5-HT1A receptors and memory

ARTICLE IN PRESS

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Neuroscience and Biobehavioral Reviews 31 (2007) 705–727

www.elsevier.com/locate/neubiorev

Review

5-HT1A receptors and memory

Alfredo Meneses�, Georgina Perez-Garcia

Department de Farmacobiologia, CINVESTAV-IPN, Tenorios 235, Granjas Coapa 14330, Mexico

Received 4 September 2006; received in revised form 3 January 2007; accepted 13 February 2007

Abstract

The study of 5-hydroxytryptamine (5-HT) systems has benefited from the identification, classification and cloning of multiple 5-HT

receptors (5-HT1–5-HT7). Increasing evidence suggests that 5-HT pathways, reuptake site/transporter complex and 5-HT receptors

represent a strategic distribution for learning and memory. A key question still remaining is whether 5-HT markers (e.g., receptors) are

directly or indirectly contributing to the physiological and pharmacological basis of memory and its pathogenesis or, rather, if they

represent protective or adaptable mechanisms (at least in initial stages). In the current paper, the major aim is to revise recent advances

regarding mammalian 5-HT1A receptors in light of their physiological, pathophysiological and therapeutic implications in memory. An

attempt is made to identify and discuss sources of discrepancies by employing an analytic approach to examine the nature and degree of

difficulty of behavioral tasks used, as well as implicating other factors (for example, brain areas, training time or duration, and drug

administration) which might offer new insights into the understanding and interpretation of these data. In this context, 8-OH-DPAT

deserves special attention since for many years it has been the more selective 5-HT drug and, hence, more frequently used. As 5-HT1A

receptors are key components of serotonergic signaling, investigation of their memory mechanisms and action sites and the conditions

under which they might operate, could yield valuable insights. Moreover, selective drugs with agonists, neutral antagonists or inverse

agonist properties for 5-HT1A (and 5-HT7) receptors may constitute a new therapeutic opportunity for learning and memory disorders.

r 2007 Elsevier Ltd. All rights reserved.

Keywords: 5-HT receptors; Memory; Consolidation; Human; Animals

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706

2. Multiple 5-HT receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706

2.1. 8-OHDPAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707

2.2. 5-HT1A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713

3. 5-HT1A receptors: behavioral learning and memory tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714

3.1. Models of amnesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718

3.1.1. Models of amnesia: roles of 5-HT1A and 5-HT7 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719

4. Pre- postsynaptic 5-HT1A receptors and memory formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720

5. 5-HT1A receptors: agonism, inverse agonism or antagonism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721

6. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722

e front matter r 2007 Elsevier Ltd. All rights reserved.

ubiorev.2007.02.001

ing author. Tel.: +5255 50612869; fax: +52 55 50612863.

ess: [email protected] (A. Meneses).

www.elsevier.com/locate/neubiorev

dx.doi.org/10.1016/j.neubiorev.2007.02.001

mailto:[email protected]

ARTICLE IN PRESSA. Meneses, G. Perez-Garcia / Neuroscience and Biobehavioral Reviews 31 (2007) 705–727706

1. Introduction

Serotonin (5-hydroxytryptamine, 5-HT) was discoveredabout 50 years ago, and currently it still continues togenerate interest as one of the most successful targets fortherapeutic applications, ranging from depression, schizo-phrenia, anxiety, and migraine headaches to learning andmemory disorders. A widely accepted definition of learningis the modification of behavior derived from experiences,and memory corresponds to the storage of these experi-ences. Memory may also be defined according to itscontent or in relation to time and its neurobiological basis:in the former case, as declarative/explicit or non-declara-tive/implicit memory, and regarding time, as short- orworking, and long-term memory (Davis and Squire, 1984;Izquierdo et al., 1999, 2006), the latter depends on proteinand mRNA synthesis. Timing questions are which thenature of memory is and in this regard whether serotoninmight be providing important insights.

Although serotonin has been implicated in learning andmemory previously (revised by Altman and Normile, 1988;Ogren, 1985), recently this notion has gained wideracceptance and interest. For instance, a Medline searchin 1999 for 5-HT and memory or 5-HT and learning

produced 394/1512 articles, respectively; whereas, a recent2007 (March) search for serotonin and memory or 5-HT and

learning or 5-HT and memory or serotonin and learning

yielded 4113 publications, respectively. Thus, in the last 7years more than 2500 papers have appeared that directly orindirectly implicate 5-HT or its receptors in learning andmemory in species ranging from humans to invertebrates,and to date, this trend continues.

Mammalian memory involves multiple brain and neuro-transmitter systems and mechanisms both at the receptorand post-receptor level. Considering its strategic neuroa-natomical localization, investigations of 5-HT involvementin memory (Meneses, 1999, 2003) have been enhancedsignificantly by the identification, classification and cloningof multiple receptors (Hoyer et al., 1994, 2002) and studiesat the post-receptor level (Raymond et al., 2001). However,the role of 5-HT1A receptors in memory has not recentlybeen modified. Reviewing more current behavioral andmolecular studies may be particularly insightful and timelyin view of the apparently contradictory notion that either5-HT1A receptor agonists or antagonists are useful in thetreatment of learning and memory disorders. Hence, themajor aim of the present work is to revise recent advancesregarding mammalian 5-HT systems, focusing in particularon 5-HT1A receptors given their physiological, pathophy-siological and therapeutic implications in cognitive pro-cesses such as learning and memory. Herein, an attemptwill be made to identify and discuss sources of discrepan-cies by using an analytic approach to examine the natureand degree of difficulty of behavioral tasks used (see, forexample, Buhot et al., 2003; Wolff et al., 2004a) and tohighlight the brain areas (e.g., hippocampus, amygdala,cortical areas; see, for instance, Lynch, 2004), training time

(e.g., number of trials), and specific drugs and theiradministration under study which might offer new insightsinto the understanding and interpretation of these data.Aiming to offer a wide focus, the results are analyzed fromdifferent perspectives (e.g., pre- vs. postsynaptic localiza-tion) repeating them in some sections. In this context, itshould be noted that even though several compounds (seeTable 1) are used in the investigation of 5-HT1A receptors,8-OH-DPAT deserves special attention because for manyyears it has been the more selective and, thus, morefrequently used 5-HT drug (Hjorth et al., 1981). Althoughseveral 5-HT receptors have been implicated in thephysiological, pathophysiological, and therapeutic me-chanisms of learning and memory (see Meneses, 1999,2003), alone or in combination with other neurotransmittersystems, the actual processes remain unclear. In addition, akey issue to determine is whether 5-HT markers (e.g.,neural levels of serotonin, reuptake sites, receptors) aredirectly (Haider et al., 2006; Schmitt et al., 2006) orindirectly (see below) contributing to the physiological andpharmacological basis of memory and its pathogenesis(Table 2), or if they represent protective or adaptablemechanisms (at least in initial stages). The 5-HT1A

receptors have been proposed as a key component ofserotonergic signaling (for review, see Pucadyil andChattopadhyay, 2006). Before we discuss 5-HT1A recep-tors, it is important to classify them within the 5-HTsystems.

2. Multiple 5-HT receptors

Apart from the 5-HT3A–3C receptors which are a uniquefamily member of the ligand-gated cation channel,mammalian 5-HT1A–1E, 5-HT2A–2c, 5-HT4, 5-HT6, and5-HT7 receptors belong to the G protein-coupled receptorsuperfamily (Barnes and Sharp, 1999; Green, 2006; Hoyeret al.; 2002; Markstein et al., 1999). The 5-HT1 receptorsare functionally; but not exclusively (see Raymond et al.,2001); coupled to Gi and/or Go protein, 5-HT2 receptors toGq, and 5-HT4, 5-HT6 and 5-HT7 receptors to Gs.Electrophysiological studies have demonstrated that5-HT1A/1B/1D//1E/1F receptor activation produces hyperpo-larization, whereas 5-HT2A/2B/2C, 5-HT3/3B, 5-HT4, and5-HT7 receptors elicit depolarization (Hoyer et al.; 2002).Since 5-HT sends projections to almost all of the forebrain;it is not surprising that a growing body of evidenceindicates that multiple 5-HT receptors modulate learningand memory by interaction with other neurotransmissionsystems (see Buhot et al., 2003; Cassel and Jeltsch, 1995;Hodges et al., 1996; Schmitt et al., 2006; Steckler andSahgal, 1995). Moreover, diverse techniques have allowedthe identification of serotonergic alterations as markers ofmemory formation and in memory disorders (see below).Serotonergic projections originate in the ascending raphenuclei localized in the brain stem; where 5-HT synthesis,storage and reuptake occur, and extend to almost allforebrain areas (Barnes and Sharp, 1999; Hoyer et al.,

ARTICLE IN PRESS

Table 1

Agonists and antagonists Of 5-Ht1a receptors

Affinity (Ki) nM Observations Reference

Agonist

Alnespirone (S 20499) 0.20 Kidd et al. (1993)

5-CT 0.20 High affinity ligand for 5-HT7

receptors

Bonaventure et al. (2002), Markstein et al. (1986)

NAN-190 0.6 High affinity ligand (Ki ¼ 0.8 nM)

for a 1-adrenergic receptors

Raghupathi et al. (1991)

NAD-299 0.6 Johansson et al. (1997)

S 15535 0.7 Millan et al. (1997)

8-OHDPAT 1.0 Moderate affinity ligand for 5-HT7

receptors

Hjorth et al. (1981), Arvidsson et al. (1984)

Flesinoxan 3.0 Ahlenius et al. (1991), Sleight and Peroutka (1991)

Tandespirone 27 Hamik et al. (1990)

Buspirone 30 Hjorth and Carlsson (1982), Newman-Tancredi et

al. (1998a)

Antagonist

WAY 100635 0.10 Fletcher et al. (1993)

Tertatolol 10 Prisco et al. (1993)

Pindolol 15 Newman-Tancredi et al. (1998b)

Propanolol 55 Newman-Tancredi et al. (1998b)

Spiperone 60 Dukic et al. (1997)

Taken from Baumgarten and Gothert (2000), Dukic et al. (1997), Fletcher et al. (1993), Hoyer et al. (1994, 2002), Middlemiss and Tricklebank (1992),

Sleight and Peroutka (1991).

A. Meneses, G. Perez-Garcia / Neuroscience and Biobehavioral Reviews 31 (2007) 705–727 707

1994; Jacobs and Azmitia, 1992) involved in learning andmemory (Meneses, 2003), thus 5-HT exerts an influence viacholinergic and glutamatergic pathways over the transferof information (for example, see Buhot et al., 2003; Casseland Jeltsch, 1995; Sirvio et al., 1994; Steckler and Sahgal,1995, and see Fig. 1). The activity of 5-HT projectionsdepends on tryptophan availability, the rate-limitingenzyme tryptophan hydroxylase, monoamine oxidase,reuptake sites, and 5-HT receptors, which also might beinfluenced by memory, aging, and amnesia (Buhot, 1997;Buhot et al., 2003; Meltzer et al., 1998; Manuel-apolinaret al., 2005; Meneses et al., 2004). In fact a direct participa-tion of 5-HT has been demonstrated inasmuch as enhancedbrain serotonin activity by means of its precursor (i.e.,tryptophan) improved memory in animals (Haider et al.,2006); but in normal elderly people, AD patients andschizoprenics (Levkovitz et al., 2003; Porter et al., 2003),and animals decreasing brain 5-HT levels by acute 5-HTdepletion impaired it (Schmitt et al., 2006). This evidence isconsistent with result that post-training (but not pre-)administration of 5-HT uptake inhibitors improved mem-ory consolidation by using multiple 5-HT receptors(Meneses, 2002, 2003). Nonetheless, here it is importantto mention that emerging evidence indicates that learning,memory consolidation (CON), and short- and long-termmemory may be regulated by the constitutive activity of5-HT receptors (Meneses, 1999, 2007; Romano et al., 2006).Indeed, hippocampal 5-HT1A and/or 5-HT7 receptors havebeen recently associated to constitutive activity (Martelet al., 2007) and gene expression such as CREB (Mahgoub

et al., 2006), which is important for memory formation(Kandel, 2001).

2.1. 8-OHDPAT

For many years 8-OH-DPAT has played an importantrole as the more selective 5-HT1A receptor agonist (Hjorthet al 1981; Sleight and Peroutka, 1991; see also Lanfumeyand Hamon, 2004). Furthermore, earlier studies estab-lished that the concentration and timing of 8-OH-DPAT inthe brain were dependent on the route of administration(Fuller and Snoddy, 1987; Perry and Fuller, 1989). It is wellknown that the ability of 8-OH-DPAT to suppress dorsalraphe cell firing or the ability of 5-HT1A receptorantagonists to increase it, varies considerably accordingwith the behavioral states and baseline firing activity of the5-HT cells, which has profound effects on memory (seeFigs. 1 and 4). More recently it was demonstrated that8-OH-DPAT displays an affinity for 5-HT7 receptors,thereby exerting some of its effects via both 5-HT1A and 5-HT7 receptors in brain areas that mediate several functionsincluding memory (Meneses, 1999; Perez-Garcia et al.,2006). This has an important functional implicationinasmuch as 5-HT1A and 5-HT7 receptors display oppositetransductional and physiological actions (see below),mainly in the context of memory being regulated by theconstitutive activity of 5-HT receptors (Meneses, 1999,2007; Romano et al., 2006). Constitutive or ligand-independent activity is defined as activity independent ofendogenous ligand, mutations in amino acid sequence,

ARTICLE IN PRESSTable

2

Behavioraltasksusing5-H

T1Areceptoragonists

andantagonists

Drugs(m

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Number

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type

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Results

Observations

Reference

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Workingmem

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Lower

dose¼

higher

dose

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etal.

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8-O

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Oneach

acquisition

trainingday

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discrim

ination


cortex

Mem

ory

by

scopolamine

Rats

Carliet

al.(1998)

Buspirone1,2.5,5,8

OHDPAT0.1,0.3,1

WAY1006350.1,0.5,1,2.5mg

(i.p

andIA

)

Pre-training

Post-training

Inhibitory

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of

buspirone

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discrim

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theeffect

ofS

15535

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8-O

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Meneses

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8-O

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PAT1(i.p.)and1mg

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Pre-testing

Elevatedplusmaze

mMem

ory

Rats

MicheauandVan

Marrew

ijk(1999)

8-O

HDPAT0.03-0.3

Spiperone0.01-0.1

Paroxetine

1WAY

1006350.003-1

(sc)

PCA

0.3-3

(i.p)

Pre-training

Passiveavoidance

(PA)

Onedayshock

training

Associative

(retentionlatency)

Variouscorticalareas

kMem

ory

WAY100635

blocked

thedeficit

by8-O

H-D

PAT

Rats

MisaneandOgren,

(2000)

8-O

H-D

PAT0.5

and4mg

Intraseptal

Pre-training

Watermaze

(WM)

Spatialreference


cortex

kMem

ory

Rats

Bertrandet

al.

(2000)

8-O

H-D

PAT,10-100mg

/kg

(sc)

Pre-training

Five-choiceserial

reactiontimetask

(5-

CSRT).

Attention

Cortex

kMem

ory

WAY

100635

blocked

thedeficit

by8-O

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depletedof5-H

T

andtreatedwithWAY

100635

CarliandSamanin

(2000)

8-O

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PAT0.1-1.0

(sc),1-

5.0mg

(ih)

Pre-training

Fearconditioning(FC)

Associativeaversive


Mem

ory

Pretreatedih

causedasevere

kMem

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C57BL/6Jmice

Administrationsc

andih

of8-O

H-

DPATinducedthe

5-H

Tsyndrome

Stiedlet

al.(2000)

8-O

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T(1-10)

NAN-190(0.001-0.5)WAY-

100635(0.001-1)mg

(icv)

Agonistpre-

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Antagonistpost-

punishment

PA

Hole

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PA:onetrialHB:

explorationof16

holes

Associative


Antagonistk

mem

ory

Agonistm

mem

ory

Mice

Galeottiet

al.(2000)

Hypericum

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4,8,

12,25Pindolol0.3,1,3(i.p.)

Pre-testing

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ory

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ory

Pindololblocked

theeffect

of

Hypericum

Mice

Khalifa

(2001)

A. Meneses, G. Perez-Garcia / Neuroscience and Biobehavioral Reviews 31 (2007) 705–727708

ARTICLE IN PRESSperforatum

MDL730052(i.p.)

WM

Spatialreference


cortex

MDL73005¼

,but-

by0.25mg/kgof

scopolamine.

Rats

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al.

(2001)

8-O

H-D

PAT0.1-0.5

(i.p)

Histidine500-1000(i.p)

Pre-test

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4choicecorrectin

5

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Spatial

reference

and

Working

mem

ory


cortex

Histidine

deficit

inducedby8-O

H-

DPAT

Rats

-increase

inbrain

histaminecontent

Isayamaet

al.(2001)

8-O

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PAT,1mg

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l-Kyn,

3mg

(ih)

Pre-training

WM

Spatialreference


cortex

8-O

H-D

PAT-

effect

by7-C

l-Kyn

Rats

Carliet

al.(2001)

8-O

H-D

PAT0.0125,0.125,

1.25and6.25mg

NAN-190

0.125or1.25mg

(IC)

Post-training

Step-downinhibitory

avoidance

Associativeaversive


Mem

ory

NAN-190

this

effect

Rats

Mello

eSouza

etal.

(2001)

8-O

H-D

PAT30mg

/kgi.p

Scopolamine30mg

/kg(FC)

Pre-training

PA

Onetraining

Associative


kMem

ory

Rats

SantucciandShaw

(2003)

[(11)C

] WAY-100635

176.5–237.9-M

Bqbolus

injectionTandospirone30mg

and60mg

Pre-test

Positronem

ission

tomography(PET).

Auditory

Verbal

LearningTest

(AVLT)

Explicitmem

ory


Hippocampus

kExplicitmem

ory

Humans

Yasunoet

al.(2003)

WAY

100635NAD-299

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PA

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100635

attenuatedkmem

ory

by

scopolamine

Rats

MisaneandOgren,

(2003)

WAY

1006350.1

(sc)

Pre-test

5-C

SRT

Sessionof100trials

or30min

oftesting

Attention

Cortex

WAY

100635

Amelioratedthek

mem

ory

inducedby

AMPA

Rats

treatedwith

AMPA

intheNBM

Balducciet

al.

(2003)

Flesinoxan0.25–1(i.p)

Diazepam

0.25–1(i.p)

Pre-training

PA

Associative


kMem

ory

Micesubjected

tosingle

anddouble-training

sessions

Tsujiet

al.(2003)

--

Operantbehavioral

paradigmsofdecision

makingandresponse

inhibition

Prefrontalcortex-

dependentlearning

andmem

ory

PrefrontalCortex

mMem

ory

5-H

T1Areceptor

knockoutmice(K

O5-

HT1A)

Pattijet

al.(2003)

WAY

1006350.3,1(i.p)

Scopolamine0.2

(sc).

Pre-trial

Object

recognition(O

R)

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Trial(T1)-Trial

(T2)

Exploration

Recognition

Hippocampus

WAY

100635xby

scopolamine

Rats

Pitsikaset

al.(2003)

8-O

H-D

PAT0.3

(sc),

Buspirone1(i.p)Fluoxetine3

(i.p),

Pre-test

Perform

anoperant-

basedcombined

DNMTP

Asessioncontained

64trials

Short-term

mem

ory

Hippocampus

kMem

ory

Rats

-trialsequence

randomized

Pacheet

al.(2003)

NAN-1900.5-1

(i.p)

Post-training

Mildly

aversivepassive

avoidance

mMem

ory

Rats

Schneider

etal.

(2003)

8-O

H-D

PATWAY100635

DR4004

Post-training

Autoshaping

Associative

appetitive



Agonistm

mem

ory,

antagonist

Rats

Analysisoncortical

andhippocampal

cyclic

adenosine

monophosphate

(cAMP)production

Manuel-A

polinar

andMeneses

(2004)

8-O

H-D

PAT15,30,60,120mg

(i.p)

Pre-training

PA

Onetraining

Associative


kMem

ory

Rats

Santucciand

Haroutunian(2004)

8-O

H-D

PAT;0.5

or4mg

(MS)

Hidden

platform

WM

Spatialworking

mem

ory

kMem

ory

Rats

Jeltschet

al.(2004)

Variable

Socialrecognition

WM

–DNMTP

Variable

Variable

mMem

ory

andk

mem

ory

Rats

andmice

Millanet

al.(2004)



2(c

onti

nued

)

Drugs(m

g/kg)

Tim

ingof

administration

Behavioraltask

Number

oftrials

Mem

ory

type

measured

Structure

dependlearning

Results

Observations

Reference

S155350.04-5.0

(sc)

WAY100,635(0.0025-0.63)

Variable

8-O

H-D

PAT0.1

(sc)

WAY-

1006350.5

(i.p)

Pre-training

PA

Oneacquisitiontrial

Associative


kMem

ory

Rats

Analysison

hippocampal

CaMKII

andPKA.

Moyanoet

al.(2004)

8-O

H-D

PAT0.1-0.3mg

/kg,

8-arm

radialmaze

Spatialappetitive


cortex

8-O

H-D

PAT

by

delta9-

tetrahydrocannabinol

Rats

Inuiet

al.(2004)

8-O

H-D

PATSB-269970DR

4004WAY

100635(i.p

orsc)

Post-training

Autoshaping

10assays

Associative

appetitive


mMem

ory

andk

mem

ory

Rats

Rats

treatedwith

mCPPandPCA

Meneses

etal.(2004)

8-O

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post-

training

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conditioning

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%ofnumber

of

responsesmade

duringCS

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appetitive


Administration

pretrainingof8-

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kmem

ory

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--

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cortex

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ory

KO

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T1A

Anim

alsyoung-

adult(3

months

old)andaged

(22

monthsold)

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al.(2004b)

Psilocybin

115and250mg

/kg

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betweenthe

twoperceptual

alternativelines

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predictions

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3days

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Cortex

Someindividualsm

mem

ory

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Carter

etal.(2005a)

[3H] 8-O

H-D

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10assays

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appetitive



mMem

ory

Rats

Protein

analysis

with

autoradiography,m

of5-H

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expressionin

differentbrain

areas

Luna-M

unguia

etal.

(2005)

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poral

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al.(2005)

SSR1815070.03-3

clozapine

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amisulpride1-3

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alstreated

withPCPandd-

amphetamine(i.p.)

Terranovaet

al.

(2005)

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cortex

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changes

inBDNFand

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BDNF

levels

analysisin

the

hippocampus

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al.

(2005)

8-O

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WM:4

trialsper

day

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single

training

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reference

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areas,Hippocampus,

subiculum,cortex

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doses8-

OHDPATmmem

ory

in

PA

andk

mem

ory

in

WM

Rats

Luttgen

etal.(2005)

Lecozotan0.01-2mg/kgi.m.

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Cortex

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chechteret

al.(2005)


ARTICLE IN PRESSDelayed

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sample

(DMTS).

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GTA)

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(90%

correct

responses)

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ance

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temporalcortex

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ory

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overexpressionof

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receptor

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mouse

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al.(2005)

8-O

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PAT1mg

(MRN)

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training

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potentiatedstartle

(FPS)

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30min

for2days

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kMem

ory

Rats

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al.(2005)

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100(i.p)

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inthe

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phospho-C

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al.

(2005)

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(oral)

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test

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withmajor

depression

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ent

.

Rats

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et

al.(2005)

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(215mg

/

kg)ketanserin(50mg)

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trackingtask

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ory

task

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term

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impaired

attentional

perform

ance,buthad

nosignificanteffect

on

spatialworking

mem

ory

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ent

withketanserin

Carter

etal.(2005b)

[F-18]M

PPF(iv)

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--

-5-H

T1Areceptork

densities

inlivingbrains

ofAlzheimer’sdisease

patients

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with

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Data

invivowere

confirm

ed

independentlybyin

vitro

Kepeet

al.(2006)

--

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recognition—

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etal.

(2006)

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prior

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ent

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withchronic

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al.(2006)

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microinjection4mg

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(DH).WAY-100635NAN-190

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within

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cortex

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and

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al.

(2006)

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both

task

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100

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al.

(2006)

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NAD-299

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training

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OHDPAT

mmem

ory,

highestdoseskmem

ory

Mice

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al(2006)



2(c

onti

nued

)

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g/kg)

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ingof

administration

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oftrials

Mem

ory

type

measured

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dependlearning

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Reference

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10063530ngCPP50ng

(mPFC)

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or30min

oftesting

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Cortex

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HDPAT

caused

byCPP

Rats

Carliet

al.(2006)

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PAT0.1-2.5

i.p

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field—elevated

plusmaze

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cortex

8-O

HDPAT

cause

exaggeratedresponse

motor

Micewithover-

expressingthe5-H

T1A

receptor

Bertet

al.(2006b)

[11C]WAY100635175–313

MBq(1,000Ci/mmol)iv

Pre

PET

Variable

Variable

Variable

Variable

¼Mem

ory

Humans

Borg

etal.(2006)

AS190.1-108-O

H-D

PAT

0.062WAY1006350.03SB-

26997010(i.p)

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10trials

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appetitive



mMem

ory

Rats

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expression5-H

T1A

and5-H

T7

receptors

into

brain

areas

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arcia

etal.

(2006)

¼Nochange;m,Mem

ory

improved;k,Mem

ory

impaired

oramnesia;

,Reversedthedeficitcausedbyscopolamine;-

,Preventedim

paired

mem

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theeffect;sc,subcutaneously;i.p,

intraperitoneally;ih,intrahippocampally;FC,into

thefrontalcortex;DR,into

thedorsalraphe;EC,into

theentorhinalcortex;IA

,intra-amygdala;DH,into

thedorsalhippocampus;IS,intra-septal;

IC,into

granularinsularcortex

oftheprefrontalcortex;MS,into

themedialseptum;MRN,into

themedianraphenucleus;mPFC,into

themedialprefrontalcortex.


ARTICLE IN PRESS

Fig. 1. Mainly 5-HT projections are showed in brain areas important for memory. 5-HT receptors acting as heteroreceptors modulate release of other

neurotransmitters.


receptor phosphorylation, or allosteric changes of theirreceptors (for review see Negus, 2006). Importantly, inmany brain regions 5-HT receptors are located on neuronslacking a direct serotonergic innervation; in parallel, 5-HTfibers often lack typical synaptic contacts with post-synaptic neurons (for recent reviews see Ciranna, 2006;Hensler, 2006). Such a mismatch between serotonergicfibers and postsynaptic 5-HT receptors has led to thesuggestion that 5-HT in the CNS may preferentially usevolume transmission and thus behave as a neuromodulatorrather than as a ‘‘classical’’ neurotransmitter. As behavior-al memory tasks, or memory status (e.g., amnesia) mightelicit a specific serotonergic tone (see below), serotoninvolume transmission would be an ideal organization.Therefore, strategies that discriminate among these sourcesof serotonergic activity will also contribute to the in vivoassessment of inverse agonist (Negus, 2006) or agonisteffects. Notably in this context, 5-HT1A receptors and theirpre- and postsynaptic distribution (see below) represent anideal goal for research.

2.2. 5-HT1A receptors

The 5-HT1A receptors are located presynaptically assomatodendritic autoreceptors in raphe nuclei where theymodulate 5-HT release (Fig. 1; postsynaptically, they mediatehyperpolarization in the lateral septum, hippocampal CA1area and dentate gyrus, amygdala, and frontal and entorhinalcortex (Buhot et al 2003; Hensler, 2006; Kia et al 1996); and,(from in-vitro evidence) coupled to Gi protein, they negativelyregulate cAMP (Hoyer et al., 1994, 2002; see Fig. 4). In fact,Raymond et al. (2001) discussed evidence also relating cAMPin vivo or ex vivo related to 5-HT1A receptors and8-OHDPAT, and new results are consistent with this finding(Manuel-Apolinar and Meneses, 2004; also see below). Inaddition, postsynaptic 5-HT receptors function as hetero-

receptors by modulating the release of other neurotransmit-ters in non-serotonergic neurons (e.g., cholinergic,glutamatergic, GABAergic) (Barnes and Sharp, 1999; Buhotet al., 2003; Jacobs and Azmitia, 1992). Considering theabove neuronal localization, these results support the role of5-HT1A receptors in normal memory and in the mnemonicaspects of several disorders including Alzheimer’s disease(AD), schizophrenia, and depression (Meltzer, 1999; Meltzeret al., 2003; Meneses, 2003; Millan, 2000; Schmitt et al.,2006). Apparently, AD is associated with decrements in some5-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, 5-HT4 and 5-HT6 receptors(Garcia-Alloza et al., 2004, 2005; Meneses, 2003). It shouldbe noted that receptor numbers could be modified byalterations in transduction, translation, posttranslationalprocessing, and metabolic turnover (see Kroeze and Roth,1998).Since AD patients present with decrements in several

5-HT receptors, including 5-HT1A (Table 2; see also Kepeet al., 2006), and genetic manipulation of these receptorsaffects memory (see, for example, Bert et al., 2005,2006a, b; Samyai et al., 2000; Wolff et al., 2004a, b), thenan important question to ask is how learning and memorymay modify the expression of 5-HT receptors in normal oraged persons and in patients suffering memory deficitsrelative to normal individuals. For instance, preclinicalresults indicate that during normal memory CON, anddepending on the brain areas involved, some 5-HTreceptors subtypes are downregulated in adult rats. Incontrast, the same cognitive process in older animalsrequires an upregulation of them (see Luna-Munguia et al.,2005; Manuel-Apolinar et al 2005; Meneses et al., 2004).Using the radioligand [3H]-5-HT or [3H]8-hydroxy-2-[di-n-propylamino]tetralin] (8-OH-DPAT) (Luna-Munguiaet al., 2005; Manuel-Apolinar et al., 2005; Meneses et al.,


2004; Tomie et al., 2003), it was reported that memoryCON of an associative learning task such as the autoshap-ing task, augmented 5-HT1A receptor expression in theamygdala, septal nucleus, various cortical areas (parietal,temporal and granular retrosplenial) and the raphe nuclei;and decreased their expression in the hippocampal CA1area, dorsal hypothalamus, and other cortical areas(frontal, occipital, and cingulate) (Luna-Munguia et al.,2005).Importantly, it was reported that 5-HT1A receptorswere increased in CA2–CA4 hippocampal regions in oldrats showing poor retention (RET) in the Morris watermaze (Topic et al., 2006). Apparently, during memoryformation, demands on 5-HT receptor expression are to bedetermined for their basal level (i.e., functional ordysfunctional status). Indeed, 5-HT receptor expressionand memory CON represent a complex relationship:during memory CON, binding sites labeled by [3H]-5-HTligand in the hippocampal CA1 area of trained adult ratsshowed a minor expression relative to untrained controls,while in aging animals more 5-HT receptors were expressedrelative to their aged control and untrained group(Meneses et al., 2004). A similar pattern of results emergewhen 5-HT4 receptors are analyzed (Manuel-Apolinaret al., 2005). Except for recent findings reported by Topicet al. (2006), notwithstanding the above findings andimplications, there is no available information about5-HT1A (or any other 5-HT) receptor expression in trainedand untrained amnesic or AD patients or in normal youngadults relative to aged persons or animals. Further supportfor the importance of 5-HT receptors in memory is seen inschizophrenic patients, who show cognitive impairment(e.g., memory deficits), as well as altered levels of diverse5-HT receptors including 5-HT1A (Table 2; Araki et al.,2006; and for review see Millan, 2000). Actually, different5-HT mechanisms have been under investigation aspotential treatments for learning and memory dysfunctionsin AD and schizophrenia (Meltzer, 1999; Meltzer et al.,2003; Meneses, 2003; Millan, 2000). For instance, schizo-phrenic patients treated with 5-HT1A partial agonists (e.g.,tandospirone, buspirone) show an amelioration of thenegative and cognitive symptoms of schizophrenia (seeMeltzer et al., 2003; Millan, 2000). Thus, modulation of 5-HT receptors (protein or mRNA) expression mightrepresent reliable index of memory formation and amnesia.Before to discuss amnesia results, it is necessary to explorememory formation.

3. 5-HT1A receptors: behavioral learning and memory tasks

As it was already mentioned, in order to identify sourcesof discrepancies among studies, an analytic approach wasused to examine the nature and difficulty degree ofbehavioral tasks used, brain areas involved (e.g., pre- vs.postsynaptic 5-HT receptors), duration of training (e.g.,number of trials), specific drugs and their timing ofadministration. In behavioral learning paradigms,5-HT1A receptors have been the most extensively studied

(Table 2). Even though current available evidence isinconsistent (see Harvey, 1996; Meneses and Hong, 1997for earlier reviews), some clear findings have emerged.From a methodological point of view, investigators haveadministered 5-HT1A drugs either before or after thelearning task and/or the pre-RET phase, with pre-trainingadministration the most frequently used (Table 2). Each ofthese drug administration protocols allows the study ofdifferent stages or phases of memory: acquisition (ACQ),CON, and/or retrieval (McGaugh, 1989; Meneses, 1999,2003; Meneses and Hong, 1997). The effects induced bypre-training injections might affect ACQ and/or reflectnonspecific changes (i.e., motivation, perception, motoractivity), whereas those behavioral and/or neurobiologicalchanges produced by post-training injections may beattributed to memory-related mechanisms since the in-formation has already been acquired and stored inmemory. Thus, these drug protocol studies have revealedthat 5-HT systems in mammals perform complex functionsin different memory models, via multiple 5-HT receptors.The results depend on 5-HT receptor subtypes, sites ofadministration (systemic or central), timing of drugadministration, and behavioral tests used (Meneses,1999). Drug effects have been examined on the samelearning task across a broad range of intracerebral sites,utilizing different learning tasks while focusing on the samesite and drugs, holding the behavioral task and infusion siteconstant while varying the drug dosage or drug type, andusing the same or different species (Meneses, 1999, 2003).Because some behavioral tasks have been used more

often, the present discussion will focus mainly on studiesincorporating these tasks: for instance, negatively moti-vated (e.g., electric shock) tasks, such as passive avoidance(PA) and active avoidance (AA), that depend on activity inthe hippocampus and other cortical areas (see, for example,Izquierdo et al., 1998, 1999, 2006) and employ one orseveral training trial and testing sessions. Using this type ofexperimental paradigm, it was observed that except for afacilitated learning ACQ elicited by tandospirone (partialagonist) at 1.0mg/kg, 5-HT1A agonists had either no effector impaired learning ACQ, CON and RET (see Table 2).Notably, Madjid et al (2006) reported that systemic(subcutaneous) pre-training administration of 8-OH-DPAT facilitated PA RET at low doses (0.01 and0.03mg/kg) in mice, but impaired PA RET at higher doses(0.1–1.0 mg/kg). These data indicate that with slightstimulation under low doses of 8-OH-DPAT, RETimproves; however, it is impaired when stimulation isexcessive. In the same study, pre-training administration of5-HT1A receptor antagonists NAD-299 (0.1–2mg/kg) andWAY-100635 (0.3–3mg/kg) enhanced PA RET, and theimpairment (1mg/kg) but without altering the facilitatory(0.03mg/kg) effects induced by 8-OH-DPAT. In addition,5-HT1A receptor ligands given immediately post-trainingfailed to alter PA RET. According to Madjid et al. (2006),these results indicate that systemic administration of5-HT1A receptor antagonists can facilitate cognitive

ARTICLE IN PRESSA. Meneses, G. Perez-Garcia / Neuroscience and Biobehavioral Reviews 31 (2007) 705–727 715

performance, most likely by enhancing hippocampal/cortical cholinergic and glutamatergic neurotransmissions.Most importantly, these results suggest that in a PA taskthere is a serotonergic tone involving 5-HT1A receptors andthat the facilitatory effect of 5-HT1A receptor antagonists isdependent on brain areas and memory stage (see, forinstance, Izquierdo et al., 2006). Moreover, pre-trainingtandospirone and 8-OH-DPAT impairment effects in PAare unaffected by the 5-HT synthesis inhibitor PCPA(parachlorophenylalanine), implying that 5-HT1A receptoragonists and partial agonists produce a reversible ante-rograde amnesia mediated by postsynaptic 5-HT1A recep-tors (Mendelson et al., 1993). Certainly, some of theseimpairment effects are mediated by the amygdala and/orhippocampus. For instance, intra-amygdala (or systemic)administration of partial (buspirone) and full (8-OH-DPAT) 5-HT1A agonists impaired inhibitory avoidance(Liang, 1999). Localized infusion of NAN-190 (a partial5-HT1A receptor antagonist) into the CA1 region of the rathippocampus and the entorhinal, posterior parietal andanterior cingulate cortices, 10min prior to a 24-h RETtesting session of 1-trial step-down inhibitory avoidance,enhanced performance, while 8-OH-DPAT hindered it(Barros et al., 2001). Thus, 5-HT1A receptor antagonistsapparently facilitate memory by reversing a serotonergictone in PA, while (excessively) increasing serotonergic5-HT1A receptor tone would impair this cognitive process.There likely exists an optimal dynamic range in which tonic5-HT1A neurotransmission improves memory in PA tasks.Importantly, in PA post-training injections of serotonininto the striatum produced strong amnesia in a PA task(Prado-Alcala et al., 2003).

On an associative and aversive learning task such as therabbit’s classically conditioned nictitating membrane (NM)response, 8-OH-DPAT (50 and 200 nmol/kg; IV) had noeffect (Welsh et al., 1998). Moreover, in the appetitivelymotivated behavioral tasks used to measure workingmemory (i.e., a delayed retrieval), dependent on thehippocampus or prefrontal cortex (Sloan and Dobrossy,2006; Sloan et al., 2006; see also for this and otherbehavioral tasks Lynch, 2004) and requiring extensivetraining and testing sessions such as delayed-matching-to-position (DMTP) or delayed nonmatch-to-sample(DNMTS) tasks, low doses of 8-OH-DPAT (see e.g., Coleet al., 1994) or the 5-HT1A partial agonists (buspirone,ipsapirone) had either no effect or enhanced ACQ or CON,but at high doses these same drugs impaired learning ACQor CON (Table 2 and for other references see, for instance,Meneses, 2003). In a mixed DNMTP/DMTP paradigmwith interspersed trials in a random sequence for theduration of a session (Pache et al., 1999, 2003), 8-OH-DPAT (0.03mg/kg) slightly but significantly improvedresponse accuracy in a delay-dependent fashion duringDMTP but not DNMTP trials. The highest dose tested of8-OH-DPAT (0.1mg/kg) impaired accuracy duringDNMTP trials independent of delay and had no significanteffect during DMTP trials, which rely more on STM

function. In addition, 8-OH-DPAT at 0.3mg/kg had noeffect on DMTP trials and induced small decreases indiscriminability. According to Stanhope et al. (1995), theseresults demonstrate some dissociation between drug-induced cognitive and motor/motivational deficits andquestion the specificity of putative cognitive impairmentsreported in many previous studies with 8-OH-DPAT. InDNMTS, pre-training administration of the 5-HT1A

antagonist WAY100635 (0.15mg/kg) alone had no effecton response accuracy, delay lever press activity and trialcompletion; however, 8-OH-DPAT (0.3mg/kg) impairedresponse accuracy in a delay-dependent manner, this effectwas reversed by WAY100635, and, together with the 5-HTuptake inhibitor fluoxetine, improved STM function(Fernandez-Perez et al., 2005). The 5-HT1A receptoragonist/antagonist S15535, [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] (0.16–0.63), improved performance in thespatial version of DNMS in mice, and in the operantversion of DNMS in old rats, S15535 (1.25–5.0mg/kg p.o.)increased response accuracy and reduced latency torespond (Millan et al., 2004; see also Bertrand et al., 2001for other 5-HT1A agonist/antagonist).In behavioral tasks requiring moderate to extensive

levels of training such as the aversive plus maze and theappetitively motivated radial maze, pre-testing systemic(1mg/kg) or intraseptal (1 mg) administration of 8-OH-DPAT induced anxiogenic-like effects in the former andimproved the ACQ of the spatial discrimination in thehippocampus-mediated radial maze in mice (Micheau andVan Marrewijk, 1999); non-selective 5-HT7 receptorantagonists (spiperone or methiothepin) (Misane andOgren, 2000, 2003) or low doses of selective 5-HT7 receptorantagonists did not alter them (Egashira et al., 2006;nonetheless, see Barnes and Sharp, 1999; Meneses andTerron, 1999 and below). Pre-training administration of alow dose (0.1mg/kg) of 8-OH-DPAT increased rate ofresponding in the radial maze and higher doses impairedmemory (Helsley et al., 1998; Winter and Petti, 1987).Intramedian raphe nucleus (MRN) pretraining injectionsof 8-OH-DPAT reduced both freezing and the fear-potentiated startle (FPS) in the contextual conditionedfear task, a hippocampus-mediated and aversively moti-vated task requiring moderate levels of training, whereaspost-training injections reduced only freezing in theaversive context without changing the FPS (Borelli et al.,2005). The authors concluded that freezing is easilydisrupted by post-training MRN injections of 8-OH-DPATwhile memory for the FPS remained unchanged. In theobject recognition (OR) task, an associative learning taskdependent on natural exploration, not requiring trainingtrials and mediated by prefrontal cortex (see Muller andKnight, 2006), systemic administration of 8-OH-DPAT(0.1 and 0.3mg/kg) dose-dependently impaired perfor-mance, and the 5-HT1A receptor antagonist WAY 100635(0.3 and 1mg/kg) antagonized these 8-OH-DPAT-inducedperformance deficits (Pitsikas et al., 2003). In theMorris water maze (MWM), an aversively motivated task

ARTICLE IN PRESS

Fig. 2. Comparison among trained groups with Pavlovian/instrumental autoshaping (A), Pavlovian autoshaping (B), random control with instrumental

contingency (C) and truly random control (D). Number of conditioned responses (closed circles) and head-pokes (open circles) are display.


requiring extensive training and depending on hippocam-pal activity, low doses (e.g., 60 mg/kg) of 8-OH-DPAT hadno effects (Hunter and Roberts, 1987) while high doses(i.e., 100–200 mg/kg) impaired spatial memory (Carli andSamanin, 1992; Carli et al., 1998; Hunter and Roberts,1987). Similarly, daily pre-training administration of8-OH-DPAT disrupted spatial navigation in MWM atmedium doses and cue navigation at high doses (Riekkinenet al, 1995). Notably, as it has been already mentioned,increased number of 5-HT1A receptors in the hippocampalCA2–CA4 regions was associated with impaired perfor-mance in MWM (Topic et al., 2006).

To study different stages or phases of memory (e.g.,ACQ, CON), as well as STM and LTM Pavlovian/instrumental autoshaping had been used (Meneses, 2003).Thus allowing to separate memory changes from modifica-tions in motivation, perception or motor activity (Meneses,1999, 2003, 2007). Importantly autoshaping as an associa-tive learning task, allows distinguishing between associativefactors contributing to learning for non-associative ones(e.g., habituation), by using a random control (Rescorla,1967) and a random control with contingency to determineinstrumental responses (see Figs. 2 and 3). This isimportant since the molecular and pharmacological studyof memory should include the above behavioral controls aswell as the traditional controls such as vehicle, positive(e.g., promemory or antiamnesic drugs) and negative (e.g.,amnesic drugs) groups. Likewise, control groups such asanimals without associative learning but receiving thepharmacological experience had been necessary to include(see Perez-Garcia et al., 2006). In the Pavlovian/instru-mental version of the autoshaping learning task, anappetitively motivated task requiring moderate training

and mediated by 5-HT1A located in the raphe nuclei,prefrontal cortex, amygdala, and hippocampus (Luna-Munguia et al., 2005), 8-OH-DPAT pre-training adminis-tration impaired ACQ but post-training injections of lowdoses enhanced memory CON in rats. This effect waseliminated by 5-HT depletion or synthesis inhibition(Meneses, 2003; Meneses and Hong, 1994b); hence,involving a presynaptic mechanism. In mice submitted toautoshaping and 8-OH-DPAT there were no changes inperformance (Vanover and Barrett, 1998), implying aspecies differences. Moreover, the 8-OH-DPAT-facilitatoryeffect was antagonized by WAY100635 and SB-269970 orDR-4004 (selective and potent 5-HT7 receptor antagonists)(Manuel-Apolinar and Meneses, 2004; Meneses, 2004), andthis evidence is in line with data showing that this drugdisplays affinity for both 5-HT1A and 5-HT7 receptors(Hoyer et al., 2002). Similar involvement of 5-HT1A and5-HT7 receptors in 8-OH-DPAT has been reported for paintests as well as hormonal and temperature responses (Faureet al., 2006; Harte et al., 2005). However, when high doses(1.0mg/kg; IP) of 8-OH-DPAT and moderate levels oftraining in the radial maze were used, performance wasimpaired and SB-269970 (at low doses, 3.0mg/kg) did notmodify this effect (Egashira et al., 2006); in this case,8-OH-DPAT was likely acting on pre- and postsynapticreceptors. Nonetheless, SB-269970 at high doses (e.g.,10.0mg/kg) blocked 5-HT7 receptors, and reversed thefacilitatory effects of 8-OH-DPAT (0.062mg/kg) in anautoshaping task (Manuel-Apolinar et al., 2005), an actioninvolving presynaptic receptors. In addition, in contrastwith the above-mentioned effects of post-training admin-istration of 8-OH-DPAT in rats, pretraining injection of8-OH-DPAT (0.15mg/kg) in a Pavlovian autoshaping task

ARTICLE IN PRESS

Fig. 3. Comparison among trained groups with Pavlovian/instrumental autoshaping (closed circles), Pavlovian autoshaping (closed triangles), random

control with instrumental contingency (open circles) and truly random control (open triangles). Behavioral parameters analyzed were conditioned

responses, head-pokes and head-pokes during the CS.


retarded memory only when a localized CS was used (Blairet al., 2004). According to these authors, this selectiveeffect cannot be explained in terms of its motor effects andis consistent with the specific suggestion that systemicadministration of 8-OH-DPAT is especially effective indisrupting learning tasks mediated by hippocampal me-chanisms. In fact, previous evidence (Meneses and Hong,1991) showed that the systemic administration of thepartial 5-HT1A receptor agonist buspirone (1–10mg/kg)impaired memory CON. In contrast, when 8-OH-DPATwas tested at 0.015–0.250mg/kg, pre-training administra-tion impaired memory CON and only low doses(0.015–0.062mg/kg) improved it; both effects were time-dependent (Meneses and Hong, 1994a). Moreover, when8-OH-DPAT was administered pre- or post-training tofree-feeding or prefeeding animals, they did not demon-strate learning, and even when it was administered toretrained food-deprived animals, the compound was alsoinactive. However, when retrained animals on a free-feeding schedule received pre- or post-training administra-tion of 8-OH-DPAT, enhanced retrieval occurred in adose-dependent manner, thus indicating that pre-trainingadministration impaired food intake and exploration,but not learning. Notably, recently using the sameautoshaping task and testing the same animals at 1.5 and24 h later (to study short- and long-term memory) post-training treatment with 8-OH-DPAT (0.031–1.0mg/kg),only 0.250 and 0.500 impaired both types of memory(Meneses and Liy-Salmeron, 2006, 2007). Together, thesedata strongly suggest a role for presynaptic 5-HT1A

receptors in memory CON and retrieval, which isindependent of food intake (Meneses, 2003; Meneses andHong, 1991; Meneses and Hong, 1994a). There is evidence

that 8-OH-DPAT provokes internalization of 5-HT1A

receptors in the raphe nuclei but not in the hippocampus,and this internalization should prevent autoinhibition ofthe firing of raphe nuclei neurons by 5-HT, thus increasing5-HT transmission in target zones (see Riad et al., 2001).Although this information may shed light on to clarify how8-OH-DPAT acting presynaptically at low doses mayimprove memory CON (Meneses, 2003; Meneses andHong, 1991, 1994a), it should keep in mind thatinternalization of receptors is also regulated by localizedmechanisms (including constitutive activity) which mightbe supporting some 5-HT receptors (Meneses, 2003;Romano et al., 2006).In rats and monkeys under an appetitive repeated-

acquisition responding (RAP) procedure requiring exten-sive training, which allows distinguishing between ACQ(learning) and performance components, 8-OH-DPAT andbuspirone produced, respectively, dose-dependent de-creases in overall response rate and increased percenterrors (Winsauer et al., 1999). In contrast, the partial5-HT1A agonists BMY7378, NAN-190 and flesinoxan hadeither no effect or impaired learning ACQ in the behavioraltests of RAP, PA, autoshaping, delayed conditionaldiscrimination (DCD), and DMTP. The 5-HT1A receptorantagonists, p-MPPI, WAY100135, S-UH-301 andWAY100635, did not alter learning ACQ or CON in thebehavioral tests of PA, DMTP, radial maze, RAP(Winsauer et al., 1999), or autoshaping (Table 2). Ingeneral, these data suggest that low doses (e.g.,0.062–0.031mg/kg) of 8-OHDPAT (likely via presynapticreceptors) have no effects or improve memory in behavior-al tasks such PA, radial and water mazes or autoshaping.Nonetheless, 8-OHDPAT at high doses or partial 5-HT1A


receptor agonists (likely acting pre- and/or post-synapti-cally) impaired memory (see e.g., Bertrand et al., 2001). Inbehavioral tasks such PA 5-HT1A receptor antagonistsmight improve memory and/or reverse amnesia,which suggests a serotonergic tone. As 8-OHDPATdisplays affinity for 5-HT1A and 5-HT7 receptors and bothseem mediate its memory effects, thus, a slight stimulationof this serotonergic 5-HT1A (and/or 5-HT7) receptors tonewould improve memory formation; however, its over-stimulation may produce the opposite effects. This conclu-sion is in line with diverse results in amnesia models andconsistent with evidence that 5-HT1A (and 5-HT7?)receptors expression is decreased in AD patients, hence itis important to investigate them in behavioral models ofamnesia.

3.1. Models of amnesia

Since factors such as the nature and difficulty degree ofbehavioral tasks, brain areas involved, duration of trainingdrugs and their timing of administration have influenceduring memory formation, it results appropriate identify-ing if these same factors would affect amnesia. It is widelyknown that amnesia may occur from natural causes (e.g.,aging), pathophysiological conditions (e.g., Alzheimerdisease, hypertension, schizophrenia) and by pharmacolo-gical means (e.g., ecstasy, antagonists for muscarinic orglutamate receptors) (Dijk et al., 1995; for reviews seeCiranna, 2006; Meneses, 1999, 2003; Santucci and Cardi-ello 2004). Indeed, drugs have been used to model theabove conditions and for testing drugs to the prevention orreduction of memory deficits. For instance, in the above-mentioned work of Riekkinen and coworkers (1995)reported that treatment with sub-amnesic (i.e., low) dosesof 8-OH-DPAT and scopolamine combined impairedmemory in naıve rats but not in trained animals or withpost-training drug administration. Riekkinen et al. (1995)concluded that combined treatment with drugs blockingmuscarinic acetylcholine receptors and activating 5-HT1A

receptors greatly impairs MWM learning/performance, butdid not impair spatial memory per se. Carli and colleagues(Carli and Samanin, 1992; Carli and Samanin, 2000; Carliet al., 1995, 1997, 1998, 1999a, b, 2001, 2006), using a two-platform spatial discrimination task in a water maze, forinstance, reported (Carli et al., 2001) that intraraphe dorsalnucleus administration of 8-OH-DPAT (1 mg/0.5 ml) orWAY 100635 (1 mg/0.5 ml), had no effect on any parameterof the rats’ performance. The authors hypothesized thatstimulation of presynaptic 5-HT1A receptors in the dorsalraphe counteracts the deficit in spatial learning caused by areduced NMDA-mediated excitatory input on pyramidalcells in the hippocampus. Also, 8-OH-DPAT (0.1–0.3mg/kg) reversed delta 9-tetrahydrocannabinol-induced impair-ment of spatial memory in the radial maze and reduction ofacetylcholine release in the dorsal hippocampus in rats(Inui et al., 2004). Importantly, Carli and colleagues havepreviously reported (Carli and Samanin, 1992; Carli et al.,

1995) that systemic administration of 8-OH-DPAT (at 0.1or 0.3 but not 0.030mg/kg; sc) impaired choice accuracy(days 1 and 2) with no effect on latency. This effect wasreversed by the intrahippocampal (CA1 area) administra-tion of the 5-HT1A antagonist WAY100135 (5 mg/ml),which alone had no effect. Thus, stimulation of 5-HT1A

receptors in the CA1 region of the dorsal hippocampusimpaired spatial but not visual discrimination in rats (Carliet al., 1997). Confirming this conclusion, the 5-HT1A

receptor agonist/antagonist S15535 infusion (1.0 and10.0 mg) into the dorsal hippocampus in the same two-platform spatial discrimination task blocked the amnesiceffects of intrahippocampal 8-OH-DPAT (5.0 mg) (Millanet al., 2004). Supporting the notion that 5-HT1A receptorantagonists are effective antiamnesic drugs, Misane andOgren (2003) reported that in a PA task the selective5-HT1A receptor antagonist NAD-299 (0.3–1.0mg/kg)reversed the RET impairment caused by scopolamine ordizocilpine, and sub-effective doses of scopolamine com-pletely blocked the facilitatory effect of NAD-299 on RET.Furthermore, during memory formation in PA the admin-istration of WAY-100635 potentiated the learning-specificincrease in the hippocampus of phosphorylated Ca2+/calmodulin-dependent protein kinase II (phospho-CaMKII) activity, as well as the phosphorylation of eitherthe CaMKII or the protein kinase A (PKA) site on theAMPA receptor GluR1 subunit (Schiapparelli et al., 2006).Likewise, 8-OH-DPAT at a high dose (i.e., 0.1mg/kg; s.c.)in a purposely 5-HT1A receptor-mediated disruption of PARET reduced PKA activity and the ensuing enhancementin phosphatase 1 (PP1) (Moyano et al., 2004). Although,unfortunately, the animals used for this memory andsignaling cascade studies (Moyano et al., 2004; Schiappar-elli et al., 2006) were not the same, these could be part ofmolecular basis of amnesia in PA. Moreover, a time-dependent sensitization (TDS) stress model of spatialmemory deficits was evaluated in the MWM, showing thatTDS stress evoked a marked deficit in spatial memory onday 7 post TDS stress and cognitive changes wereassociated with a significant increase in receptor density(Bmax) and a significant decrease in receptor affinity (Kd)for hippocampal 5HT1A receptors (Harvey et al., 2003).Likewise, the novel 5-HT1A receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan; 2.0mg/kg), reversed learning deficits in marmosets induced by theglutamatergic antagonist dizocilpine (assessed by percep-tually complex and visual spatial discrimination) and byspecific cholinergic lesions of the hippocampus (Schechter etal., 2005). However, as it was already mentioned, inbehavioral tasks such as water and radial mazes, autoshap-ing and PA amnesia could be reversed by stimulation of5-HT1A (8-OHDPAT) and/or 5-HT7 (AS 19) receptors(Manuel-Apolinar and Meneses, 2003; Perez-Garcia andMeneses, 2005a; Perez-Garcia et al., 2006). How are 5-HT1A

and 5-HT7 receptor agonists and antagonists able tonormalize and/or reverse amnesia?


3.1.1. Models of amnesia: roles of 5-HT1A and 5-HT7

receptors

As it was already mentioned some behavioral tasksproduce a 5-HT1A (or 5-HT7) receptors tone (e.g., PA task),nonetheless under amnesic conditions (e.g., scopolaminetreatment in MWM or autoshaping) the above serotonergictone is demonstrated by application of 5-HT1A receptorantagonists and agonists. For instance, memory deficits inthe Pavlovian/instrumental autoshaping task induced byglutamatergic (dizocilpine) or cholinergic blockade (scopo-lamine) were reversed by systemic administration of WAY100635 (0.3mg/kg) or 8-OH-DPAT (0.062mg/kg) (Meneses,2004). Significantly, either WAY 100635 (0.3mg/kg) or SB-269970 (10.0mg/kg) are effective by blocking their respectivereceptors without affecting memory CON, and they are ableto reverse the 8-OH-DPAT facilitatory effect; thus implicat-ing both 5-HT1A and 5-HT7 receptors (Perez-Garcia andMeneses, 2005b; Perez-Garcia et al., 2006). Indeed, it now isaccepted that 8-OH-DPAT exerts some of its effects via both5-HT1A and 5-HT7 receptors. Both 5-HT1A and 5-HT7

receptors show a similar distribution and share mechanismsof action in brain areas involved in memory (Meneses, 1999;Perez-Garcia et al., 2006; see below). Recently available forexperimental use, the selective 5-HT7 receptor agonist, (2S)-(+)-8-(1,3,5-trimethylpyrazolin-4-yl)-2-(dimethylamino) tet-ralin (AS 19), facilitated memory CON and modulatedmRNA of 5-HT7 receptor expression in a Pavlovian/instrumental autoshaping task, and WAY 100635 or SB-269970 partially or completely reversed the effect of AS 19(Perez-Garcia and Meneses, 2005a, b Perez-Garcia et al.,2006).Thus, the facilitation of memory formation and theanti-amnesic effect produced by AS 19 is consistent withsimilar evidence reported with the 5-HT1A/7 receptor agonist8-OH-DPAT. In this context, one should be bear in mindthat the above antiamnesic effects of AS 19 and 8-OH-

I. PA:

1) 8 -OHDPAT low doses

memory;

2) 8 -OHDPAT high dose

↓ ;

3) 5 - HT1A antagonists

memory or no effects

4) Pre - and / or post -

synaptic

II. WM, STM,

autoshaping, RM:

1) 8 - OHDPAT low doses

memory or no effects;

2) 8 - OHDPAT high doses

↓ memory

3) 5 - HT1A antagonists no

effects

4) Pre - and/or post -

synaptic

5-HT7

cAMP

Gs+

cAMP

CREB

P P

AC

b

GLU

5-HT1A

PKA

To the nucleus

Serotonin

release

Fig. 4. Distribution of 5-HT1A and 5-HT7 receptors, their signaling pathways (

HT1A receptors and their signaling pathway are showed (a). Serotonin release a

8-OH-DPAT displays affinity for both 5-HT1A and 5-HT7 it would behave in

DPAT may appear inconsistent with the results reported in arecent paper (Meneses, 2004) that the 5-HT7 antagonists SB-269970 and DR4004 reversed memory deficits. In essence,these 5-HT7 receptor antagonists had no effects when testedalone during memory formation. Indeed, as already men-tioned, a similar contradictory situation apparently occursregarding 5-HT1A receptors. In some behavioral learningtasks and training conditions (e.g., MWM, autoshaping),5-HT1A receptor blockades have no effect, while theirstimulation (as discussed above regarding dose-dependent8-OH-DPAT) may impair or improve performance; incontrast, under amnesic conditions both 5-HT1A receptorantagonists and agonists may be effectively antiamnesic (seeabove). Several key questions deserve attention in thiscontext (Meneses, 2004), in particular the notion that5-HT1A and 5-HT7 (and likely 5-HT6: for antagonists seePerez-Garcia and Meneses, 2005a; Schechter, 2006, and foragonists see Fone, 2006) receptor ‘‘plasticity’’ and/or‘‘unmasked’’ activity is apparent under amnesic conditions.Studies of signaling mechanisms underlying these precogni-tive effects show that 5-HT1A and 5-HT7 receptors mediatecortical and hippocampal (important areas for memoryCON; Wang et al., 2006) increases in cAMP productionfollowing administration of the 5-HT1A/7 agonist 8-OH-DPAT. Only the memory effect is completely or partiallyreversed by the selective 5-HT1A antagonist WAY100635(5-HT1A) or 5-HT7 antagonists DR4004 (Meneses, 2004) andSB269970 (Perez-Garcia et al., 2006). Likewise, memoryCON by itself modulates cAMP production (Manuel-Apolinar and Meneses, 2004), the protein and mRNAexpression of 5-HT1A, 5-HT6 or 5-HT7 receptors, which areaffected by agonists and antagonists (Luna-Munguia et al.,2005; Perez-Garcia et al., 2006). Highlighting the importanceof the behavioral nature of memory tasks is evidence thatoverexpression of 5-HT1A receptors at a younger age may

III. MWM:

1) 8-OHDPAT low doses

no effects;

2) 8-OHDPAT high doses

↓ memory,

3) 5-HT1A antagonists no

effects

4) Pre- and/or post-

synaptic

Raphe

Nuclei

5HT

5-HT1A

Gi

ACcAMP

-

PKA

a

c

8-OHDPAT

IV. OR:

1) high doses memory;

2) 5-HT1A antagonists no

effects

3) Pre - and /or post-

synaptic

central panel) and major behavioral results (lateral panels). Presynaptic 5-

ctivates both pre- and postsynaptic 5-HT1A and 5-HT7 receptors (b). Since

similar manner (c). m ¼ facilitate; k ¼ impair.


have no effect on the water maze, may improve performanceon the hippocampus-mediated hole board task, or impair PAmemory in adult animals (Bert et al., 2006a; see also below).Probably, a combination of available behavioral task ornews ones will be useful to clarify some major questions.

The summarization of the behavioral tasks anaylisis (seeFig. 4) reveals that the prototype 5-HT1A receptor agonist8-OH-DPAT (Table 2): (1) at low doses (0.1–0.016mg/kg)it had no effect or improved learning; (2) when stimulated,presynaptic 5-HT1A receptors improved learning and/orreversed learning and memory deficits; (3) when stimulated,postsynaptic 5-HT1A receptors impaired learning ACQ andretrieval, but not CON, in aversive learning (e.g., in PA,MWM) but not appetitive learning; and (4) it diminishedexploration and food intake behaviors, but did not alterlearning ACQ. Hence, (5) internalization of 5-HT1A

receptors in the raphe nuclei but not in the hippocampus,should prevent autoinhibition of the firing of raphe nucleineurons by 5-HT, thus increasing 5-HT transmission intarget zones (see Riad et al., 2001). However, internaliza-tion of 5-HT receptors is also regulated by localizedmechanisms, including constitutive activity (Meneses,2003; Perez-Garcia et al., 2006; Romano et al., 2006). (6)5-HT1A receptor antagonists may or may not have an effectby themselves on learning CON (i.e., they are silent);nevertheless, they were able to reverse the 8-OH-DPAT-induced effect (either impair or improve; but see Madjid etal., 2006), while PCA did not alter the silent characteristicof 5-HT1A receptor antagonists. (7) In behavioral taskssuch as PA and autoshaping, 5-HT1A receptor agonists andantagonists may reverse amnesia. And (8) The agonist8-OH-DPAT displays affinity for 5-HT1A and 5-HT7

receptors, with pKi values of 8.3 and 7.5, respectively,and is a potent drug for decreasing brain serotoninturnover. Therefore, 8-OH-DPAT at low doses mightstimulate presynaptic 5-HT1A (or 5-HT7) receptors, whilehigh doses would activate either 5-HT1A or 5-HT7

receptors, or both simultaneously, pre- and postsynapti-cally. A functional consequence of these actions would bethat 8-OH-DPAT at high doses activates opposite trans-duction signaling pathways (see below).

4. Pre- postsynaptic 5-HT1A receptors and memory

formation

Considering that stimulation or blockade of pre- vs.postsynaptic 5-HT1A (and 5-HT7) may produce differentialresults in memory, an important question surges: how hadthis affected memory? In this context, administration route,doses of 8-OHDPAT and where they would exert actionsbecome more important. For instance, when 8-OH-DPATis administered intraperitoneally (IP), the doses have to beabout 10-fold greater than those administered subcuta-neously (SC) to produce equivalent concentrations in therat brain and, concomitantly, it is at least 10 times morepotent in decreasing brain serotonin turnover wheninjected SC compared to IP (Fuller and Snoddy, 1987;

Perry and Fuller, 1989); thus, at high doses 8-OH-DPATwould achieve slightly higher concentrations in postsynap-tic (e.g., hippocampus) than in presynaptic areas (i.e.,raphe nuclei). Indeed, 8-OH-DPAT (1.0mg/kg) injectedsystemically impaired performance accuracy on a DNMTPtask, whereas central infusion (100 ng) into the median, butnot dorsal, raphe nucleus improved performance (War-burton et al., 1997). As already mentioned, pre-testing,intraseptal (1 mg) administration of 8-OH-DPAT producedanxiogenic effects in the plus maze and improved learningin the radial maze (Micheau and Van Marrewijk, 1999),which probably involved postsynaptic 5-HT1A receptors;thus, indicating that postsynaptic 5-HT1A receptors loca-lized in different brain areas may affect memory differen-tially. Indeed, involving postsynaptic receptors, 8-OH-DPAT pre-training injections into the hippocampal CA1area impaired performance accuracy, although the changesin performance cannot be accounted for by changes inmnemonic function (Warburton et al., 1997) and spatialdiscrimination ACQ (Carli and Samanin, 1992; Carli et al.,2001). In contrast, post-training hippocampal (CA1)infusion of 8-OH-DPAT or NAN-190 (a partial 5-HT1A

agonist) into entorhinal cortex inhibited short- but notlong-term memory on an inhibitory avoidance task, whilean intraentorhinal infusion of 8-OH-DPAT enhancedshort-term but impaired long-term memory. Neither8-OH-DPAT nor NAN-190 had effect on retrieval fromeither short- or long-term memory when given prior totesting (Izquierdo et al., 2006). While 8-OH-DPAT given inseveral postsynaptic brain areas impaired PA, in entorhinalcortex this drug (2.5 mg) enhanced STM but impaired LTM(Izquierdo et al., 1998, 2006). Post-training intra-amygdalainfusion of 8-OH-DPAT at low doses produced dose- andtime-dependent RET deficits on a PA task (Liang, 1999),while WAY 100635 at 0.1 mg enhanced RET and at 10 mgimpaired performance, but reversed the impairmentinduced by 5-HT1A agonists. Interneurons seem to mediatethe 8-OH-DPAT-induced processing of information via5-HT1A receptors within the amygdala (Stein et al., 2000).Similarly, 5-HT1A receptor blockades ameliorated thecognitive impairment induced by fornix transection (Hard-er et al., 1996) or by the NMDA antagonist dizocilpine(Bartolomeo et al., 1996). In contrast, in the median raphenucleus (MRN), likely involving presynaptic 5-HT1A

receptors, pre-training injections of 8-OH-DPAT reducedboth freezing and the fear-potentiated startle (FPS) in thecontextual conditioned fear task; post-training injectionsdecreased only freezing in the aversive context withoutchanging the FPS, indicating that freezing is easilydisrupted by post-training MRN injections of 8-OH-DPATwhile fear memory remained (Borelli et al., 2005). Notably,8-OH-DPAT stimulation of 5-HT1A receptors in the dorsalraphe nucleus ameliorates the impairment of spatiallearning caused by intrahippocampal 7-chloro-kynurenicacid in naive and pre-trained rats (Carli et al., 1998, 2001).Similarly, as it was earlier mentioned, stimulation ofpresynaptic 5-HT1A (and likely 5-HT7) receptors enhanced


memory CON and reversed scopolamine- or dizocilpine-induced amnesia in Pavlovian/instrumental autoshaping(Meneses, 2004; Meneses and Hong, 1994a, b; Perez-Garciaet al., 2006). Importantly, the glutamatergic antagonistketamine-induced amnesia, which was reversed by intra-hippocampal administration of 8-OHDPAT and sucheffects were reversed with WAY 100635 or SB-269970(Liy-Salmeron and Meneses, 2007). The dual role of pre-and postsynaptic 5-HT1A receptors has been recentlyconfirmed, as the already mentioned 5-HT1A receptoragonist/antagonist S15535 improved memory CON, RETand/or reversed amnesia in a social recognition paradigm,autoshaping, MWM, two-platform spatial discrimination,spatial DNMTS in mice and operant DNMTS in old rats;and its actions included both blockade of postsynaptic5-HT1A receptors and engagement of 5-HT1A autorecep-tors (Millan et al., 2004). It has been proposed that 5-HT1A

receptors, together with cholinergic and glutamatergicsystems, modulate memory CON in cognitively impairedanimals, supporting the notion that 5-HT1A receptorantagonists may be useful in the treatment of cognitivedisorders (Carli and Samanin, 1992; Carli et al., 2001, 2006;Luttgen et al., 2005; Madjid et al., 2006; Meneses, 2003;Manuel-Apolinar et al., 2005; Misane and Ogren, 2000,2003; Schechter et al., 2005; Stiedl et al., 2000). 5-HT1A

autoreceptors in the raphe nuclei regulate serotonergicrelease presynaptically and, postsynaptically as heterore-ceptors, mediate cholinergic, glutamatergic and GABAergicrelease in diverse brain areas including hippocampus,septum, amygdala and neocortex (Buhot et al., 2003;Francis et al., 1992; Sirvio et al., 1994; Steckler and Sahgal,1995). These brain areas and neurotransmitters arestrongly implicated in cognitive processes (Meneses,2003). Several results are reinforcing the notion thatpresynaptic 5-HT1A receptors play a role in learning andmemory: (1) Serotonergic afferents from the raphe complexto cerebral cortex are significantly decreased in AD, and5-HT autoreceptors undergo age-dependent alterations(see Meneses, 2003) including the 5-HT1A receptors(however see Topic et al., 2006). (2) Studies also showaffinity decline in cortex, hippocampus, amygdala andcholinergic basal forebrain nuclei during aging and in thebrains of AD patients. (3) An age-dependent differentialregulation of Gi protein levels occurs in the agedhippocampus. Traditionally, the search for brain areasinvolved in learning and memory has been centered onexaminations of amnesic and AD patients, cerebral lesions,and, more recently, neuroimaging. In this regard, acomplementary alternative consists in using radioligandsto show (Luna-Munguia et al., 2005; Tomie et al., 2003;Topic et al., 2006) that pre- and post-synaptic 5-HT1A

receptors may have complementary roles in memoryformation and even under certain circumstances (e.g.,amnesia, aging) playing the opposite role. As previouslymentioned, ex vivo receptor autoradiography using theradioligand [3H] 8-OH-DPAT showed that autoshapedtrained rats relative to untrained controls had an augmen-

ted presynaptic expression of 5-HT1A receptors in thedorsal and medial raphe nuclei (Luna-Munguia et al.,2005). Many postsynaptic areas displayed increasedexpression of 5-HT1A receptors including in the septalnucleus, caudate putamen, amygdala and cortical areas(e.g., parietal, temporal). Nevertheless, 5-HT1A (and likely5-HT7) receptor expression decreased in postsynapticregions found in the CA1 hippocampal area, dorsalhypothalamus, and frontal and occipital cortices. Indeed,when mRNA expression of 5-HT1A and 5-HT7 receptorswas analyzed it was found that autoshaping trainingelicited an improved expression in the postsynaptic areasof prefrontal cortex and hippocampus relative to the raphenuclei; with 5-HT1A receptors more strongly expressedthan 5-HT7 receptors (Perez-Garcia et al., 2006). Notably,it was reported that inferior learners in MWM task hadincreased 5-HT1A receptors in the CA2-CA4 hippocampalregions (Topic et al., 2006). Finally, during different stagesof PA training, [3H]-5-HT specific binding is decreased,while there is increased MAO activity and 5-HIAAtransport from serotonergic terminals (Molodtsova andIlyuchenok, 1998). Together these data confirm the notionthat, during memory formation (see above), e.g., receptorslabeled by [3H]-5-HT or 5-HT4 ligands in the hippocampalCA1 area of trained adult rats showed a minor expressionrelative to untrained controls, while in aging animals more5-HT receptors were expressed relative to their agedcontrol untrained group and in other brain areas occurredthe opposite (Meneses et al., 2004). As memory, amnesiaand aging produce dynamic changes in protein and mRNAof 5-HT receptors, and demands on 5-HT receptorexpression and function seem to be determined for theirfunctional or dysfunctional status. Hence, drugs withdiverse modes (i.e., agonism, inverse agonism and antag-onism) and sites of action (pre- and postsynaptic) would benecessary to normalize 5HT1A (and 5-HT7) receptorsfunction might be useful in the treatment of amnesia states?

5. 5-HT1A receptors: agonism, inverse agonism or

antagonism

The reason why 5-HT1A agonists and antagonists mayinfluence both normal and altered cognitive processes isunclear at present, but future experiments must be designedto address the mechanisms and conditions concerning howand where they might operate. However, having identifiedas sources of discrepancies due to the nature and difficultydegree of behavioral tasks used, brain areas (pre- vs.postsynaptic receptors), training time (e.g., number oftrials), and specific drug, the present data show that5-HT1A autoreceptors receive relatively little basal toneduring memory CON, although (slight) stimulation ofthese 5-HT1A receptors seems to be able to reverse a poorRET, probably mediating pathological and/or therapeuticbut not normal memory mechanisms in some behavioraltasks. In contrast, under some circumstances (e.g., PA taskor amnesia) memory tasks elicit a specific serotonergic


tone, where 5-HT1A receptor antagonists would be useful.Notable, as already mentioned, enhanced brain 5-HTactivity improves memory in animals and humans whereasdecreasing brain 5-HT levels by acute 5-HT depletion hasbeen shown to impair it (Haider et al., 2006; Sambeth et al.,2007; Schmitt et al., 2006). Hence, strategies discriminatingthe above sources of serotonergic tone will also contributeto the in vivo assessment of inverse agonist (Negus, 2006),agonist or antagonist effects, with 5-HT1A receptors beinga good candidate considering their tone as well as pre- andpostsynaptic localization. In fact, some years ago the5-HT1A inverse agonist SL88.0338-08 was reported tofacilitate simple habituation exploration activity in anelevated plus maze (Griebel et al., 1998). 5-HT1A receptorinverse agonists have profound effects on the intracellularsignaling cascade (see, for instance, Kushwaha et al., 2006)and perhaps on physiological responses. Certainly, impor-tant molecular changes seem to accompany memorydisorders. An interesting example of genetic manipulationand memory is represented by the 5-HT1A receptors.Hippocampal-dependent memory was impaired in micelacking 5-HT1A receptors (Sarnyai et al., 2000); however,these memory deficits seem to disappear and even to bereversed in aged mice (Wolff et al., 2004b). Moreover, 5-HT1A receptor transient overexpression impairs water-mazebut not hole-board performance (Bert et al., 2005, 2006a, b).Notwithstanding the technical difficulties, it would beinteresting to determine in conditional (i.e., temporal andneuroanatomically localized) mice the elimination or over-expression of 5-HT1A receptors in memory tasks. Notably,together these data clearly illustrate the importance of theserotonergic tone via 5-HT1A receptors and strongly high-light the importance of investigating 5-HT1A receptor inverseagonists, which might constitute a new approach in thetreatment of cognitive dysfunctions.

6. Concluding remarks

In summary, the present data indicate that the role of5-HT1A receptors in cognitive processes is more complexthan merely representing a simple imbalance. Notably,behavioral and cognitive demands exert differential andselective influence over 5-HT1A (5-HT7?) pre- and post-synaptic receptors, which might be exacerbated by amnesicstates and/or aging but reverse by pharmacologicaltreatments. Findings that 5-HT1A receptor agonists impairperformance, whereas a reduced serotonergic function mayfacilitate learning, must be reconsidered or, at least,reformulated. Likewise, findings that 5-HT1A receptoragonists and antagonists may be useful in the treatmentof memory disorders provide further support that 5-HTsystems may have an important role in normal function, aswell as in the treatment and/or pathogenesis of cognitivedisorders. Further investigation will help to delineate theinvolvement of 5-HT systems in normal cognitive pro-cesses, their role in pharmacological tools identification,their mechanisms and action sites, and to determine under

which conditions they operate. We hypothesize thatselective drugs with neutral antagonist or inverse agonistproperties for 5-HT1A receptors constitute new therapeuticopportunities in the treatment of memory disorders.

Acknowledgments

Special thanks to those private laboratories for havingprovided drugs used in this work. We thank Sofia Meneses-Goytia for revised language and Roberto Gonzalez for hisexpert assistance.

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