Sigma receptors: biology and therapeutic potential

Psychopharmacology ( . ) : 3–19DOI 10.1007/s00213-004-1920-9

REVIEW

Xavier Guitart . Xavier Codony . Xavier Monroy

Sigma receptors: biology and therapeutic potential

Received: 24 July 2003 / Accepted: 14 April 2004# Springer-Verlag

Abstract More than 20 years after the identification ofthe sigma receptors as a unique binding site in the brainand in the peripheral organs, several questions regardingthis receptor are still open. Only one of the subtypes of thereceptor has been cloned to date, but the endogenousligand still remains unknown, and the possible associationof the receptor with a conventional second messengersystem is controversial. From the very beginning, thesigma receptors were associated with various centralnervous system disorders such as schizophrenia or move-ment disorders. Today, after hundreds of papers dealingwith the importance of sigma receptors in brain function, itis widely accepted that sigma receptors represent a newand different avenue in the possible pharmacologicaltreatment of several brain-related disorders. In this review,what is known about the biology of the sigma receptorregarding its putative structure and its distribution in thecentral nervous system is summarized first. The role ofsigma receptors regulating cellular functions and otherneurotransmitter systems is also addressed, as well as ashort overview of the possible endogenous ligands.Finally, although no specific sigma ligand has reachedthe market, different pharmacological approaches to thealleviation and treatment of several central nervous systemdisorders and deficits, including schizophrenia, pain,memory deficits, etc., are discussed, with an overview ofdifferent compounds and their potential therapeutic use.

Keywords Sigma receptors . Schizophrenia . Drug abuse .Clinical potential . Brain disorder

Introduction

The process of understanding sigma receptors has been along, complicated and somewhat mysterious one, and thestory is still far from complete. In an early work, Haertzen(1970) described the psychomimetic effects of cyclazocineand nalorphine in humans. Later on, Martin and colleagues(1976), working in morphine-dependent and non-depen-dent chronic spinal dogs, reported the psychomimeticeffects of N-allyl-normetazocine (SKF 10,047). Theseeffects could not be explained by the actions on μ-opioidor κ-opioid receptors, and contributed to the proposal of aσ-opioid receptor.

Nevertheless, the enantiomeric selectivity of the sigmareceptor for the (+)-isoforms of the benzomorphans ratherthan for their (−)-isoforms (Brady et al. 1982), and the factthat the effects of sigma ligands neither in vivo nor in vitrowere blocked by classical opioid antagonists (Iwamoto1981; Vaupel 1983) led to some confusion regarding thetrue nature of sigma binding sites. Moreover, the sigmareceptor was also identified as the binding site forphencyclidine (PCP) within the N-methyl-D-aspartate(NMDA) glutamate receptor (Zukin et al. 1984; Mendel-sohn et al. 1985). However, further research in more recentyears conclusively defined the nature of sigma receptors,and they were finally reclassified as a non-opioid and non-PCP unique site (Quirion et al. 1992).

Since sigma receptors were first identified in the centralnervous system, extensive work has been performed invarious laboratories in an attempt to elucidate theirphysiological functions and, despite the initial confusion,significant advances have been made in delineating thefunctions of sigma receptors. These advances have beensummarized in several review articles describing theirknown physiological roles, as well as potential clinicaluses of sigma receptors and their ligands (Walker et al.1990; Debonnel 1993; Su 1993; Novakova 1998; Bowen2000; Maurice et al. 2001; Matsumoto et al. 2003).

This review examines the known functions of the sigmareceptors regarding the different types that have beendescribed, the cellular signals coupled to the stimulation-

X. Guitart (*) . X. Codony . X. MonroyBiological Discovery and CNS Research Department, ResearchCenter,Esteve, S.A., Mare de Deu de Montserrat 221,08041 Barcelona, Spaine-mail: [email protected].: +34-93-4466063Fax: +34-93-4466220

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blockade of the sigma receptors, and also focuses onexamining specific aspects of sigma receptor ligandsrelated to mental and neurological alterations, and theirputative therapeutic applications. This article will try tosummarize the current understanding in the study of sigmareceptors, but does not pretend to be extensive and not allthe work and references can be cited.

Classification of sigma receptors

Sigma receptors have been extensively characterized inbinding studies. These receptors are distinct from anyother known neurotransmitter receptors and have beendefined as non-opioid binding sites with high affinity for1,3-di (2-tolyl) guanidine (DTG), (+)-3-(3-hydroxyphe-nyl)-N-(1-propyl)piperidine [(+)-3-PPP], or haloperidol.

Biochemical and pharmacological studies stronglysuggest that there are multiple subtypes of sigmareceptors. The best characterized binding sites aredesignated as sigma-1 and sigma-2 receptor types(Hellewell and Bowen 1990; Quirion et al. 1992; Bowen2000). These receptor subtypes differ primarily in theirdrug selectivity. Sigma-1 sites exhibit high affinity andstereoselectivity for the (+)-isomers of pentazocine,cyclazocine, and SKF 10,047, whereas sigma-2 sitestend to prefer the (−)-stereoisomers (Bowen et al. 1993;Hellewell et al. 1994). Sigma-1 and sigma-2 receptors alsodiffer in their tissue distribution patterns, subcellularlocalizations, and apparent molecular weight (Itzhak1994; Torrence-Campbell and Bowen 1996).

The sigma-1 receptor has been recently cloned fromvarious sources, including guinea-pig liver (Hanner et al.1996), human placental choriocarcinoma cells (Kekuda etal. 1996), human brain (Prasad et al. 1998), rat brain (Sethet al. 1998; Mei and Pasternak 2001), and mouse brain(Pan et al. 1998). Based on the predicted 223 amino acid

sequence of the receptor, it shares no structural homologywith opioid receptors or other neurotransmitter receptors,although sigma receptors expressed in the central nervoussystem are highly similar to those expressed in peripheralorgans. The locus coding for the sigma-1 receptor islocated in the human chromosome 9 and in the mousechromosome 4. The gene is ∼7 kbp long and contains fourexons and three introns (Prasad et al. 1998). The aminoacid sequence of the cloned sigma-1 receptor shows nohomology with other mammalian proteins, but sharesapproximately 30% identity with the yeast gene thatencodes a sterol C8–C7 isomerase that is necessary forcholesterol synthesis (Moebius et al. 1997a,b). However, amammalian C8–C7 has been recently cloned (Hanner et al.1995), but this protein shows no similarity to either theyeast isomerase or the sigma receptor. In contrast, sigma-1receptors do not possess sterol isomerase activity (Hanneret al. 1996).

Based on hydropathy analysis of the amino acidsequence of the sigma-1 receptor, it was suggested thatthis receptor includes a single putative transmembranedomain (Mei and Pasternak 2001). Other recent studiescompared the homology between this putative transmem-brane domain and segments of other known transmem-brane domains; these studies suggested that the sigma-1receptor has two transmembrane segments, resulting in anextracellular loop of approximately 50 amino acids and anintracellular C-terminus of approximately 125 amino acids(Aydar et al. 2002). According to this model, the N-terminus is very short and also localized intracellularly.Figure 1 illustrates the two structural models that havebeen proposed for the sigma-1 receptor. The amino acidsequence is not consistent with that of a classical G-protein-coupled receptor, which makes it especiallydifficult to predict the effects of agonists or antagonistsof this receptor, at least in the traditional way, by directlinkage to stimulation or inhibition of intracellular

Fig. 1 Predicted amino acidsequence of the rat brain sigmareceptor. Different models havebeen proposed (see text fordetails). Receptor models with asingle putative transmembranedomain (a) and two putativetransmembrane domains (b)

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signaling pathways. The second hydrophobic region hasbeen suggested to be important for the binding of (+)-pentazocine (Yamamoto et al. 1999) but it still has to beelucidated whether this binding site is shared byneurosteroids. Nevertheless, biochemical studies (Beartet al. 1989; Ytzhak 1989; Connick et al. 1992) andpharmacological studies (Monnet et al. 1992a; Pascaud et

al. 1993; Gonzalez-Alvear and Werling 1995) haveidentified a substantial number of molecules with activityas agonists or antagonists at sigma-1 receptors. Further-more, a truncated form of the sigma-1 receptor hasrecently been described (Zamanillo et al. 2002), althoughthe physiological significance of this truncated receptor iscurrently unknown. Figure 2 and Table 1 show the

Fig. 2 Chemical structure ofsome sigma receptor ligandscited in this article. The bindingaffinity for the sigma-1 receptorand their activity is depicted inTable 1

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chemical structures and other characteristics of some of thebetter-known sigma-1 receptor ligands. As shown inFig. 2, the chemical structures of these ligands are highlyheterogeneous.

The sigma-2 receptor has not been as well characterizedas the sigma-1 receptor. Cloning of the sigma-2 receptorhas not yet been reported (Hellewell and Bowen 1990;Quirion et al. 1992). Both subclasses can be clearlydifferentiated not only by their function and pharmacolo-gical characteristics, but also by their molecular weight.Sigma-2 receptors have affinity for typical neuroleptics

(such as haloperidol), for DTG, and for some benzomor-phans, but they exhibit lower affinity for the (+) formsthan do sigma-1 receptors. The molecular size of thesigma-2 receptor has been reported to be 18–21 kDa, asdetermined by photoaffinity labeling and SDS gel elec-trophoresis (Hellewell and Bowen 1990; Hellewell et al.1994). Most of the studies designed to visualize sigmareceptors have used radioligands that do not completelydiscriminate between the sigma-1 and sigma-2 subtypes.In more detailed studies (McCann et al. 1994; Bouchardand Quirion 1997), it was shown that sigma-1 and sigma-2

Fig. 2 (continued)

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receptors are generally co-localized, although they may bepresent in different ratios (Leitner et al. 1994).

Sigma-2 receptors have been implicated in the regula-tion of cell proliferation and cell viability. Cytotoxicity ofsigma ligands has been observed both in vivo and in vitro(Vilner and Bowen 1993; Vilner et al. 1995). These effectsare mediated by sigma receptors; ligands with affinity forother receptors or ion channels did not exhibit cytotoxicactivity, and the pharmacological profile of these com-pounds clearly implicates sigma-2 receptors (Bowen et al.1995a). Selective sigma-1 ligands did not induce anycytotoxic effects on cells.

Endogenous ligands of the sigma receptors

Despite considerable advances in our understanding ofsigma receptors over the past several years, an endogenousligand has not yet been found. Identification of anendogenous sigma ligand would improve our under-standing of the role of sigma receptors in physiologicaland pathophysiological brain functions. A number ofknown peptides and other neurotransmitters have beenclearly shown to be ineffective in displacing selectivesigma ligands from sigma receptors. Neurotransmittersthat do not interact with the sigma receptor includeserotonin, norepinephrine, dopamine, and histamine(Weber et al. 1986; DeHaven-Hudkins and Fleissner1992); as well as several amino acids, such as glutamate,glycine, aspartate, and cysteine (Craviso and Musacchio1983; Klein and Musacchio 1989); and various peptides,such as the endorphins, dynorphins, enkephalins, andsubstance P (Samovilova et al. 1988; DeHaven-Hudkinsand Fleissner 1992).

Neuropeptide Y (NPY) deserves particular attention. Ithas been repeatedly suggested that NPY is an endogenousligand for certain sigma receptors. Roman et al. (1989a)showed that two peptides, NPY and YY, which had highaffinity for sigma receptor, both were able to displace the[3H](+)-SFK 10,047 binding. They found that IC50 valuesof these two peptides were approximately 10 nM, althoughthese results could not be repeated later by another group(Tam and Mitchell 1991).

However, in vivo experiments showed that NPY andsigma ligands can modulate NMDA-induced neuronalactivity in the hippocampus (Monnet et al. 1992c,d; Aultand Werling 1997) and NMDA-stimulated [3H]dopaminerelease from rat cortical and striatal slices (Ault andWerling 1998; Hong and Werling 2001). In a more recentstudy, autoradiography was used to show that the presenceof micromolar concentrations of sigma-1 receptor agonistsor antagonists did not alter [35S]GTPγS binding inducedby nanomolar concentrations of NPY in the rat brain.Thus, it appears that NPY does not act as an endogenousligand of sigma-1 receptors.

Steroids have also been considered as putative ligandsof sigma-1 receptors, and the interaction between steroidsand the sigma-1 receptor was first suggested from in vitrobinding experiments in guinea-pig brain and spleen. Suand collaborators (1988) showed an inhibition of [3H](+)-SKF 10,047 binding in the guinea-pig brain and of [3H]-haloperidol in the spleen by progesterone with Ki values inthe nanomolar range. Other steroids, such as testosterone,pregnenolone sulfate, or deoxycorticosterone, exhibit Kivalues in the micromolar range (McCann and Su 1991;Maurice et al. 1996). Confirming these studies, othergroups have shown that progesterone was indeed theneurosteroid which most potently inhibited the binding of

Table 1 Activity of somesigma-1 receptor ligand com-pounds

Compound Sigma-1 activity Sigma-1 affinity (IC50) References

DTG Agonist 45 de Costa and He (1994)(+)-3-PPP Agonist 48 de Costa and He (1994)(+)-SKF-10,047 Agonist 97 de Costa and He (1994)(+)-Pentazocine Agonist 5.8 Chaki et al. (1994)Haloperidol Antagonist 2.3 Chaki et al. (1994)Igmesine Agonist 39 Roman et al. (1990)Sertraline Agonist 6.8 Schmidt et al. (1989)BD-737 Agonist 2 (Ki) Bowen et al. (1992)BD-1047 Antagonist 36 Matsumoto et al. (1995)Rimcazole Antagonist 520 Schmidt et al. (1989)BMY-14,802 Antagonist 66 Koe et al. (1989)DuP734 Antagonist 10 (Ki) Tam et al. (1992)E-5842 Antagonist 5 Guitart et al. (1998)MS-377 Antagonist 73 (Ki) Takahashi et al. (1999)NE-100 Antagonist 1.6 Chaki et al. (1994)OPC-14523 Agonist 47 Oshiro et al. (2000)Panamesine Antagonist 6 Grunder et al. (1999)PRE-084 Agonist 44 Su et al. (1991)SA4503 Agonist 17 Matsuno et al. (1996a,b)SR31742A Antagonist 5.3 Poncelet et al. (1993)

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several sigma-1 ligands in different preparations, such asthe rat brain, splenocytes plasma membrane, and livermicrosomes (Ross 1991; Klein and Musacchio 1994;Yamada et al. 1994). However, many sigma-1 ligands(haloperidol, carbapentane, DTG, (+)-3-PPP, and rimca-zole) inhibit the [3H]-progesterone binding in rat liverpreparations or porcine liver solubilized fractions (Yamadaet al. 1994; Meyer et al. 1998).

Exogenous administration of neurosteroids leads to adose-dependent inhibition of [3H](+)-SKF 10,047 tosigma-1 receptors (Maurice et al. 1996). In theseexperiments, progesterone was shown to be the mostpotent inhibitor relative to pregnenolone sulphate andDHEA sulphate, although the inhibition of these last twocompounds seems to be unrelated to their in vitro affinity.Modulation of the endogenous steroid levels (adrenalec-tomy—castration) has been shown to enhance the in vivo[3H](+)-SKF 10,047 binding, while the use of pharmaco-logical agents, which augment progesterone concentration,induces a decrease of the in vivo [3H](+)-SKF 10,047binding (Phan et al. 1999). Thus, it seems clear thatneuroactive steroids may clearly interact with the sigma-1receptor being the Ki value of progesterone for the sigmareceptor compatible with an in vivo interaction (forcomprehensive and complete reviews of this area, seeMaurice et al. 1999, 2001).

The interaction of neurosteroids with the sigma receptormost likely occurs through a similar mechanism by whichneurosteroids interact with the NMDA receptor (Bowlby1993; Gore 2001; Lambert et al. 2001) or the γ-aminobutyric acid type-A (GABAA) receptor (Gundlachet al. 1986).

Sigma receptors and signal transduction

Many neurotransmitter receptors are coupled to effectorsystems through various G-proteins, and these G-proteinsplay a critical role in mediating signal transductionmechanisms. Classical examples of regulation of secondmessenger systems by the interaction of a receptor with itseffector include the G-protein coupling of cell surfacereceptors to adenylyl cyclase or phospholipase C (PLC).However, several neurotransmitter receptors are known toregulate some ion channel functions in the absence ofdirect interactions with G-proteins.

The downstream signal transduction pathways regulatedby sigma receptors have not yet been elucidated. Thus, itremains controversial whether or not sigma receptors areassociated with G-proteins. A number of studies haveinvestigated the role of G-proteins in sigma receptorfunction, as outlined below. Early radioligand bindingstudies showed that the binding parameters of severalsigma ligands, such as (+)-SKF 10,047 and (+)-3-PPP,were altered by guanosine triphosphate (GTP) and itsstable analogs such as Gpp(NH)p (Beart et al. 1989;Ytzhak 1989; Connick et al. 1992), suggesting that thesigma receptor was coupled to a G-protein signalingmechanism. More recently, it has been reported that some

sigma receptor ligands stimulate G-protein activity insynaptic membranes from mouse prefrontal cortex (To-kuyama et al. 1997, 1999) and that the binding of [35S]GTPγS in guinea-pig spleen is stimulated by (+)-penta-zocine (Maruo et al. 2000). In addition, several studieshave shown that the binding affinity of [3H](+)-3-PPP forthe sigma receptor was clearly diminished after mem-branes were treated with pertussis toxin or cholera toxin(Ytzhak 1989; Basile et al. 1992). Moreover, some cellulareffects of sigma-1 ligands may be inhibited by pretreat-ment with cholera toxin or pertussis toxin (Monnet et al.1994; Soriani et al. 1999). These findings suggested thatG-proteins are involved in, at least, some of the effects ofsigma-1 receptors.

Despite the considerable evidence suggesting that sigmasites are coupled to G-proteins, other findings imply thatthere is no such coupling, or that it is of a peculiar andcharacteristic nature. For example, the binding parametersof sigma-1 agonists were not altered in response to GTPγStreatment in membrane preparations from rat and guinea-pig cerebellum, as determined with two different radioli-gands for the sigma-1 receptor ([3H]haloperidol and [3H](+)-pentazocine) (Hong and Werling 2000). This is similarto previous findings that used guanine nucleotides andguinea-pig membrane preparations (DeHaven-Hudkins etal. 1992). In order to avoid a possible disruption of thechain effector-receptor-G-protein that could occur in abiochemical approach, autoradiographic studies were usedto show that [35S]GTPγS binding is not stimulated by thepresence of sigma-1 agonists (Hong and Werling 2000).Altogether, these data clearly suggest that a consensus onthis point is still far from being reached.

In electrophysiological studies, the effect of (+)-penta-zocine on N-methyl-D-aspartate (NMDA) responses inhippocampal neurons was not affected by pertussis toxin,whereas cholera toxin altered the effect of (+)-pentazocineeffect on potassium A-current in frog pituitary melano-trope cells (Monnet et al. 1994; Soriani et al. 1999). Incontrast, (+)-pentazocine (as high as 10 μM) has beenreported to have no effect on either basal or forskolin-stimulated adenylyl cyclase in human neuroblastoma BE(2)-C cells (Ryan-Moro et al. 1996). E-5842, a highlyselective sigma-1 receptor ligand and putative atypicalantipsychotic (Guitart and Farré 1998; Guitart et al. 1998),was shown to decrease forskolin-stimulated adenylylcyclase activity (Monroy et al. 2001). Furthermore,when rats were chronically treated with E-5842, increasesin adenylyl cyclase type-I immunoreactivity were ob-served in the brain, whereas acute treatment with E-5842had no effect on adenylyl cyclase activity (Monroy et al.2001).

Phosphoinositide turnover and inositol phosphates havealso been studied in relation to their possible regulation bysigma receptor ligands. Bowen and co-workers and otherlaboratories have shown that sigma ligands may modulatethe function of some receptors coupled to stimulation ofphosphoinositide turnover (Bowen et al. 1988, 1992;Bowen 1994; Novakova et al. 1998). In rat cardiacmyocytes, sigma ligands have been shown to affect cell

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contraction and calcium movement (Ela et al. 1996). Inthis way, a sigma-1 agonist such as BD737 causes a rapidincrease in inositol triphosphate (IP3) production, whereasBD1047, a putative sigma-1 antagonist, causes a moresustained increase in IP3 levels (Novakova et al. 1998).This effect has been explained by suggesting that BD1047may not act as a true antagonist in cardiac myocytes. Inprimary cultures of rat cortical neurons, sigma ligands(either agonists or antagonists) attenuate NMDA-inducedincreases in calcium (Hayashi et al. 1995; Klette et al.1997). However, in neuron-like cultured cell lines and inbrain synaptosomes, sigma-1 receptor ligands (includingpurported agonists and antagonists) failed to increase IP3levels (Cutts et al. 1993).

It has recently been shown that the sigma-2 receptorregulates Ca2+ release from endoplasmic reticulum stores,and that this effect was reversed by sigma receptorantagonists (Bowen et al 1996; Vilner and Bowen 2000).This study also showed that two different types ofincreases in Ca2+ occur in response to sigma-2 ligands;one is immediate, transient, and is likely derived from theendoplasmic reticulum, whereas the other is sustained andhas been suggested to be derived from mitochondrialstores (Vilner and Bowen 2000). It has also been proposedthat the activation of sigma-2 receptors initiates a Ca2+-dependent process in PC12 cells, which may regulateamphetamine-stimulated dopamine release via Ca2+/cal-modulin kinase II (Weatherspoon and Werling 1999). Incontrast to sigma-1 receptors, it has been proposed thatsigma-2 receptors are lipid raft proteins that would affectcalcium signaling through sphingolipid products (Gebre-selassie and Bowen 2002; Crawford et al. 2002).

Based on the findings outlined above, it has beenhypothesized that different cell types respond to sigma-1receptor activation in different ways (Novakova et al.1995, 1998). More recently, activation of sigma-1receptors by (+)-pentazocine has been shown to decreasePLC-mediated hypoglossal activity in isolated guinea-pigbrainstem preparations and to induce the translocation ofprotein kinase C to the plasma membrane via a novelmechanism of action of intracellular receptors (Morin-Surun et al. 1999). In a recent study, the changes in PLCactivity in different brain regions (including the striatumand the frontal cortex) have been described in response toeither single or repeated doses of the sigma-1 ligand E-5842 (Romero et al. 2000). In addition to changes in PLCactivity, levels of PLCβ and the associated G-proteinGq/11α were also upregulated in the frontal cortex of ratschronically treated with E-5842. Sigma receptors havealso been repeatedly linked to the modulation of proteinkinases, especially protein kinase C (Morin-Surun et al.1999; Derbez et al. 2002; Nuwayhid and Werling 2003)

Taken together, the data clearly suggest that classicalsecond messenger systems play a role in the action ofsigma ligands, although this probably occurs via amechanism different from the classical and well-describedones. Are there different types of sigma-1 receptors indifferent cell types? Is the sigma-1 binding proteinrecently cloned merely a component of multi-subunit

receptors? Is the sigma receptor only an auxiliary subunitof concrete ion channels? Further studies are required toanswer these and other important questions.

Sigma receptors as modulators

Cooperation between sigma-1 receptors and ion channelsmust be considered when characterizing the signal trans-duction pathways and cellular mechanisms by which thesereceptors function. Sigma receptors have been shown tomodulate various ion channels in several cell types (Morioet al. 1994; Soriani et al. 1999; Wilke et al. 1999a;Lupardus et al. 2000; Aydar et al. 2002; Karasawa et al.2002; Zhang and Cuevas 2002). Sigma receptors inhibitvoltage-gated potassium channels (Wilke et al. 1999b),and pentazocine and SKF 10,047 can modulate potassiumchannels in peptidergic nerve terminals despite intraterm-inal perfusion with GTPγS or GDPβS, suggesting that G-proteins do not play a role in these responses (Lupardus etal. 2000). Based on experiments performed in cell-attached patches, it has been reported that the sigmareceptor and ion channels must be in close vicinity tocooperate (Lupardus et al. 2000), which would argueagainst the existence of a classical mechanism by whichchannels are modulated through G-proteins and proteinphosphorylation (Wickman and Clapham 1995; Jonas andKaczmarek 1996). A recent report (Aydar et al. 2002) hasshown that sigma receptors associate with the voltage-gated potassium channel Kv1.4, which suggests thatprotein–protein interactions may play a role in sigmareceptor signal transduction.

In recent years, Su’s laboratory has presented elegantresults showing the molecular mechanism that governs theregulation of intracellular calcium signaling at the endo-plasmic reticulum through the participation of sigma-1receptors. It has been suggested that ternary complexesoccur as a result of interactions between the sigma receptorand various other proteins, including IP3 receptors andankyrin (Hayashi and Su 2001). According to this model,under the stimulation of the sigma-1 receptors by receptoragonists [cocaine or (+)-pentazocine or neurosteroids], thesigma-1 receptor/ankyrin complex would dissociate fromthe IP3 receptors and would be translocated to the plasmaor nuclear membranes. In the presence of a sigma-1receptor antagonist, this effect would be avoided andsigma-1 receptors would dissociate from ankyrin and IP3receptors which would stay on the endoplasmic reticulum.Following with this model, and based on the studiesperformed in NG-108 cells (Hayashi et al. 2000; Hayashiand Su 2001), in resting conditions, the dissociation of thesigma-1 receptor/ankyrin complex elicited by sigma-1agonists produces no detectable influence on calciumefflux from the endoplasmic reticulum and the cells needto be stimulated in the sense that appropriate levels of IP3are necessary. Under these conditions the dissociation ofthe sigma-1 receptor/ankyrin complex from IP3 receptorswould facilitate and indirectly promote the calcium effluxfrom these receptors (see a recent paper of Su and Hayashi

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2003 for a comprehensive review). Although this is a veryinteresting hypothesis, it still has to explain how theagonists and the antagonists of the sigma-1 receptors reachthe intracellular sites where the sigma-1 receptors/ankyrin/IP3 receptors are. This model implies that sigma-1 ligands,such as cocaine, (+)-pentazocine, or NE-100, are able toeasily cross the plasma membrane to reach the intracellularstores of sigma-1 receptors, but does not explain how.

Other experimental evidences also suggest that sigmareceptors play a role in modulating intracellular calciumlevels. In this sense, it was shown that calcium channelmodulators have differential effects on the binding of [3H]-DTG to sigma receptor sites (Rothman et al. 1991).Another study showed that sigma ligands can regulateintracellular calcium levels via modulation of the nicotinicacetylcholine receptor in chromaffin cells (Paul et al.1993). Catecholamine release induced by nicotine receptorstimulation was inhibited by (+)-pentazocine, haloperidol,and (−)-SKF 10,047.

Regulation of high-voltage-activated calcium channelsby sigma receptors has also been described in culturedhippocampal pyramidal neuron preparations, where in-creases in intracellular free calcium were blocked by sigmaligands (Church and Fletcher 1995). A similar result wasobserved in neuroprotection experiments using sigmaligands in rat primary cortical neurons, where sigma-mediated neuroprotection was shown to be mediatedthrough the modulation of intracellular calcium levels andvoltage-gated calcium channels (Klette et al. 1995). It hasbeen recently shown that sigma receptor agonists rapidlydepress peak calcium-channel currents, using the perfo-rated-patch configuration of the whole cell patch-clamprecording technique in neurons from the superior cervicalganglia (Zhang and Cuevas 2002).

It has also been suggested that sigma receptors canregulate glutamatergic transmission by functionally mod-ulating the NMDA receptor complex (Monnet et al. 1990,1992b; Ohno and Watanabe 1995; Bouchard et al. 1997;Maurice and Lockhart 1997; Gronier and Debonnel 1999).Iontophoretic or intravenous administration of DTG, asigma ligand, potentiates NMDA-induced firing of CA3pyramidal neurons (Monnet et al. 1992b). A similarpotentiation has been described using other sigma ligands(Debonnel and deMontigny 1996; Bergeron and Debonnel1997), generally considered to be agonists of the receptor.The effect was not observed in response to sigma-1antagonists, such as haloperidol, NE-100, or BMY 14802.Interestingly, most sigma agonists produce bell-shapeddose–response curves on the NMDA-induced effect(Couture and Debonnel 1998), and this has been suggestedto be due to the recruitment of different subtypes of sigmareceptors at higher doses (Bergeron and Debonnel 1997).Administration of the new selective sigma-2 ligand Lu 28-179 (Moltzen et al. 1995) dose dependently potentiated theNMDA response in the CA3 region of rat hippocampus,whereas ibogaine, a sigma-2 ligand with moderate affinityfor the receptor (Bowen et al. 1995b), slightly increasedthe NMDA response (Couture and Debonnel 1998). Toexplain such differences, it has been proposed that several

sigma-2 receptor subtypes may exist (Couture andDebonnel 1998). However, it is important to note thatthese effects are not exclusive to sigma-1 ligands or mixedsigma-1/sigma-2 ligands. Taken together, these electro-physiological studies suggest that one function of sigmareceptors is modulation of NMDA responses.

Anatomical distribution of sigma receptors

Early studies on the subcellular distribution of sigmareceptors indicated that [3H] (+)-SKF 10,047 binding siteswere enriched in the microsomal fraction of rat brain(McCann and Su 1990) and in non-synaptic areas of theplasma membrane (Roman et al. 1989b). Subcellularlocalization studies have shown that the sigma-1 receptoris primarily associated with neuronal perikarya anddendrites, and localized to the plasma membrane, themitochondrial membrane, and the endoplasmic reticulum(McLean and Weber 1988). Given this unusual distribu-tion, it has been proposed that, on activation, the sigma-1receptor is translocated from the endoplasmic reticulum tothe plasma membrane or to the nuclear membrane (Morin-Surun et al. 1999; Hayashi and Su 2001).

Different studies showed the particular distribution ofsigma-2 receptors inside the cell. These receptors havebeen proposed to be intracellular receptors (Bowen 2000)located in the membranes of the endoplasmic reticulumand mitochondria, and may, therefore, release calciumfrom these intracellular stores.

The anatomical distribution of sigma-1 receptors in thecentral nervous system has been well characterized. Sigmareceptors were first visualized using different radioligands,such as [3H] (+)-3-PPP, [3H]-SKF 10,047, [3H]-DTG, or[3H]NE-100 (Samovilova et al. 1988; Largent et al. 1986;Jansen et al. 1991; Okuyama et al. 1995a), and bindingsites were reported to be concentrated in limbic structures(including different areas of the hippocampus as thepyramidal and non-pyramidal layers, and the granularlayer of the gyrus dentatus), areas of the forebrainincluding the septum, the paraventricular nucleus of thehypothalamus, the anterodorsal thalamic nucleus, and indiscrete regions of the midbrain and hindbrain such as thedorsal raphe, the substantia nigra and the locus coeruleus,and in the cerebellum.

Recently, in situ hybridization and immunohistochem-ical techniques have been used to study sigma receptorlocalization (McLean and Weber 1988; Alonso et al. 2000;Zamanillo et al. 2000). Sigma receptors were found to bewidely distributed, although they seem to be concentratedin brain areas involved in motor functions, in limbic areas,sensory areas, and areas associated with endocrinefunctions (McCann et al. 1994).

A more detailed study was able to discriminate betweenthe two subtypes of sigma receptors and showed thatsigma-1 and sigma-2 receptors are differentially distrib-uted in the brain (Bouchard and Quirion 1997). By meansof autoradiographic studies using [3H]-DTG (with thepresence of (+)-pentazocine), Bouchard and Quirion

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(1997) showed the sigma-2 distribution in the rat brain.Only a few areas in the brain are particularly enriched withsigma-2 sites, these areas being implicated in the controlof posture and movement (Walker et al. 1990, 1994).

Using immunohistochemistry with a specific antibodyagainst the sigma-1 receptor, the distribution of thisreceptor in the adult rat central nervous system has beendescribed (Alonso et al. 2000). High levels of sigma-1immunostaining were associated with neurons in specificbrain regions, including the olfactory bulb, several hypo-thalamic nuclei, the septum, the central gray, certain motornuclei of the hindbrain, and the dorsal horn of the spinalcord. Intensely immunostained cells were observed in thehippocampus (especially in the dentate gyrus). Interest-ingly, in the dorso-lateral striatum only a small number ofweakly stained cells could be observed, whereas moder-ately immunostained cells were observed in the nucleusaccumbens.

Figure 3 shows the regional distribution of the sigma-1receptor as determined by means of Western blot using adifferent antibody (Zamanillo et al. 2002) than that used inthe immunohistochemical studies. The distribution of thesigma-1 receptor protein is compared with its mRNAdistribution.

In addition to the central nervous system, the sigma-1receptor is also widely distributed in peripheral organs. Inthe digestive tract (Samovilova and Vinogradov 1992),binding assays and autoradiographic studies showed thatsigma-1 receptors are enriched in the mucosal andsubmucosal regions, with less labeling in the muscularregions. Sigma-1 receptors are also present in the liver(Dumont and Lemaire 1991; Hellewell et al. 1994;Maurice et al. 1996), kidney (Hellewell et al. 1994),heart (Jansen et al. 1992; Ela et al. 1994), and sexualorgans (Jansen et al. 1992). In a similar way to the sigma-1receptor, sigma-2 receptor has also been found in differentorgans, including liver and kidney in high densities(Hellewell et al. 1994).

Potential therapeutic applications of sigma receptor ligands

Although further experiments are clearly needed todelineate the precise mechanisms of action and theendogenous ligand(s) of sigma receptors, a large numberof pharmacological, biochemical, and even therapeuticfunctions have been proposed for these receptors (Su andJunien 1994). Given the widespread distribution of sigmareceptors in the central nervous system, sigma ligands maybe useful in the treatment of different central disorders.These may eventually include modulation of mooddisorders, amnesic and cognitive deficits, the effectsproduced by drugs of abuse, tardive dyskinesia, potenti-ation of analgesia, and others. Moreover, in view of theirdistribution in peripheral organs, sigma receptors couldalso be implicated in gastrointestinal movements underconditions of stress, duodenal bicarbonate secretion,contraction of vas deferens, regulation of plasma levelsof corticosterone, prolactin, adrenocorticotropin, contrac-tility of cardiac cells, and many others.

While this article was being prepared, our laboratory,together with another group, produced a sigma-1 receptorknockout mouse (Langa et al. 2003). The study of theseanimals should help to clarify the role of sigma-1 receptorsin different physiological and pathophysiological pro-cesses where these receptors have been implicated.However, as these mice still express the sigma-2 receptor,they may also help to dissociate the involvement of sigma-1 and sigma-2 receptors in the manifestation of differentpathologies. The generation of these animals shouldundoubtedly start a new era of research in the field ofsigma receptors; but, although some phenotypical aspectshave already been disclosed (Langa et al. 2003), others arestill being studied (unpublished results from our labora-tory), and possible compensatory mechanisms to the lackof the sigma-1 receptor should not be discarded.

Sigma ligands and schizophrenia and movementdisorders

The first suggestion that sigma receptors might beinvolved in the pathophysiology of schizophrenia arosefrom the finding that synthetic ligands such as (+)-SKF10,047 exhibited psychotomimetic effects and from thefact that many neuroleptics exhibit high affinity for sigmareceptors. These findings led to speculation that sigmareceptors could play a role in the antipsychotic actions ofthese drugs (Gillgan and Tam 1994).

In addition to the role played by the central dopami-nergic system in schizophrenia, it is also important toconsider the glutamate system and the intricate relation-ship between dopamine, glutamate, and sigma receptors inthis disease. The role of NMDA in the pathogenesis ofschizophrenia has generated considerable interest becausePCP, an NMDA receptor channel-blocking agent, caninduce a schizophrenia-like psychosis in humans. Severalpost-mortem studies have shown abnormalities in gluta-mate concentrations and glutamate receptor densities in

Fig. 3 Regional distribution of the sigma-1 receptor in the rat brain.a Typical Western-blot image using an antibody specific for thesigma-1 receptor. Note the different relative distribution of thesigma-1 receptor protein. b Graph showing the distribution ofsigma-1 receptor mRNA in several brain areas as studied usingNorthern blot. FC frontal cortex, ST dorso-lateral striatum, CBcerebellum, PC parietal cortex, NA nucleus accumbens, HPhippocampus, LC locus coeruleus, DR dorsal raphe, VT ventraltegmental area, SN substantia nigra

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schizophrenic brains, and some biochemical and beha-vioral studies have suggested that antipsychotic drugs mayalter NMDA receptor functions.

However, there is no correlation between the affinity ofneuroleptic drugs for sigma receptors and their therapeuticefficacy. Thus, it has been suggested that sigma receptorsmay instead mediate the undesirable motor side effects ofantipsychotic drugs (Walker et al. 1990; Walker et al.1994). Moreover, the relationship between the ability ofneuroleptics to interact with sigma-1 and sigma-2receptors and their tendency to induce dystonic reactionsin humans has recently been studied (Matsumoto andPouw 2000). It has been suggested that the motor sideeffects induced by neuroleptics could be mediated throughboth sigma-1 and sigma-2 receptors.

Sigma receptors have been detected in cortical andlimbic structures in human post-mortem brain (Weissmanet al. 1998), and a selective loss of sigma sites inschizophrenia has been reported (Weissman et al. 1991).However, studies on polymorphisms of the sigma-1receptor gene and schizophrenia have yielded contra-dictory results (Ishiguro et al. 1998; Ohmori et al. 2000;Uchida et al. 2003). No selective sigma ligand has yetbeen marketed as an antipsychotic drug, but manydescriptions of novel putative antipsychotic compoundswith high affinity for the sigma receptor have beenreported (Chaki et al. 1994; Bartoszky et al. 1996;Takahashi et al. 1999).

Among these, [α-(4-fluorophenyl)-4-(5-fluoro-2-pyri-midinyl)-1-piperazine-butanol hydrochloride] (BMY14802) is a compound with high affinity for sigma,serotonin-1A, and serotonin-2 receptors, and a weakaffinity for dopamine and other neurotransmitter receptors(Taylor and Dekleva 1987). BMY 14802 was firstidentified as an antipsychotic candidate based on classicalneuropharmacological tests. BMY 14802 inhibits apomor-phine-induced climbing in mice (Taylor et al. 1993) andinhibits apomorphine-induced stereotypy in rats with lesspotency than that of haloperidol—a prototypical com-pound—but similar potency to that of clozapine. BMY14802 is also able to block sensitization to methamphet-amine (Ujike et al. 1992), and the development ofsensitization to cocaine (Ujike et al. 1996), which is apharmacological model of schizophrenia.

BMY 14802 exhibited a favorable pre-clinical profilesuggesting that it held promise as a drug that couldmediate antipsychotic effects in humans without produ-cing the untoward extrapyramidal side effects associatedwith standard neuroleptics. However, results of clinicaltrials showed no significant improvement in psychiatricsymptoms in response to BMY 14802 treatment (Gewirtzet al. 1994).

4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-tria-zol-1-il)butyl] pyridine citrate (E-5842) is a compoundwith remarkable affinity for the sigma-1 receptor, and withlow-to-moderate affinity for other central nervous systemreceptors, including several dopamine, serotonin, andglutamate receptors (Guitart et al. 1998). E-5842 hasbeen widely tested as an antipsychotic at the pre-clinical

level. E-5842 inhibits apomorphine-induced climbing inmice and inhibits the conditioned avoidance response inrats with ED50 values different from those of dopamine D2

antagonists such as haloperidol (also a sigma receptorligand) and risperidone (Guitart et al. 1998). E-5842 alsodose dependently inhibits amphetamine-induced locomo-tor activity in rats, with no apparent induction of catalepsy.Acute administration of E-5842 also increases the expres-sion of Fos protein in selected regions of the rat forebrain(Guitart and Farré 1998), similar to what has been shownwith panamesine (EMD 57455), a selective sigma receptorligand that has been tested as a putative antipsychotic inclinical trials. In the case of E-5842, Fos levels wereincreased in the prefrontal cortex and the nucleusaccumbens, with little effect in the dorso-lateral striatum,clearly suggesting the possibility that this sigma com-pound may exert antipsychotic activity.

Sigma receptors may also interact with or modulate thefunction of glutamatergic receptors. Repeated administra-tion of E-5842 alters immunoreactivity levels of varioussubunits of the ionotropic glutamate receptors (Guitart etal. 2000), an effect that had been previously described forother antipsychotic drugs (Fitzgerald et al. 1995; Tasceddaet al. 1999), but not for any known sigma-1 receptorligands.

N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phe-nyl]-ethylamine monohydrochloride (NE-100) is anotherputative antipsychotic compound with high affinity for thesigma-1 receptor, and lower affinity for the sigma-2,dopamine, serotonin, and PCP receptors (Okuyama et al.1993; Chaki et al. 1994). NE-100 antagonizes thebehavioral effects of PCP and does not induce catalepsyin rats (Okuyama et al. 1993, 1994, 1995b). NE-100 andother sigma-1 antagonists have also been shown toregulate dopamine release through the NMDA receptor(Chaki et al. 1998) or to modulate NMDA-inducedcurrents in dopaminergic neurons. Together with the datafrom studies of E-5842 (Guitart et al. 1998), experimentalevidence clearly suggests that sigma compounds canmodulate both dopaminergic and glutamatergic neuro-transmission.

Remoxipride has considerable binding affinity for thesigma receptor and has been shown to exhibit atypicalantipsychotic activity in humans. However, subchronicadministration of remoxipride did not affect either thedensity or the affinity of sigma-1 receptors in the rat brain(Ericson and Ross 1992), as determined by [3H] (+)-3-PPPradioligand binding. This fact is quite remarkable, giventhat haloperidol, which is also a sigma-1 receptor antag-onist, has been reported to decrease sigma-1 bindingwithout affecting sigma-1 mRNA levels in rat and guinea-pig brain (Inoue et al. 2000). Furthermore, repeatedadministration of E-5842 has been shown to increasesigma-1 receptor mRNA levels in several brain areas(Zamanillo et al. 2000).

Over the last decade, other compounds with highaffinity for the sigma receptor have been evaluated forpossible use in the treatment of schizophrenia. NPC16377, MS-377, SR-31742A, and some other compounds

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mentioned above have been described as potent andselective sigma ligands with antipsychotic potential. Someof these, like remoxipride, BMY 14802, or SR-31742A,have been discontinued, whereas panamesine and SL82.0715 exhibited favorable efficacy in open clinicalstudies (Frieboes et al. 1997).

Along with the putative beneficial effects of certainsigma ligands as antipsychotic drugs, it has beenhypothesized that sigma ligands could also contribute tothe various undesirable motor side effects observed afterlong-term treatment with antipsychotic drugs. There isanatomical evidence supporting a role for sigma receptorsin the motor side effects of certain neuroleptics (Walkerand Martin 1994). Brainstem nuclei that control musclesthat mediate the motor side effects of neuroleptics areenriched in sigma receptors (Bouchard and Quirion 1997),and as mentioned previously, substantial levels of sigmareceptors are found in the basal ganglia (Gundlach et al.1986). Furthermore, brain regions such as the cerebellumand the red nucleus, which are clearly related to dystonicreactions, are also enriched in sigma receptors (McLeanand Weber 1988; Bouchard and Quirion 1997). In earlystudies, it was shown that selective sigma receptoragonists may elicit dystonic reactions when directlyinjected into the red nucleus (Matsumoto et al. 1990),whereas injection of non-sigma ligands failed to inducesuch reactions (Matsumoto et al. 1990, 1995). The abilityof some sigma receptor antagonists to attenuate orofacialdyskinesias and dystonic reactions in animals suggests thatthese drugs may hold promise as potential therapeuticapproaches to prevent such undesired movements (Matsu-moto et al. 1995; Tran et al. 1998). The sigma-2 receptorseems to play the most important role in controlling motorfunction (Walker et al. 1993). Conversely, the sigma-1receptor was thought to be less important (McCraken et al.1999). Nevertheless, a subsequent study comparing neu-roleptic binding to the sigma-1 and sigma-2 receptors andthe induction of dystonic reactions (Matsumoto and Pouw2000) suggested that sigma-1 receptors also play a role inmotor functions. Other studies seem to confirm theimportance of both receptors in the regulation of dystonicreactions (Okumura et al. 1996; Ghelardini et al. 2000;Yoshida et al. 2000).

Sigma ligands and drugs of abuse

Drug addiction is among the most serious problems facingsociety today, and it is clear that the psychological aspectsof addiction are mediated via neurobiological mechanismsin the brain (Nestler 2001). Unfortunately, there arecurrently no effective pharmacological treatments for theabuse of cocaine, D-amphetamine, and other abused drugs.

As it has been described below, the central dopaminer-gic neurotransmission systems that are likely involved inthe pathophysiology of schizophrenia may be modulatedby sigma receptors. Central dopaminergic systems alsorepresent, at least in part, the neuroanatomical substrate ofdrug addiction. Sigma-1 receptors have been hypothesized

to be involved in the effects of cocaine, given the affinityof cocaine for the receptor (Sharkey et al. 1988; Ritz andGeorge 1993; Matsumoto et al. 2001; Su and Hayashi2001; Maurice et al. 2002). Selective sigma-1 receptorantagonists such as BMY 14802, BD1047, and BD1063(Menkel et al. 1991; McCraken et al. 1999) decrease thelocomotor effects of cocaine, which has also beenobserved when mice are treated with antisense oligodeox-ynucleotides corresponding to the sequence of sigma-1receptors (Matsumoto et al. 2001, 2002). In another set ofexperiments, it has been shown that sigma-1 antagonistsmay attenuate the behavioral sensitization induced bycocaine (Ujike et al. 1996). It has also been shown thatintraperitoneal administration of sigma-1 antagonists, suchas NE-100 and BD1047, significantly attenuated orblocked the cocaine-induced conditioned place preference,a paradigm used to evaluate the rewarding properties ofthis drug and other drugs of abuse (Romieu et al. 2000).Changes in gene expression induced by cocaine have alsobeen reported in the brains of mice. The upregulation bycocaine of three genes identified as the fos-related antigen-2, the G-protein coupled receptor 27 and the ataxiatelangiectasia murine homolog was prevented by the useof the sigma-1 antagonist BD1063, suggesting that someprotective actions of the sigma receptor antagonistsinvolve transcriptional mechanisms (Matsumoto et al.2003).

When taken together, these data support the idea thatactivation of sigma-1 receptors by cocaine can beimportant for both the short-term and long-term effectsof the drug. The data also suggest that sigma-1 receptorsrepresent a useful target for the development of futuretherapeutic strategies (see Maurice et al. 2002; Matsumotoet al. 2003 for comprehensive reviews). However, a directrole of sigma-1 receptors in other aspects of cocaineaddiction has not been established.

A role for sigma-1 receptors in the actions of otherpsychostimulant drugs has also been proposed. Repeatedadministration of methamphetamine increased [3H] (+)-pentazocine binding in rat brain (Itzhak 1993). Sigmaligands also block the development of behavioral sensi-tization induced by repeated administration of metham-phetamine (Ujike et al. 1992; Takahashi et al. 2000). Othersigma-1 receptor antagonists, such as NPC 16377 and E-5842, have also been reported to partially block D-amphetamine-stimulated locomotor activity (Clissold et al.1993; Guitart et al. 1998).

The role of sigma-2 receptors in the effects of drugs ofabuse is less clear, and the investigation of their roleopposing the actions of cocaine is complicated by the lackof an amino acid sequence of the receptor that can be usedto construct useful antisense oligodeoxynucleotides. How-ever, the sigma-2 receptor system has been shown tomodulate amphetamine-stimulated dopamine release invitro (Izenwasser et al. 1998; Weatherspoon and Werling1999). More recently, it has been shown that SM-21, anovel sigma-2 antagonist (Ghelardini et al. 2000), canattenuate the locomotor-stimulating effects in cocaine inmice (Matsumoto and Mack 2001), although the mecha-

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nism of action of SM-21 has yet not been fullycharacterized

Memory and attention deficits

It has been proposed that sigma agonists have beneficialeffects in several models of amnesia. Some sigma-1ligands have been shown to prevent or reverse scopol-amine-induced amnesia in rats and mice (Earley et al.1991; Matsuno et al. 1994). Receptor agonists increaseacetylcholine release in both the hippocampus and thefrontal cortex (Matsuno et al. 1993, 1995) and maypotentiate several NMDA-evoked responses in selectedregions of the hippocampus (Hong and Werling 2000).SA4503 is a highly selective sigma-1 receptor agonist thathas been shown to reverse scopolamine-induced amnesiaand to attenuate learning impairments in animals withcortical cholinergic dysfunctions (Matsuno et al. 1997;Senda et al. 1998a). However, SA4503 protects retinalcells against glutamate-induced neurotoxicity (Senda et al.1998b). SA4503 has also been shown to attenuate deficitsin spatial working and reference memory induced bydizocilpine in the delay-interposed radial maze task (Zouet al. 2000). In a similar way, PRE-084, a selective sigma-1 receptor agonist, reduces MK-801-induced learningimpairments in mice (Maurice et al. 1994).

Neuroactive steroids may also play a role in themodulation of memory by sigma receptors. Neuroactivesteroids may modulate GABAA receptor function andvarious NMDA-evoked responses, and can also interactwith sigma receptors (Maurice et al. 1999, 2001).Pregnenolone, dehydroepiandrosterone (DHEA), and pro-gesterone exhibit significant affinity for the sigma-1receptor. Pregnenolone, DHEA, and their sulfate estershave also been shown to enhance memory retentionproperties in learning-impaired mice (Flood et al. 1992;Maurice et al. 1997). In another set of experiments, it wasshown that sigma-1 agonists, such as PRE-084, SA4503,DHEA, pregnenolone, and their sulfate esters, attenuatedthe β25–35-amyloid peptide-induced learning impairmentin mice by interacting with sigma-1 receptors (Maurice etal. 1997, 1998). In these experiments, progesteronebehaved as an antagonist, blocking the effects ofneuroactive steroids, and some sigma-1 agonists.

Depression and anxiety

Recent studies have identified novel putative antidepres-sant compounds that have little, if any, effect on endog-enous biogenic amine levels. Sigma receptor agonists arebeing considered as such putative antidepressants (Matsu-no et al. 1996a; Ukai et al. 1998; Sanchez and Papp 2000).Selective sigma-1 receptor agonists such as (+)-pentazo-cine, (+)-SKF 10,047, or SA4503 decrease the duration ofimmobility in the forced swimming test and in the tailsuspension test (Matsuno et al. 1996b; Ukai et al. 1998;Urani et al. 2001), two experimental models widely used

to assess the antidepressant activity of new compounds.The sigma receptor agonist OPC-14523 (Oshiro et al.2000; Tottori et al. 2001) and the selective sigma-1receptor agonist igmesine (JO 1784) also show antide-pressant-like activity in pre-clinical animal models(Roman et al. 1990; Akunne et al. 2001). In a recentstudy (Urani et al. 2002), it has been shown that theantidepressant-like activity of igmesine requires modula-tion of intracellular calcium mobilization. In line withwhat was referred in the previous section, neurosteroidshave also been suggested to have a beneficial effect ondepressive states through a sigma-1 receptor-mediatedeffect (Maurice et al. 1996; see also Maurice et al. 2001;Van Broekhoven and Verkes 2003, for reviews).

The selective sigma-2 receptor ligand Lu 28-179(siramesine) exhibits antidepressant activity in the chronicmild stress model of depression (Sanchez and Papp 2000).In another study, the effects of Lu 28-179 were assessed invarious animal models of anxiety in rodents. Lu 28-179facilitated the exploratory behavior of mice and rats in theblack and white two-compartment box. Repeated treat-ment with Lu 28-179 significantly increased the durationof social interaction compared with controls, and noanxiogenic-like effects were observed on withdrawal.Furthermore, Lu 28-179 reversed shock-induced suppres-sion of drinking in rats (Sanchez et al. 1997). Lu 28-179 iscurrently under development in clinical trials as a potentialtreatment for anxiety (Heading 2001). It was recentlyreported that (+)-pentazocine and the antidepressantsimipramine and fluvoxamine, which have activity atsigma-1 receptors, may enhance the nerve growth factor-induced neurite sprouting in PC12 cells (Takebayashi et al.2002). This is of interest in that it has been proposed thatthe therapeutic actions of antidepressants may involveneurite sprouting.

Pain

A possible role for sigma receptors in antinociception wassuggested from studies that showed a relationship betweensigma systems and opioid analgesia (Chien and Pasternak1993, 1994). In this sense, an antiopioid sigma-1 systemhas been proposed to exist in mice and rats, where sigma-1receptor antagonists would potentiate opioid analgesia(Chien and Pasternak 1993, 1995). Using the tail-flickassay, it has been shown that sigma-1 antagonists, such ashaloperidol, have no effect on tail-flick latencies whengiven alone, but significantly increase the analgesicresponse to morphine. Haloperidol also increases tail-flick latencies in response to treatment with selectivekappa receptor agonists with low intrinsic analgesicactivity, whereas the sigma-1 agonist (+)-pentazocinediminishes this tail-flick latency.

In a series of elegant experiments, the specificity ofmodulation of opioid analgesia by sigma-1 receptors wasassessed using antisense oligodeoxynucleotides to down-regulate sigma-1 receptors (King et al. 1997; Mei andPasternak 2002). Mice that received antisense treatment

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showed a markedly enhanced response to both kappareceptor drugs and morphine, similar to the effects ofhaloperidol.

Conclusions and final remarks

Sigma receptors have been described for more than25 years and, in some ways, they remain controversial.Although considerable effort has been directed towardsdefining the intracellular pathways that mediate sigmareceptor signaling, and some second messenger system hasbeen associated with sigma receptors (calcium, IP3, PKC),the possible intracellular pathways have not been fullyworked out. Neither has any endogenous sigma receptorligand yet been discovered, despite considerable effort inthis area. However, the landscape is becoming clearer asmore information on the biology, pharmacology, andfunction of these receptors becomes available. An increas-ing body of evidence suggests that the sigma receptor maybe unique, in that it may modify synaptic transmissionthrough the regulation of other neurotransmitter receptors.Thus, sigma receptor ligands may modulate glutamate anddopamine release. Several years ago, when the hypothe-tical roles of sigma receptors were first being identified,the possible therapeutic implications of sigma ligandswere merely speculative. Today, it seems that sigmareceptors may be involved in many neuronal processes, aswell as in the pathophysiology of certain psychiatricdisorders, including depression, schizophrenia, motordisturbances, pain, drug addiction, attention deficitdisorders, and probably cancer (an issue that has notbeen addressed in this review). Identification of theputative endogenous ligand(s) for sigma receptors shouldgreatly help to clarify the picture. Despite this gap in ourknowledge, many significant advances have taken placeover the past several years in the field of sigma receptorresearch. The generation of knockout mice for the sigma-1receptor has recently been reported, and these animalsshould undoubtedly start a new era of research in the fieldof sigma receptors. Altogether, these advances mayeventually lead to the therapeutic use of sigma receptorligands for treatment and/or prevention of some of thesedevastating human psychiatric disorders.

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