors [1,7,65,132], implicating functional interactions.
The possibility that 5-HT1A, 5-HT2A/2B/2C and 5-HT3 recep-
tor-mediated behavior is subject to functional interactions is
supported by the finding that ketanserin or ondansetron
blocked the facilitatory effect on learning consolidation
induced by 8-OH-DPAT [83–85,87,88]. These results
could indicate that those 5-HT receptors play opposite
roles during the cognitive processes. Indeed, 5-HT1A
agonists are directly inhibitory upon serotonergic neurons
in the raphe nuclei (possibly at insufficient doses to affect
post-synaptic 5-HT1A receptors), thus for this inhibition the
net effect may be disinhibitory for postsynaptic neurons that
express 5-HT1A receptors, and simultaneously dysfacilita-
tory for postsynaptic neurons expressing 5-HT2, 5-HT3
and 5-HT4 receptors [1].
4. 5-HT1B/1D and 5-HT2A/2B/2C receptors manipulation on
cognitive behavioral tests
Most of the preclinical studies have demonstrated that
drugs displaying preferential affinity for 5-HT1B/1D or
5-HT2A/2B/2C receptors [53] modulate learning ACQ and
CON [80]. For instance, as shown in Table 3, TFMPP and
quipazine improved conditioned responses, while all other
drugs impaired learning acquisition or consolidation in the
behavioral tasks of PA, WM or RM, DCD or AUTO. DOI
had no effect or impaired learning ACQ, CONS and RET in
PA test; nonetheless, this drug did not affect learning ACQ
in WM or improve consolidation in AUTO. LSD and DOM
improved learning ACQ in the classical conditioned
nictitating membrane (CCNM) preparation, while the
antagonists BOL, MDL11939 and pizotifen produced a defi-
cient learning ACQ [46]. As Table 3 shows, except for DOI,
all other drugs tested in the AUTO task produced a deficient
learning consolidation.
5. 5-HT1B/1D receptors: agonism, inverse agonism and
antagonism
The 5-HT1B (formerly named 5-HT1Db) and 5-HT1D
(formerly named 5-HT1Da) receptors [54,74] occur [53,
101] in brain areas associated with cognitive processes
[79]. In this regard, neurochemical and electrophysiological
studies have shown that this stimulation mediates 5-HT
release [1,53,102,103,132] in structures involved in cogni-
tive processes. The number of 5-HT1B/1D receptors in the
hippocampus and cortex of AD patients is actually reduced
(Table 1, Refs. [40,77,79]). As already mentioned, drugs
displaying preferential affinity for 5-HT1B/1D, receptors,
e.g. TFMPP, mCPP and 1-NP, produced decrements in
learning acquisition and consolidation (Table 3, [53,80]).
Also, these drugs display affinity for several 5-HT receptor
subtypes [41,46,53,54,74,80,135], behave as agonists/
antagonists [40,42] and some possess negative intrinsic
activity [4,46,74]. Hence, whether the effects observed
with these compounds could be attributed to the stimulation
or blockade of 5-HT receptors is unclear. To counter these
disadvantages there are several important advantages for
5-HT1B/1D-drug use in learning and memory research. For
instance, in interaction experiments, the 5-HT1B/1D receptor
antagonist GR127935, at 10 mg/kg, strongly antagonized
the decrease in learning produced by the 5-HT1B/1D receptor
agonists GR46611, TFMPP and mCPP; interestingly, PCA
pretreatment completely inhibited decrease and increase
in learning consolidation produced by GR46611 and
GR127935, respectively [87,88]. In addition, GR127935,
at 1.0 mg/kg, decreased learning consolidation; while at
10.0 mg/kg it increased performance the 5.0 mg/kg dose
showed an intermediate, non-significant effect [88].
GR127935 also provided evidence for an endogenous
5-HT interaction with 5-HT1B/1D receptors, since this
antagonist eliminated the increment in learning induced
by fluoxetine, but failed to modify the procognitive effect
induced by 8-OH-DPAT [87,88]. Together these findings
suggest that presynaptic 5-HT1B (or 5-HT1D?) receptor
stimulation decreases learning consolidation, while postsy-
naptic 5-HT1B receptor stimulation seems to facilitate this
process [80,83,87,88]. This conclusion is sustained by the
finding that fluoxetine improved learning consolidation by
favoring the interaction of 5-HT with various 5-HT post-
synaptic receptors, including the 5-HT1B/1D subtype [81].
In this regard, and more importantly, central (i.c.v.) 5-HT-
moduline administration, at 100 and 500, but not 50 mg/kg,
increased learning consolidation [52]. At 50 mg/kg, 5-HT-
moduline antagonized TFMPP, GR46611 and GR127935
decrements, and converted the inactive middle dose of
GR127935 into a dose-enhancing learning consolidation,
while 100 mg/kg of 5-HT-moduline reversed the deficit
induced by scopolamine [52]. 5-HT-moduline is an
endogenous tetrapeptide, which selectively, and in a non-
competitive manner, interacts with 5-HT1B/1D receptors and
behaves allosterically, possibly as an antagonist or inverse
agonist [31]. Similarly, the inverse 5-HT1B receptor agonist
SB 224289A [136] facilitated learning consolidation,
inhibited the impairment effects elicited by scopolamine
or dizocilpine, and, together with a subeffective dose of
GR127935, facilitated performance [52]. Interestingly,
5-HT1B receptor knockout mice exhibited an enhanced
spatial memory performance [181].
 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
6. 5-HT2A/2B/2C receptors: agonism or inverse agonism
and antagonism
The 5-HT2 receptor family includes three subtypes:
5-HT2A (formerly named 5-HT2), 5-HT2B (formerly named
5-HT2F), and 5-HT2C (previously included in the 5-HT1
family and named 5-HT1C). This classification has made
clear that most of the existing drugs for these receptors
are nonselective and behave as mixed agonist/antagonist,
neutral antagonist and/or inverse agonist [46,78,79].
Whether the effects observed with drugs displaying affinity
for 5-HT2A, 5-HT2B and 5-HT2C receptors could be attribut-
able to the stimulation or blockade of 5-HT receptors is
unclear at present. Notwithstanding these limitations, it
has been traditionally accepted that 5-HT2A/2C receptor
blockade improves learning (see Refs. [5,46,63,78–80,
163] for reviews). Thus, while the 5-HT2A/2C receptor
antagonists, ketanserin or ritanserin, administration
improved spatial discrimination and learning consolidation
[5,59], injection of the 5-HT2A/2B/2C receptor agonists/
antagonists, TFMPP, mCPP, 1-NP or mesulergine decreased
learning and memory (Table 3, Refs. [78,79]), and the 5-
HT2A/2C agonist DOB produced a dose-dependent impair-
ment of PA retention, while ketanserin and pirenperone
were ineffective. It should be noted that when 5-HT2 recep-
tor antagonists, pre- vs post-training administration, have
been compared contradictory effects are observed (Table
3). The reason for such discrepancies is unclear, although
it is certain that consideration has to be given to the different
doses and times of drug administration together with beha-
vioral tests employed [78,79]. For instance, pre-training
DOI, at 3 but not 1 mg/kg injection impaired learning on
initial spatial navigation development strategies; appar-
ently, DOI pre-training injection interfered with non-cogni-
tive performance in a working memory test [110,164].
Further experiments have revealed that the 5-HT2A/2B/2C
receptor agonist DOI facilitated learning consolidation
[88], and this effect was enhanced by ketanserin, but
reversed by ritanserin, mesulergine and PCA [85]. The
selective 5-HT2A receptor antagonist MDL100907 [58,62,
92] had no effect on learning consolidation by itself, but
was able to eliminate the DOI and ketanserin effects, and
inhibited the impairment effects elicited by TFMPP, mCPP,
1-NP or mesulergine without altering the increase in learn-
ing consolidation induced by 8-OH-DPAT [85,87,88].
These data point toward a possible 5-HT2A and 5-HT2C
receptors involvement in learning consolidation and could
suggest that the MDL100907 “silent” activity in learning
consolidation may have significant implications in the
development of antipsychotic drug development with no
cognitive side effects [78]. In this regard, it has been
suggested [174] that by altering excitatory transmission,
5-HT2A receptors would be expected to influence higher
order functions, including cognition, and electrophysiolo-
gical and biochemical studies indicate that both DOI
and LSD are potent partial agonists of cortical 5-HT2A
1117
receptors [174]. On the contrary, considering that
5-HT2B receptors occur in the cortex, hippocampus
and amygdala (Table 1, [1,9,27,132]), and that the
5-HT2B/2C antagonist SB 200646A [64] alone had no
effect on learning consolidation, while its co-administra-
tion with MDL100907 facilitated learning consolidation
[89], a role in learning and memory for this receptor
cannot be excluded.
Additional support to the contention that neutral 5-HT
receptor antagonists or inverse agonists could be new
therapeutic tools is provided by the finding that methio-
thepin or ketanserin intra-septal infusion enhanced retention
in a footshock avoidance test [34], and systemic admini-
stration of methiothepin improved learning consolidation
in AUTO (Table 3). As ketanserin and methiothepin display
inverse agonism for 5-HT1A, 5-HT1B/1D, 5-HT2A/2C and
5-HT7 receptors [4,28,46,52–54,63,74,79,80,84,95] this
contention must be taken with caution. Interestingly, the
5-HT2A receptor agonists, DOI and DOM, and the 5-HT2A/
2C receptor antagonists, ketanserin and pirenperone had no
effect or enhanced associative learning, while the 5-HT2A/2C
receptor antagonists MDL11939, pizotifen and cyprohepta-
dine impaired performance [46,79,80,122,123]. Ritanserin
and MDL11939, but not LY53857, retarded acquisition in
associative learning test, possibly acting as 5-HT2A/2C
inverse agonists [129,130]. It is noteworthy that post-
training injection of ketanserin improved learning consoli-
dation in aged rats and mice in an aversively motivated task
[5,114] and reversed cycloheximide-induced amnesia [93],
and also that 5-HT2 receptor mutant mice exhibited abnor-
mal performance in a WM test but normal acquisition of
appetitively motivated operant lever-press response [177].
Notably, the mixed 5-HT2 agonist/antagonist mCPP
impaired episodic and semantic memory in AD patients,
but only slight affected performance in age-matched control
[63,77], and in AD appears to compromise the 5-HT2A/2C
receptors (Table 1, Refs. [5,7,41,63]).
7. 5-HT3 receptor
Apparently, 5-HT3 receptors are conserved in AD
(Table 1, Refs. [20,79,80]) and preliminary studies indicate
that in some AD patients 5-HT3 antagonists reversed the
scopolamine- and age-induced impairments on cognitive
measures [20,105]. The 5-HT3 receptor antagonists
ondansetron, granisetron, tropisetron, itasetron, SEC-579
and WAY100579 seem to have procognitive effects and
counteract deficits in learning associated with dysfunction
of central cholinergic neurons during aging [20,50,51,
100,172]. However, ondansetron failed to attenuate the
scopolamine-induced impairment in Stone maze [20], and
has been abandoned due to lack of efficiency in AD patients
[172]. It has been suggested that the effective action of 5-
HT3 receptor antagonists may be task dependent and require
chronic treatment [20], and, differential effects have been
1118 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
observed to be induced with 5-HT3 receptor antagonists in
PA and WM tests [104]. In addition, pharmacological,
physiological and structural studies have provided evidence
for subtypes of 5-HT3 receptors (see [33], for a recent
review). Interestingly, 5-HT3B and transcripts of this subunit
are coexpressed with the 5-HT3A subunit in the amygdala,
caudate and hippocampus [176].
Preclinical studies indicate that the 5-HT3 agonist 1-(m-
chlorophenyl)-biguanide (mCPBG) impaired learning CON,
whereas tropisetron and ondansetron improved perfor-
mance, and reversed the effect induced by mCPBG [51].
Most importantly, the mCPBG, tropisetron or ondansetron
effects were significantly decreased by PCA pretreatment,
thus implying that the activation and blockade of 5-HT3
receptors may be involved in learning impairment and
enhancement, respectively [51]. Likewise, electrophysio-
logical studies have shown that 5-HT3 heteroreceptors
modulate the activity of several neurotransmitters, including
cholinergic and glutamatergic systems [1,20,53,57,
107,120], possibly localized in the amygdala, hippocampus
and on non-5-HT neurons [50,79,83,100,107]. 5-HT3
receptor agonists administration enhanced hippocampal
cholinergic function and this effect was eliminated by
5HT3 receptor antagonist’s co-administration [16,121]. In
this regard, in autoradiographic studies 5-HT3 receptors
have been identified in the amygdala, hippocampus and
entorhinal cortex (Table 1, [79]), which are not reduced
when 5,7-DHT is administered into the dorsal raphe nucleus
[57]. Some of these 5-HT3 heteroreceptors could be located
on the soma, axon and/or the GABAergic interneurones
nerve terminals [32,53,134], which could be consistent
with the finding that 5-HT3 (hetero?)receptors mediate
learning and memory processes [120]. Indeed, 5-HT3
antagonists administered into amygdala improved learning
[20] and electrophysiological studies have shown 5-HT3
receptors acting as heteroreceptors in septum, hippocampus,
nucleus magnocellularis and cortex (Table 1) modulate
glutamatergic neurotransmission [1,16,20,53]. Thus, while
neural firing inhibition through autoreceptors involves
somatodendritic 5-HT1A receptors, the inhibitory or facilita-
tory effect of 5-HT release is mediated by 5-HT1B/1D or
5-HT3 receptors [1,20,53,74], respectively. Notably, in
contrast with the traditional fast, transient, rapidly desensi-
tized, depolarizing ionotropic action for 5-HT3 receptor
agonists, a slow, depressant action with little or no desensi-
tization mediated by metabotropic 5-HT3 receptors has been
reported [70].
8. 5-HT4 receptors
There is evidence indicating that the 5-HT4 receptors
number decrease in AD (Table 1). Autoradiographic studies
indicate that 5-HT4 receptors are localized in the habenula,
hippocampus and amygdala (Table 1, [29,79,83]) and
electrophysiological studies have shown that 5-HT4
receptors mediate a slow, long-lasting excitatory response
in the hippocampus [1,29,182]. The 5-HT4 receptor agonists
BIMU1 or BIMU8 improved social learning ACQ,
prevented amnesia and reversed deficits in learning and
memory following hypercapnia and hypoxia [36–
39,68,72]. Similarly, pre-training BIMU1 or BIMU8 injec-
tion enhanced ACQ, while post-training impaired learning
CON on AUTO task [82]. BIMU1 enhanced short-term
memory in social olfactory learning and this effect was
blocked by the 5-HT4 receptor antagonist GR125487
[68,72,183]. The 5-HT4 receptor agonist RS67333 reversed
the performance deficit produced by atropine and this effect
was blocked by 5-HT4 receptor antagonists [29]. Interest-
ingly, the 5-HT4 receptor agonist RS17017 enhanced
delayed matching performance in young and old macaques
[124]. Moreover, post-training administration of the 5-HT4
receptor antagonists, SDZ 205-557 and GR125487 or PCA
pretreatment, did not affect learning per se in AUTO task
[82]. However, SDZ 205-557 and GR125487, but not PCA,
were able to reverse BIMU1 and BIMU8 effect, suggesting a
5-HT4 postsynaptic mechanism [82]. Centrally administered
BIMU1 and BIMU8 prevented scopolamine, dicyclomide or
hypoxic-induced amnesia in PA test [36]. In this study [36],
the SDZ 205-557 or GR125487 administration immediately
after the training session produced an amnesic effect, while
BIMU1 or BIMU8 administered before the training session
prevented the 5-HT4 antagonists-induced amnesia. Finally, it
should be noticed that in contrast with those results obtained
with 5HT3 receptor agonists and antagonists [16,20,121], the
administration of 5HT4 agonists enhances cortical release of
acetylcholine, while their co-administration with 5HT4
receptor antagonists eliminates this effect.
With regard to the contradictory effects observed with
5-HT4 receptor antagonists (i.e. no effect in AUTO test vs
impairment effect in PA task), it must be mentioned that
these could be due to drug administration time, species
and behavioral task used, as well as the fact that BIMU1
and BIMU8 display affinity for 5-HT4 and 5-HT3 receptors,
while SDZ 205-557 and GR125487D are very potent and
selective drugs of 5-HT4 receptors [29,53,68,82]. Notably,
5-HT4 receptors spliced variants have been identified (i.e.
4(a), (b), (c), (d) [12], and (e) [184]). Under these experi-
mental conditions [12], the two previously described highly
potent 5-HT4 antagonists, SB207266 and GR125487,
behaved as inverse agonists on the intrinsically active
5-HT4 receptor. In contrast, RS 100235, described to be
the most potent 5-HT4 antagonist to date, acted as a neutral
antagonist (i.e. was able to competitively inhibit the inverse
agonist effect of GR125487) on 5-HT4 receptor transiently
expressed in COS-7 or LLC-PK1 cells. Two other 5-HT4
antagonists, RS 39604 and SB 204070, behaved as partial
agonists, but as full potent antagonists on colliculi neurons
in primary culture [12]. Significantly, SL65.0102, a 5-HT4
receptor partial agonist, improved retention in young and
old rats in the linear maze and object recognition test
[10].
 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
9. 5-HT1E, 5-HT1F, 5-HT5A/5B, 5-HT6, 5-HT7A/7B and
5-HTP receptors
5-HT1E, 5-HT1F, 5-HT5A/5B, 5-HT6, 5-HT7A and 5-HTP
receptors have been localized in brain structures involved
in cognitive processes (Table 1, Refs. [53,54,74,79,
83,115,116,176]). For instance, 5-HT1F receptors are present
in fronto-parietal (layers III–V) and cingulate cortex, hippo-
campus (dentate gyrus, CA1–CA3), caudate-putamen,
amygdala, entorhinal cortex and hypothalamic areas. Inter-
estingly, the 5-HT1F receptor agonist LY344864 improved
learning CON [175]. 5-HT5A knockout mice showed
increased exploratory activity (altered habituation?) when
exposed to new environments [48]. The selective 5-HT6
receptor antagonist Ro 04-6790 produced a behavioral
syndrome similar to that seen following treatment with
antisense oligonucleotides, which was dose-dependently
antagonized by atropine [115], suggesting a modulatory
role for 5-HT6 receptors in cholinergic neurones. Notably,
when 5-HT6 knockout mice were exposed to a new environ-
ment, they exhibited a normal habituation behavior [123].
Recent evidence obtained in our laboratory indicates that
neither the selective 5-HT7 receptor antagonist DR4004
[137] nor the 5-HT2B/2C/2A/7 receptor antagonist LY215840
[21] had effect in learning CON [175]; however, the
latter drug was able to eliminate the deficit induced by
scopolamine or dizocilpine [89]. This finding could be
consistent with the evidence that 5-HT7 receptors are co-
localized in glutamatergic neurons of hippocampus and
amygdala [122]. Apparently, aging reduced 5-HT7 receptors
([187], but see [188]), and interestingly, i.c.v. 5-HT7 anti-
sense oligonucleotide treatment significantly reduced
[ 3H]-5-HT binding to hypothalamic 5-HT7 receptors, with-
out affecting the exploratory activity (i.e. habituation?) on
day four [17].
10. 5-HT uptake/transporter complex
The 5-HT re-uptake site/transporter complex is respon-
sible for the 5-HT released re-uptake [77]. 5-HT uptake
inhibition or facilitation could be expected to enhance
5-HT input to neurons in brain areas involved in cognitive
processes [57], and this contention is supported by the
finding that postsynaptic 5-HT receptors mediate a facil-
itating effect in learning consolidation induced by 5-HT
uptake inhibitors (SSRIs) [5,41,63,78,81,83]. For
instance, the SSRI fluoxetine was able to reverse an
impaired learning consolidation induced by serotonergic
drugs such as TFMPP and mCPP, as well as impairing the
effect induced by scopolamine (a cholinergic antagonist)
and dizocilpine (a glutamatergic antagonist) [83,87], or
aging [79,86]. Even though it has been suggested that
SSRIs could have primarily behavioral (e.g. depression)
rather than cognitive dysfunctions in AD patients, in non-
demented elderly depressed patients treated with the
1119
SSRIs paroxetine improved both depressive symptoms
and cognitive function [77]. Apparently some SSRIs
improve information processing per se in AD patients
[47]. Furthermore, the SSRI fluoxetine produced marked
increases in language acquisition in a young idiopathic
autism subgroup of children [178]. Notably, and para-
doxically with regard to SSRIs action mode, the antide-
pressant tianeptine [23], which apparently increases
neuronal 5-HT uptake [22], improved spatial retention
and learning consolidation and reduced working memory
errors, but did not improve acquisition [23,30,118,175].
Acutely, tianeptine increases significantly neuronal 5-HT
uptake in cortical and hippocampal synaptosomes
prepared from rat brain and it increases efflux of hippo-
campal 5-hydroxyindoleacetic acid in free-moving
animals [67]. Tianeptine effects on serotonergic neuro-
transmission are complex, e.g. it causes a hippocampal
activity direct modulation in CA1, but not CA3 [67]
area, which may be responsible for its effects on memory
[118]. Collectively, these findings strongly suggest that
the 5-HT facilitation or inhibition mechanism are
involved in cognitive processes, and this contention is
consistent with the evidence that AD seems to be asso-
ciated with a decrement in the serotonergic transporters
number in dorsal raphe, hippocampus, entorhinal cortex
and platelets (Table 1, Refs. [6,7,117], but see Ref. [77]).
Further support of the contention that the 5-HT uptake/
transporter mechanism represents a major therapeutic
mechanism target in cognitive dysfunctions treatment is
provided by the evidence that in animal and humans,
repeated administration of 3,4-methylenedioxymeth-
amphetamine (MDMA: “ecstasy”) impaired memory,
purportedly due to a loss of 5-HT uptake sites [180]. It
must be noticed also that neurotoxic amphetamines such
as MDMA and PCA cause extensive degeneration of fine
5-HT axons in the forebrain, while some groups of beaded
5-HT axons and serotonergic cell bodies in the brainstem
are unaffected [57]. Serotonergic depletion induced by p-
chlorophenylalanine (PCPA), PCA or 5,7-dihydroxytryp-
tamine (5,7-DHT) has produced inconsistent results on
learning and memory tests [5,41,78,79]. Such inconsisten-
cies may be attributed to differences in age, behavioral
tasks, drug doses and pharmacological times employed in
such studies [75,78]. More important to the present
context is the evidence that an acute increase in serotonin
release induced by PCA impaired retention performance
in both passive avoidance and radial maze; thus suggest-
ing that 5-HT excessive release, but not depletion,
produces retention deficits [113]. In fact, even a forebrain
serotonin virtual depletion (i.e. producing a 97.3% in the
frontal cortex and 99.6% in the hippocampus) induced by
PCPA or the combined 5,7-DHT lesions of dorsal and
median raphe nuclei (i.e. provoking a 87% in the cortex
and 88% in the hippocampus) has no effect per se in
learning and memory processes ([110], see Ref. [111]
for a review).
1120 A. Meneses / Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125
11. Concluding remarks
Abundant evidence sustains the hypothesis that 5-HT
pathways, 5-HT re-uptake site/transporter complex and
5-HT receptors show a regional distribution in brain areas
implicated in learning and memory. The 5-HT system role
in learning and memory is yet to be established; however,
available evidence strongly indicates that presynaptic
5-HT1A, 5-HT1B, 5-HT2A/2C and 5-HT3 receptors, post-
synaptic 5-HT2B/2C and 5-HT4 receptors and 5-HT uptake/
transporter sites are involved in these processes. The finding
that an increase in 5-HT levels provoking the multiple post-
synaptic 5-HT receptors activation, as occurred with 5-HT
uptake facilitators and inhibitors, enhances learning
suggests that the 5-HT role in cognitive processes is more
complex than that representing a simple imbalance. The
findings that 5-HT1A, 5-HT2A, 5-HT2C/2B and 5-HT4 receptor
antagonists did not alter learning and memory could imply a
reformulation of the notion that 5-HT system activation
impairs learning and memory, whereas a reduced serotoner-
gic function may enhance these processes. Available
evidence strongly suggests that the 5-HT system role may
be important in normal function, treatment and/or pathogen-
esis of cognitive disorders. Further investigation will help to
specify the 5-HT system nature involvement in cognitive
processes to identify pharmacological treatments, their
mechanisms and action sites and to determine under
which conditions they operate. In this regard, it is probable
that selective drugs with neutral antagonist or inverse
agonist properties for, at least, 5-HT1A, 5-HT1B (5-HT1D?),
5-HT2A/2B/2C, 5-HT4A,4B,4C,4D and 5-HT7 receptors, could
indeed constitute a new therapeutic opportunity for learning
and memory alterations.
Acknowledgements
This research was supported by CONACYT Grant
28398M.
Appendix A
Glossary of drugs: 2-Bromolysergic acid diethylamide
(BOL); Conditioned response (CR); 3-ethyl-2,3dihydro-2-
oxo benzimidazole-1-(3a-tropyl) carboxamide hydrochloride
hydrate [BIMU1]; 3-isopropyl-2,3-dihydro-2-oxo-1h-benzi-
midazole-1-(3a-tropyl)carboxamide [BIMU8]; (^)-8-
hydroxy-2-(di-n-propilamino)tetralin [8-OH-DPAT]; (;)-
2,5-dimethoxy-4-iodoamphetamine [DOI]; N-[4-methoxy-3-
(4-methyl-1-piperazinyl) phenyl]-2 0 -methyl-4 0 -5(-methyl-
1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamidede-
hydrochloride monohydrate (GR127935); 5-hydroxytrypta-
mine (5-HT); long-term potentiation (LTP); N-(3
trifluromethylphenyl)piperazine hydrochloride [TFMPP];
1-(3-chlorophenyl)piperazine dihydrochloride [mCPP];
1-(m-chlorophenyl)-biguanide hydrochloride [mCPBG];
N-methyl-d-aspartate [NMDA]; 1-(1-naphthyl)piperazine
hydrochloride [1-NP]; n-t-butyl,3-[1-[4(2-methoxy)phenyl]-
piperazinyl]-1-phenylpropionamide [WAY 100135]; N-[2-
[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-
cyclohexanenecarboxamide trihydrochloride (WAY
100635); p-chloroamphetamine (PCA); 2-methoxy-4-
amino-5-chloro-benzoic acid 2-(diethylamino ester) [SDZ
205-557]; 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-
imidazol-1-yl)methyl]H-carbazol-4-1hydrochloride dehy-
drate [ondansetron]; N-(3 trifluromethylphenyl)piperazine
hydrochloride [TFMPP]; (S)-5-fluoro-8-hydroxy-2-(dipropy-
lamino)-tetralin hydrochloride [(-)-S-UH-301]; 3-tropanyl-
3,5-dichlorobenzoate [MDL-72222]; (3a-tropanyl)-1H-
indole-3-carboxylic acid ester [tropisetron]; unconditioned
stimulus [US].
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