The interaction between neuroactive steroids and the σ1 receptor function: behavioral consequences and therapeutic opportunities

Brain Research Reviews 37 (2001) 116–132 www.elsevier.com / locate / bres

Review

The interaction between neuroactive steroids and the s 1 receptor function: behavioral consequences and therapeutic opportunities q ˆ Tangui Maurice a , *, Alexandre Urani a,b , Van-Ly Phan a , Pascal Romieu a a

Behavioural Neuropharmacology Group, INSERM U. 336, Institut de Biologie, 4 Bvd Henri IV, 34060 Montpellier, France b Pfizer GRD, 3 /9 Rue de Loge, B.P. 100, 94265 Fresnes Cedex, France Accepted 31 July 2000

Abstract Steroids, synthesized in peripheral glands or centrally in the brain — the latter being named neurosteroids — exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABAA , NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the s 1 protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, s 1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the s 1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as s 1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective s 1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.  2001 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Behavioral pharmacology Keywords: Neuroactive steroid; Sigma 1 (s 1 ) receptor; Learning and memory; Depression; Aging; Aging-related cognitive deficits

Contents 1. Introduction ............................................................................................................................................................................................ 2. The s 1 receptor is a target for non-genomic effects of neuroactive steroids .................................................................................................. 2.1. The s 1 receptor............................................................................................................................................................................... 2.2. Distribution of the s 1 receptor ......................................................................................................................................................... 2.3. The s 1 receptor as an intracellular calcium mobilization modulatory protein ....................................................................................... 2.4. Non-genomic effects of neuroactive steroids ..................................................................................................................................... 2.5. The s 1 receptor / neuroactive steroids interaction ............................................................................................................................... 3. Differential involvement of the s 1 receptor in the mnesic effects of neuroactive steroids .............................................................................. 3.1. Anti-amnesic effects of s 1 receptor agonists ..................................................................................................................................... 3.2. Neuroactive steroids / s 1 receptor interaction in learning and memory ................................................................................................. 3.3. Results using in vivo antisense strategy............................................................................................................................................. 4. s 1 Receptor / neuroactive steroids interaction in depression ......................................................................................................................... 4.1. s 1 Receptor agonists and neuroactive steroids show antidepressant potentials...................................................................................... 4.2. Endocrine manipulations..................................................................................................................................................................

q

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The present manuscript details an invited lecture presented at the International Meeting Steroids and Nervous System, Torino, Italy, February 11–14, 2001. *Corresponding author. Tel.: 133-467-601-186; fax: 133-467-540-610. E-mail address: [email protected] (T. Maurice). 0165-0173 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0165-0173( 01 )00112-6

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 – 132 5. Therapeutic potential ............................................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction The concept of neurosteroids was introduced in the early 1980s by Baulieu and co-workers to designate the pools of steroids, including pregnenolone, dehydroepiandrosterone (DHEA), their sulfate esters, progesterone, allopregnanolone (3a-hydroxy-5a-pregnan-20-one), whose levels were higher in the brain than in plasma, and unrelated to peripheral sources. Fifteen days after removing the sources of circulating steroids, by adrenalectomy and gonadectomy (AdX / CX) in rats, no difference in the brain levels of these steroids could be measured as compared to non-operated animals [15,16]. Evidence has now been provided for de novo synthesis of neurosteroids in cells of the nervous system, mainly by oligodendrocytes [35,42,43]. These neurosteroids, as well as circulating steroids crossing the blood–brain barrier and reaching the brain, can influence neuronal functions by classical genomic effects — by binding to intracellular receptors activating transcription factors and regulating gene expression — or through non-genomic, rapid effects — by binding or indirectly modulating the activity of several neurotransmitter receptors and ion channels [80,112]. A more recent concept is that, among these targets, some neuroactive steroids interact with an atypical neuromodulatory receptor, namely the s 1 receptor [8,73,85,119]. Selective agonists of this recently cloned receptor have potent anti-amnesic, anti-depressant and anti-stress effects, while selective antagonists have antipsychotic and antiaddictive property [73]. The importance of the neuroactive steroids / s 1 receptor interaction in neuropsychopharmacology is receiving increasing attention. The present review will present new data concerning the s 1 receptor, particularly focusing on its cellular role as a sensor / modulator for the mobilization of intracellular calcium pools, and on its localization achieved using immunohistochemical techniques. The physiopathological consequences of neuroactive steroids / s 1 receptor interaction will be detailed, especially animal models of amnesia and depression, as well as therapeutic perspectives offered by use of selective s 1 receptor agonists against age-related cognitive deficits.

2. The s 1 receptor is a target for non-genomic effects of neuroactive steroids

2.1. The s1 receptor The s binding site was initially described as a subtype of opiate receptors by Martin and co-workers [56], where it mediates the unique psychotomimetic effects of the

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prototypic ligand N-allylnormetazocine ((6)-SKF-10,047) in the chronic spinal dog. The opiate syndromes were classified as m for the effects induced by morphine, s for the ones induced by (6)-SKF-10,047 and k for ketocyclazocine [56]. The observation that certain behaviors elicited by N-allylnormetazocine are resistant to blockade by classical opiate receptor antagonists such as naloxone or naltrexone [132] led to a complete distinction between s non-opiate binding sites and the classical m-, k-, and d-opiate receptors [102]. The s sites were then confounded with the high affinity phencyclidine (PCP) binding sites, located inside the ion channel associated with the NMDA receptors, because of the shared affinities of several compounds, including PCP and N-allylnormetazocine, for both s and PCP sites [102]. Any confusion between these receptors was cleared up by the availability of more selective drugs, such as dizocilpine or N-[1-(2thienyl)cyclohexyl]piperidine (TCP) for the PCP sites; haloperidol, (1)-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine ((1)-3-PPP), igmesine, (1)-cis-N-methyl-N-[2-(3,4dichlorophenyl)ethyl]-2-(1-pyrrolidinyl) cyclohexylamine (BD737), among others, for s sites. It is now well established that the s sites represent unique binding sites in the brain and peripheral organs, distinct from any other known sites. The pharmacological identification of s sites was characterized by their ability to bind several chemically unrelated drugs with high affinity, including psychotomimetic benzomorphans, PCP and derivatives, cocaine and derivatives, amphetamine, certain neuroleptics, many new ‘atypical’ antipsychotic agents, anticonvulsants, cytochrome P450 inhibitors, monoamine oxidase inhibitors, histaminergic receptor ligands, peptides from the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families, as well as some steroids [68,73]. The pharmacological identification and localization of s binding sites was achieved through the use of various radioligands, such as [ 3 H](1)-SKF-10,047, [ 3 H](1)-3PPP, [ 3 H]haloperidol, [ 3 H]1,3-di-O-tolylguanidine 3 3 ([ H]DTG), [ H](1)-pentazocine [14,28,51,81,120]. Pharmacological studies rapidly led to the distinction of two classes of s sites, termed s 1 and s 2 [101]. The s 1 sites have high affinity and stereoselectivity for the (1)-isomers of SKF-10,047, pentazocine and cyclazocine, whereas s 2 sites have lower affinity and show opposite stereoselectivity [34]. DTG, (1)-3-PPP and haloperidol are non-discriminating ligands with high affinity for the two subtypes. In addition, s 1 sites are allosterically modulated by phenytoin [87], are sensitive to pertussis toxin, the modulatory effects of guanosine triphosphate [37,39], and down-regulated following a subchronic treatment with haloperidol [38,59]. It has also been shown that several

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drugs, such as haloperidol, reduced haloperidol, a-(4fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1piperazinebutanol (BMY-14802), rimcazole, or N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) act as antagonists in several physiological and behavioral tests relevant to s 1 pharmacology (see Table 1) [49,90,121,122]. The s 1 receptor has been completely sequenced and its

promoter region sequence analyzed for transcription factorbinding sites in different species. Hanner and co-workers [29] described the initial cloning of the receptor from guinea-pig liver. It has since been cloned from a human placental cell line, T leukemia Ichikawa cell line and human brain [40,45,99], mouse kidney [115], mouse brain [92] and rat brain [114]. The amino acid sequences of the different purified receptors are highly homologous. The

Table 1 Pharmacological profiles and behavioural activities of s 1 receptor-related drugs cited in the review Drugs

s 1 activity

s1 Ligands (1)-SKF-10,047 (1)-pentazocine Dextrometorphan SA4503 PRE-084 OPC-14523 Carbetapentane (1)-3-PPP Igmesine BD737 Cocaine DTG Haloperidol Reduced haloperidol Rimcazole BMY-14,802 NE-100 BD1047 BD1063

s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1 s1

Peptides NPY CGRP

s 1 agonist s 1 agonist

Steroids Pregnenolone Pregnenolone sulfate

s 1 agonist s 1 agonist

DHEA DHEA sulfate

s 1 agonist s 1 agonist

Progesterone

s 1 antagonist

Dihydrotestosterone Androterone Testosterone 5a-Androstane-3,17-dione Deoxycorticosterone

Low s 1 Low s 1 Low s 1 Low s 1 Low s 1

Antidepressants Fluoxetine Imipramine Hypericum perforatum

s 1 agonist Low s 1 affinity s 1 agonist

agonist agonist agonist agonist agonist agonist agonist agonist agonist agonist agonist agonist antagonist antagonist antagonist antagonist antagonist antagonist antagonist

Other activity

Behavioural activity

Refs.

5-HT 1B agonist

Anti-amnesic, anti-depressant Anti-amnesic, anti-depressant Anti-depressant Anti-amnesic, anti-depressant Anti-amnesic, anti-depressant Anti-depressant

[44,64,65,88,89] [66,77] [44,140] [63,72,74,77,113] [72,76,77,96] [123] [83] [17,64] [17,48,62,125] [73] [73] [64,66] [8,49,64,77,106] [49] [17] [66,67,77,121,122] [88,90,105,126] [85] [85]

s 2 agonist

Anti-amnesic Anti-amnesic, anti-depressant

s 2 agonist s 2 agonist

Anti-amnesic Antagonist Inactive Antagonist Antagonist

s 2 agonist s 2 agonist

[68,73] [68,73]

Anti-amnesic Anti-amnesic, anti-depressant

NMDA negative GABAA positive modulator

Antagonist

[8,77,119] [8,10,12,20,27,36,75,77,85] [88,105,106,108,110,126,127] [8,77] [8,21,22,75,77,85,88,105, 106,126,127] [8,74,75,85,105] [119] [119] [119] [119] [119] [119]

5-HT transporter inhibitor 5-HT transporter inhibitor 5-HT transporter inhibitor

Anti-depressant a Anti-depressant Anti-depressant

[123,125,129] [123,125] [93,104]

Drugs devoid of s1 activity TCP Dizocilpine Desipramine

NMDA antagonist NMDA antagonist 5-HT transporter inhibitor

Amnesic Amnesic Anti-depressant

[102] [66,67,74,76] [125]

Steroids Epipregnanolone Allopregnanolone

NMDA negative modulator GABAA positive modulator

Amnesic Amnesic

[94,95] [110]

a

NMDA positive modulator NMDA positive modulator GABAA negative modulator

Anti-amnesic Anti-amnesic

GABAA negative modulator

Anti-amnesic Anti-amnesic, anti-depressant

affinity affinity affinity affinity affinity

The anti-depressant activity may not involve the s 1 receptor.

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mouse s 1 receptor shared 87% identity and 91% similarity with the previously cloned guinea-pig sequence, 90% identity and 93% similarity with the human s 1 receptor, and 92% identity and 96% similarity with the rat s 1 receptor. However, s 1 receptors share no homology with known mammalian proteins, indicating that the s 1 receptor is a distinct entity from any other known receptors. Results also demonstrate that an identical s 1 receptor is expressed in peripheral tissues and brain. The s 2 site remains unidentified. It is still unclear whether it represents a single site or a family of related proteins. It was first characterized in pheochromocytoma PC12 cells [33]. It was defined as presenting high affinity and stereoselectivity for (2)-benzomorphans, with an apparent molecular weight of 18–21 kDa [33,34]. Some selective and high affinity s 2 site-ligands are now available. Several functions have been proposed, including regulation of motor function by induction of dystonia after in situ administration in the red nucleus [60,61], regulation of ileal function [47], or blockade of tonic potassium channels [7,41,138]. Agonists at s 2 sites also induced changes in cell morphology and apoptosis in various cell types by producing transient but sustained increases in [Ca 21 ] i from different intracellular stores. The s 2 agonists induced apoptosis in drug-resistant cancer cells, enhanced the potency of DNA damaging agents, and down-regulated expression of p-glycoprotein mRNA. Thus, s 2 site agonists may be useful in the treatment of drug-resistant cancer [9].

2.2. Distribution of the s1 receptor The s 1 receptor-distribution in the brain has been extensively studied using radiographic procedures such as in vitro or in vivo binding, autoradiography, or positron emission tomography. In rodents, high levels of s 1 sites were detected in the hippocampal pyramidal cell layers, hypothalamus, pontine and cranial nerve nuclei, and cerebellum [14,26,28,51,81,118]. However, the different radioligands used in these studies showed different affinity and selectivity for the s 1 sites. Thanks to the cloning and sequencing of the s 1 receptor, polyclonal antibodies are now available to examine the immunohistochemical distribution of the s 1 protein. Using an antibody directed against a 20-amino acid peptide corresponding to fragment 143–162 of the cloned rat s 1 protein, we recently described s 1 immunostaining throughout the rostro-caudal regions of the rat central nervous system [1] (see Fig. 1). The s 1 receptor immunostaining appeared to be associated with ependymocytes bordering ventricular areas, and mainly with neurons located within the parenchyma. This labeling is observed in the whole central nervous system, but high to moderate immunostaining level is always associated with neurons located within specific structures. The highest level of immunostaining is observed in the granular layer of the olfactory

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bulb, various hypothalamic nuclei, the dentate gyrus of the hippocampus, motor nuclei of the hindbrain and the dorsal horn of the spinal cord. Moderate levels of immunostaining are associated with the pyramidal cells of the hippocampal layers CA 1 –CA 3 , the superficial layers II–IV of the cerebral cortex, the lateral septum, the nucleus centralis of the amygdala, and the central gray. Only faint immunostaining was associated with neurons located in the caudate putamen and the cerebellum. The immunolocalization of the s 1 receptor was also established in the mouse brain [96] (Phan et al., submitted). Only mild differences appeared between results in the rat. In the hippocampus, the CA 1 –CA 3 pyramidal layers were as intensively immunostained as the dentate gyrus. Some large but scattered moderately immunostained neurons were observed in the caudate putamen as well as in the septum, the amygdala and the nucleus accumbens. Moderate immunostaining was also observed in the granular layer of the cerebellum. Electron microscopic studies (see Fig. 2) indicated that s 1 receptor-immunostaining was mostly associated with neuronal perikarya and dendrites, where it was either dispersed throughout the cytoplasm or associated with membranes, including both the limiting plasma membrane and the membrane organelles such as mitochondria, some cisternae of the endoplasmic reticulum, and vesicles present in the vicinity of the Golgi apparatus or dispersed within the dendritic profiles. At the level of synaptic contacts, intense immunostaining was associated with postsynaptic structures, including the postsynaptic thickening, and some polymorphous vesicles. In rats, but not in mice, the presynaptic axons were devoid of immunostaining [1,96] (Phan et al., submitted). Immunolabeling studies showed that the distribution of the s 1 protein was in accordance with what could be expected from the previously described autoradiographic studies. Moreover, it allowed visualization of the protein at the cellular and sub-cellular levels, a technique that may give valuable information for future studies, particularly concerning the putative cellular translocations following receptor activation [31,86].

2.3. The s1 receptor as an intracellular calcium mobilization modulatory protein Recent evidence indicates that s 1 receptors directly 21 modulate intracellular calcium ([Ca ] i ) mobilization through a complex mechanism. Initially, Ela and co-workers [18] showed that exposure of cardiomyocytes in culture to s 1 receptor agonists, such as (1)-3-PPP, haloperidol, and (1)-pentazocine, exerted specific changes in contractility, [Ca 21 ] i transients and beating rates. The time-course of changes in contractility and [Ca 21 ] i transients showed a complex but reproducible pattern, with an initial decrease followed by an important increase, and a final decrease. The increase in [Ca 21 ] i and its following decrease ap-

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Fig. 2. Subcellular neuronal localization of the s 1 receptor in the C57Bl / 6 mouse hypothalamus. Vibratome sections were treated for the peroxidase immunostaining of s 1 receptor in absence of Triton X-100. Immunostained sections were rinsed in 0.1 M cacodylate buffer, pH 7.3, postfixed in 1% OsO 4 , then dehydrated in graded concentrations of ethanol and embedded in araldite. Punches of 1.5 mm in diameter were cut and mounted on araldite blocks. Ultrathin sections were cut and observed using an EM-900 Zeiss electron microscope without counterstaining or with slight uranyl acetate staining. Within the cell body of an hypothalamic neuron, electron dense precipitates are associated with membranes including: (A) the limiting plasma membrane; (B) the membrane thickening facing synaptic contacts (arrows); (C) the membrane of mitochondria; (D) the membrane of vesicles or of elongated cisternae of the endoplasmic reticulum; and (E) the nuclear limiting membrane. Note that the axonal profiles (Ax) that form synaptic contacts with labeled dendrites are devoid of immunostaining. Ax, axonal profile; De, dendritic profile; er, endoplasmic reticulum profile; mi, mitochondria; nu, nucleus; ve, presynaptic vesicles. Adapted from Ref. [96].

Fig. 1. Immunohistochemical labeling of the s 1 receptor in coronal sections of the rat brain. Rats were perfused with 4% paraformaldehyde and 0.5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4. The brain was dissected and fixed by immersion in the same fixative but without glutaraldehyde for 2–4 days. It was then cut either with a vibratome into 40–50-mm thick sections. Sections were successively incubated with the purified primary s 1 receptor antibody, diluted 1:200; with a peroxidase-labeled Fab fragment of goat IgG anti-rabbit IgG, diluted 1:1000; and with 0.1% 3,39-diaminobenzidine diluted in 0.05 M Tris buffer, pH 7.3, in the presence of 0.2% H 2 O 2 . Immunostained sections were mounted in permount and observed under a light microscope. (A) Rostro-caudal distribution: filled and open circles represent cell bodies exhibiting intense or moderate immunostaining, respectively. (B) Sagittal section of the olfactory bulb showing intense labeling throughout the granular and glomerular layers. (C) Regions of the anterior olfactory nucleus are devoid of immunolabeling. (D) Higher magnification shows that within the GRL, immunostaining is essentially associated with the cytoplasm of neurons. (E) Immunostaining in the superficial layers of the pyriform cortex. (F) Immunolabeling in the septum. (G) In the hippocampus, intense immunostaining is associated with neurons located in the dentate gyrus, and more moderately with those located in the CA 1 –CA 3 layers. Higher magnification of the dentate gyrus (H) and CA 3 area. Moderate immunostaining is associated with neurons located in the superficial layers of the fronto-parietal cortex (J). Intense immunostaining is associated with neurons located in the supraoptic (K), the periventricular (L) and the arcuate (M) nuclei. Higher magnification in (M) shows that the immunostaining is associated with both the neuronal cytoplasm and with dotted structures dispersed between immunostained neurons. Intense immunostaining is associated with the ependymocytes bordering the third ventricle (L), whereas the optic chiasma is devoid of immunostaining (K). 12, hypoglossal nucleus; 3 V, third ventricle; 4 V, fourth ventricle; A, amygdaloid complex; Acb, accumbens nucleus; Aq, cerebral aqueduct; AON, anterior olfactory nucleus; AR, arcuate nucleus; CA1–CA3, fields of hippocampal pyramidal layers; Cb, cerebellum; CC, central canal of the spinal cord; CG, central gray; Cx, cerebral cortex; DG, dentate gyrus; DH, dorsal horn of the spinal cord; GL, glomerular layer of the olfactory bulb; GRL, granular layer of the olfactory bulb; IG, induseum griseum; IO, inferior olive; LC, locus coeruleus; LV, lateral ventricle; M, mammillary complex; O, olivary complex; OC, optic chiasma; PCx, piriform cortex; Pe, periventricular hypothalamic nucleus; Pr5, trigeminal nucleus; RN, raphe nucleus; Rt, reticular thalamic nucleus; S, septum; SO, supraoptic nucleus; Sol, nucleus of the solitary tract; Sp5, nucleus of the trigeminal nerve; ST, striatum. V, third ventricle. Scale bars550 mm. Adapted from Ref. [1].

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peared to be mediated by corresponding changes in Ca 21 influx [18]. These authors suggested that the time course of the s 1 agonist effect involved either a primary action on Ca 21 channels, or an action of Ca 21 fluxes via modulation of K 1 channels. Furthermore, several antipsychotic drugs, including s 1 ligands, were reported to block voltagedependent calcium channels [19,25,103]. More recently, the role of the s 1 receptor in regulating Ca 21 in NG-108 cells has been extensively studied [30]. Initially, the s 1 agonists (1)-pentazocine and PRE-084 were found to potentiate the bradykinin-induced increase in [Ca 21 ] i in a bell-shaped manner. Secondly, after depletion of endoplasmic reticulum Ca 21 stores, the depolarization-induced increase in [Ca 21 ] i was potentiated by PRE-084, but inhibited by (1)-pentazocine. Both effects were blocked by an antisense oligodeoxynucleotide targeting the s 1 receptor [30]. More recently, the same authors [31] suggested that the s 1 receptor could regulate the coupling of the inositol 1,4,5-trisphosphate (InsP3 ) receptor with the cytoskeleton via an ankyrin B protein. They observed that (1)-pentazocine dissociated ankyrin B from InsP3 receptor in NG-108 cells, and this dissociation correlated with the efficacy of each ligand in potentiating the Ca 21 efflux induced by bradykinin. These results, consistent with subcellular localization of the s 1 receptor observed in electronic microscopy studies [1,96], suggested that the s 1 receptor may play a particular role as a sensor / modulator for neuronal intracellular Ca 21 mobilization. Such an effect, occurring in post-synaptic neurons downstream to neurotransmission events, may explain — or strengthen the validity of — the apparent wide-range and non-selective neuromodulatory effects induced by selective s 1 receptor ligands.

2.4. Non-genomic effects of neuroactive steroids Since the initial report of the anesthetic properties of progesterone [116], the biological effects of steroids in the central and peripheral nervous systems have been extensively studied. Neuroactive steroids include both steroids from the periphery which are transported through the blood–brain barrier and act within the brain, and locally synthesized neurosteroids. Their physiological actions, demonstrated from embryogenic through adult life, involve both some genomic actions mediated by nuclear steroid receptors and non-genomic neuromodulatory actions affecting several neurotransmitters and second messenger systems. Neuroactive steroids include the neurosteroids pregnenolone, dehydroepiandrosterone, their sulfate esters, progesterone, allopregnanolone, plus steroids not synthesized centrally, such as testosterone, 17b-estradiol, corticosterone, and their metabolites. Evidence is now accumulating to show that they are allosteric modulators of GABAA , NMDA, cholinergic and s 1 receptors. The non-genomic actions of neuroactive steroids and their physiopathological consequences have been reviewed

[6,13,23,50,53,73,82,112]. We will focus on recent progress concerning the behavioral relevance — in memory processes and response to a paradigm of depression — and therapeutical prospects of the neuroactive steroids / s 1 receptor interaction.

2.5. The s1 receptor /neuroactive steroids interaction The first evidence for an interaction between steroids and s 1 receptors was provided by Su and co-workers [119] from in vitro binding experiments in the guinea-pig brain and spleen. Among the different steroids tested, progesterone was the most potent inhibitor of radioligand binding to the s 1 site, with Ki values in the 300 nM range [119]. Progesterone was also a potent inhibitor of s 1 site-binding in rat brain membrane preparations, and in 3-[(3cholamidopropyl)dimethylamino]-1-propane sulfonate (CHAPS)-solubilized extracts, with a Ki in the 200 nM range [79]. These observations, together with the selectivity of [ 3 H]progesterone binding to s 1 receptors [79] suggested that the link between progesterone and s 1 receptors is direct and not due to an interaction with membrane lipids. Testosterone, deoxycorticosterone, or pregnenolone sulfate also inhibited the binding to s 1 sites, with Ki values in the low micromolar range [79,119]. These observations were extended, using not only 3 3 [ H](1)-SKF-10,047, but also [ H]dextromethorphan, 3 3 [ H](1)-3-PPP, or [ H]haloperidol as radiotracers for s 1 sites in the rat brain, splenocytes, plasma membranes and liver microsomes [49,75,139]. Progesterone appeared to be the most potent inhibitor. Dihydrotestosterone, androsterone, testosterone, 5a-androstane-3,17-dione and deoxycorticosterone gave Ki values in the micromolar range [119]. Pregnenolone, DHEA or their sulfate esters appeared less efficient. Additionally, numerous s 1 ligands, including haloperidol, carbetapentane, DTG, (1)-3-PPP, or rimcazole, potently inhibited [ 3 H]progesterone binding in rat liver microsomal membrane preparations and in porcine liver-solubilized fractions [83,139]. Systemic administration of steroids dose-dependently inhibited the in vivo binding of [ 3 H](1)-SKF-10,047 to s 1 sites [75]. Progesterone was also found to be the most potent inhibitor, with a significant inhibition at 10 mg / kg. Pregnenolone sulfate and DHEA sulfate gave significant effects at 40 mg / kg, which were unrelated to their in vitro affinity. In addition, binding levels of [ 3 H](1)-SKF-10,047 were significantly reduced in pregnant female mice as compared to nonpregnant ones or males [75]. It was also observed that modulation of endogenous steroid levels affected in vivo [ 3 H](1)-SKF-10,047 binding-parameters [97]. Suppression of peripheral steroids by adrenalectomy / castration enhanced [ 3 H](1)-SKF-10,047 binding. Finasteride, an inhibitor of 5a-reductase that catalyzes the conversion of progesterone to 5a-pregnane-3,20-dione, was used to augment progesterone levels. Treatment of surrenalectom-

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ized / castrated mice with finasteride led to a significant decrease of in vivo [ 3 H](1)-SKF-10,047 binding-levels [97]. Thus, neuroactive steroids directly interact with s 1 sites, progesterone appearing to be the most efficient inhibitor. Its Ki value might be expected to be reached in local physiological concentrations, suggesting a functional interaction with s 1 receptors in the brain. Pregnenolone and DHEA sulfate, which are inefficient in vitro, affected in vivo binding, suggesting that under physiological conditions, these steroids could also interact with s 1 receptors. The physiological tests used to describe s 1 pharmacology also allow demonstration of neuroactive steroid / s 1 receptor interactions. Monnet and co-workers [85] reported that the NMDA-evoked [ 3 H]norepinephrine release from preloaded rat hippocampal slices was potentiated by DHEA sulfate and inhibited by pregnenolone sulfate. These effects were blocked by the s 1 antagonists haloperidol and BD1063, or by progesterone. Bergeron and co-workers [8] reported that the excitatory electrophysiological response of rat CA 3 hippocampal pyramidal neurons to microiontophoretic applications of NMDA could be potentiated by DHEA. This effect was also sensitive to the s 1 antagonists haloperidol and NE-100, or to progesterone. The above results were the first demonstration of the physiological importance of the s 1 receptor as a target for neuroactive steroids. In addition, both in vitro and in vivo effects of DHEA or pregnenolone were blocked by pertussis toxin, indicating that the s 1 receptor, although unrelated to classical seven transmembrane domains receptors, may be in some way coupled to G i / o proteins.

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that they could improve cholinergic-dependent memory processes either during the acquisition, consolidation, or the retention phase [64]. Another very selective s 1 receptor agonist, SA4503, reversed scopolamine-induced amnesia and attenuated the learning impairments in rats with cortical cholinergic dysfunction, such as ibotenic acid-induced lesions of the basal forebrain, in the passive avoidance test, and in the Morris water-maze test [63,113]. Similarly, DTG or PRE-084 reduced learning impairments induced by scopolamine or mecamylamine in mice [66,76]. Scopolamine-induced amnesia was not affected, but mecamylamine-induced amnesia was significantly attenuated, indicating that s 1 receptor ligands may also potently modulate nicotinic cholinergic receptor-mediated behaviors [66,76]. This result was in accordance with the neuromodulatory effect exerted by s 1 receptor ligands on the nicotinic receptor. In addition, s 1 receptor ligands show anti-amnesic effects against impairments induced after blockade of the NMDA receptor. High affinity s 1 receptor ligands, such as DTG, (1)-SKF10,047, (1)-pentazocine, PRE-084, and SA4503 attenuated learning impairments induced in mice by dizocilpine in various behavioral tests [66,74,76,141]. The involvement of hippocampal NMDA receptors was clearly demonstrated by showing that intra-hippocampal administration of (1)-SKF-10,047, ineffective by itself, prevented the dizocilpine-induced increase in the number of working errors in a three-panel runway task in rats [89].

3.2. Neuroactive steroids /s1 receptor interaction in learning and memory 3. Differential involvement of the s 1 receptor in the mnesic effects of neuroactive steroids

3.1. Anti-amnesic effects of s1 receptor agonists The s 1 receptor agonists have not yet been reported to affect memory capacities by themselves, but have been demonstrated to have beneficial properties in several models of amnesia (Table 1) (for reviews, see Refs. [68,73]). Earley and co-workers [17] initially demonstrated that several s 1 receptor ligands reversed, in a dose-dependent manner, amnesia induced by scopolamine in the rat. DTG, (1)-3-PPP and igmesine prevented scopolamineinduced amnesia in the step-through type passive avoidance task, whereas (1)-SKF-10,047 and rimcazole were inactive. The s 1 receptor agonists, (1)-SKF-10,047, (6)pentazocine, DTG, (1)-3-PPP, also prevented amnesia induced by cholinergic dysfunction, using scopolamine or the serotonin depleter p-chloroamphetamine, in a stepdown type passive avoidance task in mice [64,65]. Interestingly, effects on p-chloroamphetamine-induced amnesia were observed when s 1 receptor agonists were administered before training as well as before retention, indicating

Neuroactive steroids have been shown to affect memory performances by themselves and to alleviate several pharmacological models of amnesia. Pregnenolone, DHEA and their sulfate esters, enhanced memory retention in an active avoidance learning task in mice after central administration [20]. Pregnenolone sulfate was the most potent of these compounds. Its long-duration effect, still observable 1 week after administration, suggested to these authors that pregnenolone was serving as a precursor of other steroids, which ensured a near-optimal modulation of transcription of immediate-early genes required for the facilitation of the plastic changes in memory processes [20]. Pregnenolone sulfate also enhanced memory formation when administered after the first session of training in a spontaneous alternation task in rats [78], or in an appetitive reinforced Go–No Go visual discrimination task in mice [84]. These results suggest that pregnenolone sulfate might have a specific effect on memory consolidation processes, rather than acquisition. DHEA, and its sulfate ester, improved age-related deficits in a footshock active avoidance training in aged mice. DHEA administered centrally prevented the amnesia induced by administration of the vehicle dimethylsulfoxide (DMSO) alone. DHEA sulfate, adminis-

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tered systemically or centrally immediately after training, or given in the drinking water for 2 weeks, facilitated memory retention in a step-down passive avoidance test in mice, but did not improve acquisition [21,22]. The beneficial effects of neuroactive steroids were also tested in experimental models of amnesia. Pregnenolone sulfate counteracted deficits induced by different NMDA receptor antagonists. Administration of this steroid dose-dependently reduced the learning deficit and motor impairment induced by pretraining-administration of the competitive antagonist 3-((6)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in a step-through passive avoidance task in the rat [108]. Limited effect of pregnenolone sulfate alone on passive avoidance response were observed, suggesting that the potent reduction of CPP-induced impairments by this neuroactive steroid is not due to intrinsic memory enhancement properties, but rather to its positive pharmacological action on NMDA receptors [57]. The steroid also blocked the impairments induced by D-AP5 in an active avoidance test in mice [58]. In addition, administration of pregnenolone sulfate in rats prevented the cognition deficits induced by dizocilpine, a non-competitive NMDA receptor antagonist [110]. Pregnenolone sulfate infusion in adrenalectomized / castrated rats prevented the learning deficits induced by dizocilpine [12]. Interestingly, blockade of 5a-reductase activity led to the disappearance of the pregnenolone sulfate effect, leading the authors to suggest that an increase in allopregnanolone could mediate the pregnenolone sulfate effect. The interaction between neuroactive steroids and s 1 receptors was shown in learning and memory processes, initially using crossed pharmacology studies with selective antagonists. The memory enhancing effect of DHEA sulfate against dizocilpine-induced learning impairments could be blocked by preadministration of the s 1 receptor antagonist BMY-14,802 [67]. The anti-amnesic effects of SA4503 against learning impairments induced by dizocilpine or N v -nitro-L-arginine methyl ester ( L-NAME), the nitric oxide synthase inhibitor, could be blocked by progesterone, in a similar manner as that of haloperidol [74]. The interaction between s 1 receptor ligands and neuroactive steroids appears to also be of critical relevance to cholinergic-associated memory mechanisms [126]. Indeed, the beneficial effects of DHEA sulfate and pregnenolone sulfate against scopolamine-induced learning impairments in mice could be blocked by NE-100. Recently, the pro-mnesic effects of pregnenolone and DHEA sulfates were directly evaluated in a modified passive avoidance task in mice [106]. Both steroids facilitated retention when given either pre- or post-training, but not before the retention test. These effects could be antagonized by haloperidol [106]. The anti-amnesic potencies of s 1 receptor agonists and neuroactive steroids were also evaluated in a basic model of Alzheimer’s disease-type amnesia, where learning deficits were produced in mice

that had been treated centrally with b 25 – 35 -amyloid related peptide [77]. The b 25 – 35 -amyloid peptide-induced amnesia is sensitive to cholinomimetics or NMDA / glycine modulatory site agonists [69,70]. The s 1 receptor agonists, (1)-pentazocine, PRE-084 or SA4503, attenuated, in a dose-dependent and bell-shaped manner, the b 25 – 35 amyloid peptide-induced deficits in the spontaneous alternation task and step-down passive avoidance tests [77]. All effects were blocked by BMY-14,802 and haloperidol. In parallel, DHEA, pregnenolone, and their sulfate esters, also dose-dependently reduced b 25 – 35 -amyloid peptide-induced deficits. Progesterone behaved as an antagonist, blocking the beneficial effects of both the active steroids and the s 1 receptor agonists. Conversely, haloperidol blocked the effects induced by the active steroids, showing a clear crossed pharmacology between s 1 receptor ligands and steroids on memory processes [77]. These observations strongly suggest that part of the anti-amnesic properties of neuroactive steroids on NMDAand acetylcholine-dependent learning and memory processes implicates, beside direct effects on these neurotransmitter receptors and their interaction with the GABAergic systems, an interaction with s 1 systems. However, from these studies, no specificity of actions were observed between pregnenolone or DHEA, both steroids acting as potent anti-amnesic agents.

3.3. Results using in vivo antisense strategy Following cloning of the protein, the implication of the s 1 receptor in learning and memory processes could be firmly established using an in vivo antisense strategy [72] (Maurice et al., submitted). A phosphorothioate-modified antisense oligodeoxynucleotide, targeting s 1 receptor DNA, was administered in mice intracerebroventricularly for 3 days. This treatment led to a 58–60% reduction of the number of s 1 sites in the ipsilateral hippocampus, and to a 33–38% reduction in the cortex, as assessed using Scatchard analyses of in vitro binding experiments [72] (Maurice et al., submitted). The anti-amnesic effects of PRE-084 or SA4503, observed against the learning impairments induced by dizocilpine or scopolamine, were blocked after administration of s 1 antisense oligodeoxynucleotide, but not after a saline- or a control s 1 mismatch oligodeoxynucleotide-treatment. These observations showed that: (i) the s 1 receptor is not obligatory for optimal learning capacities in control animals; (ii) the receptor is neither necessary for NMDA-mediated learning processes in control conditions, nor for the establishment of the deficits induced by dizocilpine; (iii) the cloned s 1 receptor is likely to represent the subtype of receptor mediating the anti-amnesic effects of s 1 agonist, providing a molecular basis for the involvement of the s 1 receptor in memory processes [72]. Surprisingly, the in vivo antisense strategy revealed

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some discrepancies for the anti-amnesic effects induced by neuroactive steroids (Maurice et al., submitted). Antisense oligodeoxynucleotide treatment directed against the s 1 receptor led to a complete blockade of the anti-amnesic effects mediated by DHEA sulfate, confirming that the steroid effects involve primarily an interaction with s 1 receptors. Conversely, pregnenolone sulfate still induced a potent anti-amnesic effect in s 1 receptor antisense-treated animals, data suggested that it interacted more directly and efficiently with GABAA receptors and / or NMDA receptors, to mediate its behavioral effects. Indeed, pregnenolone is known to effectively positively modulate the activation of NMDA receptor complexes. In particular, this steroid-augmented NMDA receptor-mediated increase in intracellular Ca 21 in hippocampal neuronal cultures [10,36,134], and increased the convulsant potency of NMDA [52]. The steroid may be acting through a specific extracellularly directed modulatory site located on the receptor complex, which is distinct from either the spermine, glycine, phencyclidine, arachidonic acid, Mg 21 and redox sites [95]. Interestingly, some other steroid sulfates, like pregnanolone sulfate or epipregnanolone sulfate inhibited the NMDA response, through a similar direct action on the NMDA receptors, which may involve a distinct site on the complex [94,95]. DHEA or its sulfate ester is also considered to be an excitatory steroid. It acts as a negative allosteric modulator of the GABAA receptor [54]. It potentiates several responses to NMDA in vitro and in vivo [8,85]. However, the latter effect is unlikely to be related to the effect of pregnenolone effect on NMDA receptors, since DHEA sulfate did not interact directly with the NMDA receptor [46,94]. In addition, DHEA has been reported to attenuate the neurodegeneration in primary hippocampal cultures exposed to glutamate, NMDA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid [46,55,133]. On the other hand, pregnenolone sulfate was found to potentiate NMDAinduced neurodegeneration in cell cultures or on the isolated retina treated with glutamate [27,135]. Such difference were also observed in vivo, with pregnenolone precipitating appearance of learning deficits observed in mice exposed to an hypoxic insult by repetitive inhalation of carbon monoxide, whereas DHEA completely protected the animals [71]. Indeed, the direct and efficient action of pregnenolone is consistent with its ability to enhance the NMDA-induced toxicity. As established through the antisense studies, DHEA or its sulfate ester potentiates the NMDA-evoked responses through its interaction with the s 1 receptor. Pregnenolone was reported to act as an inverse agonist on the s 1 receptor in vitro [85] but inefficient in vivo [8]. Agonists of the s 1 receptor exert a bell-shaped concentration dependency, since at low dosage they allow a limited facilitation of NMDA receptor activation and at higher doses become inefficient or inhibit the NMDA-mediated responses [8,68,71,85].

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4. s 1 Receptor / neuroactive steroids interaction in depression

4.1. s1 Receptor agonists and neuroactive steroids show antidepressant potentials Neuroactive steroids and s ligands have independently been suggested to play an important role in depression. Indeed, both modulate noradrenergic and glutamatergic neurotransmissions which play important roles in behavioral despair [11,124]. Consequently, s 1 receptor agonists [44,48,62,88,123,125,128] and some neuroactive steroids [98,105,128] show efficacious antidepressant-like effects in several animal models (Table 1). Several clinical studies suggest a link between the endogenous levels of neuroactive steroids and the depressive state. Pregnenolone level in the cerebrospinal fluid is decreased in subjects with an affective illness, particularly during episodes of active depression [24]. Fluoxetine, a selective serotonin reuptake inhibitor, induced the level of allopregnanolone in the cortex and hippocampus of the rat, probably by acting directly on 3a-hydroxysteroid oxidoreductase activity [129]. During depression, there was a significant decrease in allopregnanolone and pregnanolone concentrations in human plasma [111]. After successful treatment with antidepressants, allopregnanolone and pregnanolone levels were increased in the cerebrospinal fluid of treated patients. In contrast, when treatment failed, the level of allopregnanolone and pregnanolone failed to increase [130]. A correlation was observed between the levels of pregnenolone, and its sulfate, and symptom severity in premenstrual syndrome, which was opposite to that for 5a-dihydroprogesterone and allopregnanolone whose levels increased when symptom severity decreased [133]. In alcoholic subjects, the levels of plasma allopregnanolone and allotetrahydrodeoxycorticosterone were markedly lower than those of control subjects during the early withdrawal phase, when anxiety and depression scores were the highest [109]. Depression ratings in abstinent alcoholic patients were negatively correlated with plasma levels of DHEA and DHEA sulfate [32]. These observations together suggest the clinical importance of neuroactive steroid in the physiopathology of mood disorders. Moreover, in an open trial, DHEA administered to depressive patients with low DHEA levels significantly reduced depression ratings [137]. A double-blind study confirmed this result [136]. The s 1 agonists had antidepressant-like effects in several animal models. Igmesine (see Fig. 3A,B), SA4503, (1)-pentazocine, DTG or OPC14523 reduced immobility in swim test [62,117,123] and in the tail suspension test [48,125]. (1)-SKF-10,047, dextrometorphan and igmesine reduced the stress-induced colonic activity and the conditioned fear stress [44,140]. Interestingly, maximum response of OPC14523 was higher than to either fluoxetine

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Fig. 3. The antidepressant-like effect of the selective s 1 receptor agonist igmesine in the forced swimming test. Each mouse was placed in a glass cylinder (ø 12 cm) filled with water (22–238C). The animal was forced to swim for 15 min on day 1. It was placed again into the water and forced to swim for 6 min on day 2. The duration of immobility during the last 5 min was measured. The mouse was considered as immobile when it stopped struggling and moved only to keep its head above water. Drugs (mg / kg i.p.) were administered 30 min before the session on day 2. Finasteride, the 5a-reductase inhibitor that led to accumulation of endogenous progesterone, was administered at 25 mg / kg twice, 14 and 2 h before the session on day 2. Adrenalectomy / castration (AdX / CX): after pentobarbital anesthesia, adrenal glands were removed and testes were ligatured and cut, through an incision in the scrotum. Animals received an injection of gentamycin 10 mg / kg i.p. and recovered within few hours from surgery. After surgery, drinking tap water was replaced by saccharose 1%, NaCl 0.9% solution. Animals were used for behavioral experiments 6 days after surgery. (A) Dose–response effect of igmesine in control Swiss mice. (B) Antagonism of the igmesine-induced effect by the selective s 1 receptor antagonist BD1047. (C) Crossed pharmacology: antagonism of the igmesine-induced effect by the steroid progesterone. (D) Dose–response effect of igmesine in AdX / CX animals and attenuating effect of finasteride treatment. (E) Blockade of the augmented effect induced by igmesine in AdX / CX mice by BD1047. **P,0.01 versus the Veh-treated group; [[P,0.01 versus the igmesine-treated group (Dunnett’s test). Adapted from Ref. [128].

or imipramine, and elicited antidepressant action faster than fluoxetine or imipramine [123]. The antidepressant effect observed after chronic treatment with s 1 agonists was not accompanied by side effects like decrease in body

weight, unlike classic antidepressants such as desipramine or fluoxetine [125]. St John’s wort (hypericum perforatum), a well-known natural antidepressant, has components with significant affinity for the s 1 receptor [104].

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Hypericum perforatum extract was shown to provide a beneficial effect on behavioral despair in rats through an activation of the s 1 receptor [93]. Even though no clinical study has yet been published, these results suggest that s 1 receptor agonists could be used as novel antidepressants with significant clinical efficacy. The interaction between neuroactive steroids and s 1 receptor, and the resultant crossed pharmacology, has also been shown in the model of behavioral despair. In particular, DHEA and pregnenolone sulfates significantly reduced the immobility time observed in the forced swim test. This effect was blocked by the selective s 1 antagonists NE-100 [105] and BD1047 (Urani et al., submitted). A similar result was observed in the model of conditionedfear–stress where the sulfates of pregnenolone and DHEA attenuated, in a NE-100-sensitive manner, the motor suppression induced by previous electric footshock [88]. In parallel, progesterone blocked the antidepressant-like effect in the forced swim test induced by the s 1 agonist igmesine [128] (see Fig. 3C) or (1)-SKF-10,047 [88]. At doses where neither (1)-SKF-10,047, nor DHEAS where efficient, an additive effect could be observed, since combination of both drugs induced a significant reduction of the stress-induced motor suppression in the conditioned fear stress [88]. This result, in parallel to the clear crossed pharmacology, suggests that these neuroactive steroids and s 1 agonists both act through the same target. Several experiments suggest a common mechanism of action between some neuroactive steroids and s 1 ligands in mood disorders linked to stress. Such a neuroactive steroid / s 1 receptor interaction might lead to a novel therapy which included s 1 ligands and neuroactive steroids. Such as therapeutic approach might be used for treatment-resistant depression. One of the principal interests of such therapy might be the lack of side-effects, contrarily to what is observed with classical antidepressants.

4.2. Endocrine manipulations Stress has been shown to affect levels of several neuroactive steroid. Swim stress induced an increase in allopregnanolone and allotetrahydrodeoxycorticosterone in the cortex of rats [100]. Electric footshock induced an increase in pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone in the brain of adult or aged rat [2–5]. It was thus expected that physiological modulation of neuroactive steroids levels during stress or acute depressive state may affect the efficacy of s 1 receptor agonists in vivo. This question was addressed through selective endocrine manipulations. In AdX / CX animals deprived of circulating steroids, treatment with trilostane, an inhibitor of the 3b-hydroxysteroid dehydrogenase, decreases progesterone levels, whereas treatment with finasteride, a 5a-reductase inhibitor, leads to an accumulation of progesterone in the brain

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[42,43]. The in vivo [ 3 H](1)-SKF-10,047 binding levels to s 1 sites in the mouse forebrain appeared significantly increased in AdX / CX mice and further increased after trilostane-treatment. Conversely, finasteride-treatment led to a significant decrease of binding as compared to AdX / CX animals [97]. Thus, s 1 sites are directly and tonically inhibited by endogenous steroids. Among neuroactive steroids, progesterone appeared to be the most important modulator because of the high affinity of the steroid for these sites, and because of the significant inverse-correlation observed between progesterone levels after treatment and the binding levels. Swim stress induced an increase in the level of progesterone and a decrease in [ 3 H](1)-SKF-10,047 binding to the s 1 receptor in the hippocampus of control animals [127]. These effects were enhanced in AdX / CX mice, but completely blocked following treatment with trilostane. A significant inverse-correlation was observed between progesterone increase and the inhibition of in vivo binding to s 1 sites after stress [127]. These observations confirmed that some neurosteroids modulate the efficacy of s 1 receptor agonists in the response to stress and depression, as was previously observed in learning and memory processes [97]. Furthermore, the reverse correlation between progesterone levels and the binding to s 1 receptors suggests that progesterone could be an endogenous s 1 receptor ligand.

5. Therapeutic potential As described in this review, selective s 1 receptor agonists show potent anti-amnesic and anti-depressant properties. Clinical development for these compounds can be anticipated, particularly taking into account their lack of effects in control animals and the absence of reported side-effects [73]. However, the results and literature detailed above indicates that in control animals with normal levels of neuroactive steroids the efficacy of s 1 receptor agonists may be limited, particularly against depressive states. Conversely, it is expected that these compounds might present a preserved, if not enhanced, efficacy in steroid-depleted subjects [128]. In particular, cognitive deficits or depressive states may constitute a suitable therapeutic indication for selective s 1 receptor agonists [96]. A comparative study of the immunohistochemical labeling of the s 1 receptor between young adult (2 months old) and aged (24 months old) C57Bl / 6 mice revealed a remarkable preservation of labeling [96] (Phan et al., submitted). The structures presenting high or moderate levels of immunolabeling, olfactory bulbs, hippocampus, cortex, hypothalamus, midbrain, etc., showed a similar labeling in aged and young adults animals, as illustrated in Fig. 4A. The importance of decrease in some decrease levels

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Fig. 4. The therapeutic interest of selective s 1 receptor agonists against the aging-related cognitive deficits. (A) Comparison of the s 1 receptor immunohistochemical distribution in the 2- and 24-month-old C57Bl / 6 mouse. Sagittal sections showing the highly preserved distribution of the immunolabeling throughout the whole brain. (B) Comparison of the neurosteroidal levels in the 2- and 24-month-old C57Bl / 6 mouse. Measurements of progesterone, pregnenolone and DHEA in the whole brain showed significant 55–64% diminitions for 24-month-old as compared to 2-month-old animals. CPu, caudate putamen; Crb, cerebellum; Cx, cortex; GL, glomerular layer; GRL, granular layer; H, hippocampus; IC, inferior colliculus; LSO, lateral superior olive; NAc, nucleus accumbens; OB, olfactory bulb; PCx, piriform cortex; R, red nucleus; SN, substancia nigra; So, supraoptic nucleus; Th, thalamus. **P,0.01, ***P,0.001 versus 2-month-old group (Welch’s test). Adapted from Ref. [96].

during aging, and their effects on neuronal function and behavior is presently being investigated. Some steroid levels decrease markedly during aging [91]. For example, about 60% decreases were observed in the levels of some free neuroactive steroids measured in the brain of aged C57Bl / 6 mice as compared to young adults (Fig. 4B). The substantial age-related decrease of plasma or central levels of these steroids that occurs concurrently with involution of the zona reticularis indicates that these steroids might play a role in the incidence of age-related cognitive deficits. Indeed, correlation between hippocampal pregnenolone sulfate levels and the learning ability of aged rats and memory performances in a water-maze and a two-trial recognition task was observed in aged rats. Animals with better performances had greater levels of pregnenolone sulfate [107,131]. Furthermore, pregnenolone sulfate administered into the hippocampus temporarily corrected the memory deficits of aged rats when given immediately after acquisition trial [131]. In parallel, a single systemic injection of DHEA sulfate immediately after training improved the impairment of memory in middle-aged and old mice submitted to a footshock active avoidance test, bringing it back to levels

observed in young mice [21]. Furthermore, this neuroactive steroid plays a physiological role in preserving and / or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Such observations suggests that the neuromodulatory action of pregnenolone sulfate and / or DHEA sulfate reinforce neurotransmitter systems. Furthermore, since their levels decrease in blood with age, neuroactive steroids could be important endogenous substrates for effective memory capacities [91,108]. A therapeutic interest in selective s 1 receptor agonists is thus suggested from concomitant observations in aged animals (Fig. 4): (i) preservation of s 1 receptor-immunolabeling [96], and (ii) significant decrease of brain levels of progesterone. A preliminary study was recently performed in order to determine whether a selective s 1 receptor agonist (PRE-084) could ameliorate the spatial learning in aged animals, using a water-maze procedure [96]. Aged C57Bl / 6 mice, 2 or 24 months old, were trained to locate a visible platform and then an invisible platform. Finally, a transfer test under saline or PRE-084 treatment was performed. Aged, but not young adult animals showed learning deficits unrelated to visual im-

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pairment. PRE-084 treatment allowed aged mice to learn the new platform location, in terms of decreased latencies to the platform during training and increased presence in the platform quadrant during retention. These experiments demonstrate the efficacy of a selective s 1 agonist to reverse age-related memory deficits in mice. Further studies are necessary to confirm the therapeutic value of selective s 1 receptor agonists against age-related cognitive deficits. A crucial question remains to determine if such compounds could be used as an efficient hormone replacement therapy during aging, i.e., their efficacy following long-term chronic treatment on cognitive deficits and on neuroactive steroid levels.

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