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

Review

The interaction between neuroactive steroids and the s receptor1qfunction: behavioral consequences and therapeutic opportunities

a , a,b a a* ˆTangui Maurice , Alexandre Urani , Van-Ly Phan , Pascal RomieuaBehavioural Neuropharmacology Group, INSERM U. 336, Institut de Biologie, 4 Bvd Henri IV, 34060 Montpellier, France

bPfizer 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 asmodulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA ,A

NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the s protein. This receptor has been1

cloned in several species, and highly selective synthetic ligands are available. At the cellular level, s agonists modulate intracellular1

calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergicsystems. At the behavioral level, the s receptor is involved in learning and memory processes, the response to stress, depression,1

neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as s agonists, while1

progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recentresults on memory and depression. The therapeutical interest of selective s receptor agonists in alleviating aging-related cognitive1

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 (s ) receptor; Learning and memory; Depression; Aging; Aging-related cognitive deficits1 1

Contents

1. Introduction ............................................................................................................................................................................................ 1172. The s receptor is a target for non-genomic effects of neuroactive steroids .................................................................................................. 1171

2.1. The s receptor............................................................................................................................................................................... 1171

2.2. Distribution of the s receptor ......................................................................................................................................................... 1191

2.3. The s receptor as an intracellular calcium mobilization modulatory protein ....................................................................................... 1191

2.4. Non-genomic effects of neuroactive steroids ..................................................................................................................................... 1222.5. The s receptor /neuroactive steroids interaction ............................................................................................................................... 1221

3. Differential involvement of the s receptor in the mnesic effects of neuroactive steroids .............................................................................. 1231

3.1. Anti-amnesic effects of s receptor agonists ..................................................................................................................................... 1231

3.2. Neuroactive steroids /s receptor interaction in learning and memory ................................................................................................. 1231

3.3. Results using in vivo antisense strategy............................................................................................................................................. 1244. s Receptor /neuroactive steroids interaction in depression ......................................................................................................................... 1251

4.1. s Receptor agonists and neuroactive steroids show antidepressant potentials...................................................................................... 1251

4.2. Endocrine manipulations.................................................................................................................................................................. 127

qThe 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: maurice@medecine.univ-montp1.fr (T. Maurice).

0165-0173/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0165-0173( 01 )00112-6

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 117

5. Therapeutic potential ............................................................................................................................................................................... 127References................................................................................................................................................................................................... 129

prototypic ligand N-allylnormetazocine ((6)-SKF-10,047)1. Introductionin the chronic spinal dog. The opiate syndromes wereclassified as m for the effects induced by morphine, s forThe concept of neurosteroids was introduced in thethe ones induced by (6)-SKF-10,047 and k forearly 1980s by Baulieu and co-workers to designate theketocyclazocine [56]. The observation that certain be-pools of steroids, including pregnenolone, dehydroepian-haviors elicited by N-allylnormetazocine are resistant todrosterone (DHEA), their sulfate esters, progesterone,blockade by classical opiate receptor antagonists such asallopregnanolone (3a-hydroxy-5a-pregnan-20-one), whosenaloxone or naltrexone [132] led to a complete distinctionlevels were higher in the brain than in plasma, andbetween s non-opiate binding sites and the classical m-, k-,unrelated to peripheral sources. Fifteen days after remov-and d-opiate receptors [102]. The s sites were thening the sources of circulating steroids, by adrenalectomyconfounded with the high affinity phencyclidine (PCP)and gonadectomy (AdX/CX) in rats, no difference in thebinding sites, located inside the ion channel associatedbrain levels of these steroids could be measured aswith the NMDA receptors, because of the shared affinitiescompared to non-operated animals [15,16]. Evidence hasof several compounds, including PCP and N-allylnor-now been provided for de novo synthesis of neurosteroidsmetazocine, for both s and PCP sites [102]. Any confusionin cells of the nervous system, mainly by oligodendrocytesbetween these receptors was cleared up by the availability[35,42,43]. These neurosteroids, as well as circulatingof more selective drugs, such as dizocilpine or N-[1-(2-steroids crossing the blood–brain barrier and reaching thethienyl)cyclohexyl]piperidine (TCP) for the PCP sites;brain, can influence neuronal functions by classical gen-haloperidol, (1)-3-(3-hydroxyphenyl)-N-(1-propyl)-piper-omic effects — by binding to intracellular receptorsidine ((1)-3-PPP), igmesine, (1)-cis-N-methyl-N-[2-(3,4-activating transcription factors and regulating gene expres-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl) cyclohexylaminesion — or through non-genomic, rapid effects — by(BD737), among others, for s sites. It is now wellbinding or indirectly modulating the activity of severalestablished that the s sites represent unique binding sitesneurotransmitter receptors and ion channels [80,112]. Ain the brain and peripheral organs, distinct from any othermore recent concept is that, among these targets, someknown sites. The pharmacological identification of s sitesneuroactive steroids interact with an atypical neuro-was characterized by their ability to bind several chemical-modulatory receptor, namely the s receptor [8,73,85,119].1ly unrelated drugs with high affinity, including psycho-Selective agonists of this recently cloned receptor havetomimetic benzomorphans, PCP and derivatives, cocainepotent anti-amnesic, anti-depressant and anti-stress effects,and derivatives, amphetamine, certain neuroleptics, manywhile selective antagonists have antipsychotic and anti-new ‘atypical’ antipsychotic agents, anticonvulsants, cyto-addictive property [73]. The importance of the neuroactivechrome P450 inhibitors, monoamine oxidase inhibitors,steroids /s receptor interaction in neuropsychopharmacol-1histaminergic receptor ligands, peptides from the neuro-ogy is receiving increasing attention. The present reviewpeptide Y (NPY) and calcitonin gene-related peptidewill present new data concerning the s receptor, par-1(CGRP) families, as well as some steroids [68,73].ticularly focusing on its cellular role as a sensor /modulator

The pharmacological identification and localization of sfor the mobilization of intracellular calcium pools, and onbinding sites was achieved through the use of variousits localization achieved using immunohistochemical tech-

3 3radioligands, such as [ H](1)-SKF-10,047, [ H](1)-3-niques. The physiopathological consequences of neuroac-3 3tive steroids /s receptor interaction will be detailed, PPP, [ H]haloperidol, [ H]1,3-di-O-tolylguanidine1

3 3especially animal models of amnesia and depression, as ([ H]DTG), [ H](1)-pentazocine [14,28,51,81,120]. Phar-well as therapeutic perspectives offered by use of selective macological studies rapidly led to the distinction of twos receptor agonists against age-related cognitive deficits. classes of s sites, termed s and s [101]. The s sites1 1 2 1

have high affinity and stereoselectivity for the (1)-isomersof SKF-10,047, pentazocine and cyclazocine, whereas s2

sites have lower affinity and show opposite stereoselectivi-2. The s receptor is a target for non-genomic effects1

ty [34]. DTG, (1)-3-PPP and haloperidol are non-dis-of neuroactive steroidscriminating ligands with high affinity for the two subtypes.In addition, s sites are allosterically modulated by2.1. The s receptor 11

phenytoin [87], are sensitive to pertussis toxin, themodulatory effects of guanosine triphosphate [37,39], andThe s binding site was initially described as a subtypedown-regulated following a subchronic treatment withof opiate receptors by Martin and co-workers [56], where ithaloperidol [38,59]. It has also been shown that severalmediates the unique psychotomimetic effects of the

118 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

drugs, such as haloperidol, reduced haloperidol, a-(4- promoter region sequence analyzed for transcription factor-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- binding sites in different species. Hanner and co-workerspiperazinebutanol (BMY-14802), rimcazole, or N,N-di- [29] described the initial cloning of the receptor frompropyl-2-(4-methoxy-3-(2-phenylethox- guinea-pig liver. It has since been cloned from a humany)phenyl)ethylamine (NE-100) act as antagonists in sever- placental cell line, T leukemia Ichikawa cell line andal physiological and behavioral tests relevant to s phar- human brain [40,45,99], mouse kidney [115], mouse brain1

macology (see Table 1) [49,90,121,122]. [92] and rat brain [114]. The amino acid sequences of theThe s receptor has been completely sequenced and its different purified receptors are highly homologous. The1

Table 1Pharmacological profiles and behavioural activities of s receptor-related drugs cited in the review1

Drugs s activity Other activity Behavioural activity Refs.1

s Ligands1

(1)-SKF-10,047 s agonist Anti-amnesic, anti-depressant [44,64,65,88,89]1

(1)-pentazocine s agonist Anti-amnesic, anti-depressant [66,77]1

Dextrometorphan s agonist Anti-depressant [44,140]1

SA4503 s agonist Anti-amnesic, anti-depressant [63,72,74,77,113]1

PRE-084 s agonist Anti-amnesic, anti-depressant [72,76,77,96]1

OPC-14523 s agonist 5-HT agonist Anti-depressant [123]1 1B

Carbetapentane s agonist [83]1

(1)-3-PPP s agonist s agonist Anti-amnesic [17,64]1 2

Igmesine s agonist Anti-amnesic, anti-depressant [17,48,62,125]1

BD737 s agonist [73]1

Cocaine s agonist [73]1

DTG s agonist s agonist Anti-amnesic [64,66]1 2

Haloperidol s antagonist s agonist Antagonist [8,49,64,77,106]1 2

Reduced haloperidol s antagonist [49]1

Rimcazole s antagonist Inactive [17]1

BMY-14,802 s antagonist Antagonist [66,67,77,121,122]1

NE-100 s antagonist Antagonist [88,90,105,126]1

BD1047 s antagonist s agonist [85]1 2

BD1063 s antagonist s agonist [85]1 2

PeptidesNPY s agonist Anti-amnesic [68,73]1

CGRP s agonist Anti-amnesic [68,73]1

SteroidsPregnenolone s agonist NMDA positive modulator Anti-amnesic [8,77,119]1

Pregnenolone sulfate s agonist NMDA positive modulator Anti-amnesic, anti-depressant [8,10,12,20,27,36,75,77,85]1

GABA negative modulator [88,105,106,108,110,126,127]A

DHEA s agonist Anti-amnesic [8,77]1

DHEA sulfate s agonist GABA negative modulator Anti-amnesic, anti-depressant [8,21,22,75,77,85,88,105,1 A

106,126,127]Progesterone s antagonist NMDA negative Antagonist [8,74,75,85,105]1

GABA positive modulator [119]A

Dihydrotestosterone Low s affinity [119]1

Androterone Low s affinity [119]1

Testosterone Low s affinity [119]1

5a-Androstane-3,17-dione Low s affinity [119]1

Deoxycorticosterone Low s affinity [119]1

AntidepressantsaFluoxetine s agonist 5-HT transporter inhibitor Anti-depressant [123,125,129]1

Imipramine Low s affinity 5-HT transporter inhibitor Anti-depressant [123,125]1

Hypericum perforatum s agonist 5-HT transporter inhibitor Anti-depressant [93,104]1

Drugs devoid of s activity1

TCP NMDA antagonist Amnesic [102]Dizocilpine NMDA antagonist Amnesic [66,67,74,76]Desipramine 5-HT transporter inhibitor Anti-depressant [125]

SteroidsEpipregnanolone NMDA negative modulator Amnesic [94,95]Allopregnanolone GABA positive modulator Amnesic [110]A

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

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 119

mouse s receptor shared 87% identity and 91% similarity bulb, various hypothalamic nuclei, the dentate gyrus of the1

with the previously cloned guinea-pig sequence, 90% hippocampus, motor nuclei of the hindbrain and the dorsalidentity and 93% similarity with the human s receptor, horn of the spinal cord. Moderate levels of immuno-1

and 92% identity and 96% similarity with the rat s staining are associated with the pyramidal cells of the1

receptor. However, s receptors share no homology with hippocampal layers CA –CA , the superficial layers II–IV1 1 3

known mammalian proteins, indicating that the s receptor of the cerebral cortex, the lateral septum, the nucleus1

is a distinct entity from any other known receptors. Results centralis of the amygdala, and the central gray. Only faintalso demonstrate that an identical s receptor is expressed immunostaining was associated with neurons located in the1

in peripheral tissues and brain. caudate putamen and the cerebellum. The immunolocaliza-The s site remains unidentified. It is still unclear tion of the s receptor was also established in the mouse2 1

whether it represents a single site or a family of related brain [96] (Phan et al., submitted). Only mild differencesproteins. It was first characterized in pheochromocytoma appeared between results in the rat. In the hippocampus,PC12 cells [33]. It was defined as presenting high affinity the CA –CA pyramidal layers were as intensively im-1 3

and stereoselectivity for (2)-benzomorphans, with an munostained as the dentate gyrus. Some large but scatteredapparent molecular weight of 18–21 kDa [33,34]. Some moderately immunostained neurons were observed in theselective and high affinity s site-ligands are now avail- caudate putamen as well as in the septum, the amygdala2

able. Several functions have been proposed, including and the nucleus accumbens. Moderate immunostaining wasregulation of motor function by induction of dystonia after also observed in the granular layer of the cerebellum.in situ administration in the red nucleus [60,61], regulation Electron microscopic studies (see Fig. 2) indicated thatof ileal function [47], or blockade of tonic potassium s receptor-immunostaining was mostly associated with1

channels [7,41,138]. Agonists at s sites also induced neuronal perikarya and dendrites, where it was either2

changes in cell morphology and apoptosis in various cell dispersed throughout the cytoplasm or associated withtypes by producing transient but sustained increases in membranes, including both the limiting plasma membrane

21[Ca ] from different intracellular stores. The s agonists and the membrane organelles such as mitochondria, somei 2

induced apoptosis in drug-resistant cancer cells, enhanced cisternae of the endoplasmic reticulum, and vesicles pres-the potency of DNA damaging agents, and down-regulated ent in the vicinity of the Golgi apparatus or dispersedexpression of p-glycoprotein mRNA. Thus, s site agon- within the dendritic profiles. At the level of synaptic2

ists may be useful in the treatment of drug-resistant cancer contacts, intense immunostaining was associated with[9]. postsynaptic structures, including the postsynaptic thicken-

ing, and some polymorphous vesicles. In rats, but not in2.2. Distribution of the s receptor mice, the presynaptic axons were devoid of immuno-1

staining [1,96] (Phan et al., submitted).The s receptor-distribution in the brain has been Immunolabeling studies showed that the distribution of1

extensively studied using radiographic procedures such as the s protein was in accordance with what could be1

in vitro or in vivo binding, autoradiography, or positron expected from the previously described autoradiographicemission tomography. In rodents, high levels of s sites studies. Moreover, it allowed visualization of the protein at1

were detected in the hippocampal pyramidal cell layers, the cellular and sub-cellular levels, a technique that mayhypothalamus, pontine and cranial nerve nuclei, and give valuable information for future studies, particularlycerebellum [14,26,28,51,81,118]. However, the different concerning the putative cellular translocations followingradioligands used in these studies showed different affinity receptor activation [31,86].and selectivity for the s sites.1

Thanks to the cloning and sequencing of the s receptor,1

2.3. The s receptor as an intracellular calciumpolyclonal antibodies are now available to examine the 1

mobilization modulatory proteinimmunohistochemical distribution of the s protein. Using1

an antibody directed against a 20-amino acid peptideRecent evidence indicates that s receptors directlycorresponding to fragment 143–162 of the cloned rat s 11

21protein, we recently described s immunostaining through- modulate intracellular calcium ([Ca ] ) mobilization1 i

out the rostro-caudal regions of the rat central nervous through a complex mechanism. Initially, Ela and co-work-system [1] (see Fig. 1). The s receptor immunostaining ers [18] showed that exposure of cardiomyocytes in culture1

appeared to be associated with ependymocytes bordering to s receptor agonists, such as (1)-3-PPP, haloperidol,1

ventricular areas, and mainly with neurons located within and (1)-pentazocine, exerted specific changes in contrac-21the parenchyma. This labeling is observed in the whole tility, [Ca ] transients and beating rates. The time-coursei

21central nervous system, but high to moderate immuno- of changes in contractility and [Ca ] transients showed ai

staining level is always associated with neurons located complex but reproducible pattern, with an initial decreasewithin specific structures. The highest level of immuno- followed by an important increase, and a final decrease.

21staining is observed in the granular layer of the olfactory The increase in [Ca ] and its following decrease ap-i

120 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 121

Fig. 2. Subcellular neuronal localization of the s receptor in the C57Bl /6 mouse hypothalamus. Vibratome sections were treated for the peroxidase1

immunostaining of s receptor in absence of Triton X-100. Immunostained sections were rinsed in 0.1 M cacodylate buffer, pH 7.3, postfixed in 1% OsO ,1 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. Withinthe cell body of an hypothalamic neuron, electron dense precipitates are associated with membranes including: (A) the limiting plasma membrane; (B) themembrane thickening facing synaptic contacts (arrows); (C) the membrane of mitochondria; (D) the membrane of vesicles or of elongated cisternae of theendoplasmic reticulum; and (E) the nuclear limiting membrane. Note that the axonal profiles (Ax) that form synaptic contacts with labeled dendrites aredevoid of immunostaining. Ax, axonal profile; De, dendritic profile; er, endoplasmic reticulum profile; mi, mitochondria; nu, nucleus; ve, presynapticvesicles. Adapted from Ref. [96].

Fig. 1. Immunohistochemical labeling of the s receptor in coronal sections of the rat brain. Rats were perfused with 4% paraformaldehyde and 0.5%1

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 2–4days. It was then cut either with a vibratome into 40–50-mm thick sections. Sections were successively incubated with the purified primary s receptor1

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 dilutedin 0.05 M Tris buffer, pH 7.3, in the presence of 0.2% H O . Immunostained sections were mounted in permount and observed under a light microscope.2 2

(A) Rostro-caudal distribution: filled and open circles represent cell bodies exhibiting intense or moderate immunostaining, respectively. (B) Sagittalsection of the olfactory bulb showing intense labeling throughout the granular and glomerular layers. (C) Regions of the anterior olfactory nucleus aredevoid 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 isassociated with neurons located in the dentate gyrus, and more moderately with those located in the CA –CA layers. Higher magnification of the dentate1 3

gyrus (H) and CA area. Moderate immunostaining is associated with neurons located in the superficial layers of the fronto-parietal cortex (J). Intense3

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, granularlayer of the olfactory bulb; IG, induseum griseum; IO, inferior olive; LC, locus coeruleus; LV, lateral ventricle; M, mammillary complex; O, olivarycomplex; OC, optic chiasma; PCx, piriform cortex; Pe, periventricular hypothalamic nucleus; Pr5, trigeminal nucleus; RN, raphe nucleus; Rt, reticularthalamic 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].

122 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

21peared to be mediated by corresponding changes in Ca [6,13,23,50,53,73,82,112]. We will focus on recent pro-influx [18]. These authors suggested that the time course of gress concerning the behavioral relevance — in memorythe s agonist effect involved either a primary action on processes and response to a paradigm of depression — and1

21 21Ca channels, or an action of Ca fluxes via modulation therapeutical prospects of the neuroactive steroids /s11of K channels. Furthermore, several antipsychotic drugs, receptor interaction.

including s ligands, were reported to block voltage-1

dependent calcium channels [19,25,103]. More recently,21 2.5. The s receptor /neuroactive steroids interactionthe role of the s receptor in regulating Ca in NG-108 11

cells has been extensively studied [30]. Initially, the s1

The first evidence for an interaction between steroidsagonists (1)-pentazocine and PRE-084 were found to21 and s receptors was provided by Su and co-workers [119]potentiate the bradykinin-induced increase in [Ca ] in a 1i

from in vitro binding experiments in the guinea-pig brainbell-shaped manner. Secondly, after depletion of endo-21 and spleen. Among the different steroids tested, progester-plasmic reticulum Ca stores, the depolarization-induced

21 one was the most potent inhibitor of radioligand binding toincrease in [Ca ] was potentiated by PRE-084, buti

the s site, with K values in the 300 nM range [119].inhibited by (1)-pentazocine. Both effects were blocked 1 i

Progesterone was also a potent inhibitor of s site-bindingby an antisense oligodeoxynucleotide targeting the s 11

in rat brain membrane preparations, and in 3-[(3-receptor [30]. More recently, the same authors [31] sug-cholamidopropyl)dimethylamino]-1-propane sulfonategested that the s receptor could regulate the coupling of1

(CHAPS)-solubilized extracts, with a K in the 200 nMthe inositol 1,4,5-trisphosphate (InsP ) receptor with the i3

range [79]. These observations, together with the selectivi-cytoskeleton via an ankyrin B protein. They observed that3ty of [ H]progesterone binding to s receptors [79](1)-pentazocine dissociated ankyrin B from InsP receptor 13

suggested that the link between progesterone and sin NG-108 cells, and this dissociation correlated with the 121 receptors is direct and not due to an interaction withefficacy of each ligand in potentiating the Ca efflux

membrane lipids. Testosterone, deoxycorticosterone, orinduced by bradykinin.pregnenolone sulfate also inhibited the binding to s sites,These results, consistent with subcellular localization of 1

with K values in the low micromolar range [79,119].the s receptor observed in electronic microscopy studies i1

These observations were extended, using not only[1,96], suggested that the s receptor may play a particular13 321 [ H](1)-SKF-10,047, but also [ H]dextromethorphan,role as a sensor /modulator for neuronal intracellular Ca3 3mobilization. Such an effect, occurring in post-synaptic [ H](1)-3-PPP, or [ H]haloperidol as radiotracers for s1

neurons downstream to neurotransmission events, may sites in the rat brain, splenocytes, plasma membranes andexplain — or strengthen the validity of — the apparent liver microsomes [49,75,139]. Progesterone appeared to bewide-range and non-selective neuromodulatory effects the most potent inhibitor. Dihydrotestosterone, andros-induced by selective s receptor ligands. terone, testosterone, 5a-androstane-3,17-dione and deoxy-1

corticosterone gave K values in the micromolar rangei

2.4. Non-genomic effects of neuroactive steroids [119]. Pregnenolone, DHEA or their sulfate esters ap-peared less efficient. Additionally, numerous s ligands,1

Since the initial report of the anesthetic properties of including haloperidol, carbetapentane, DTG, (1)-3-PPP, or3progesterone [116], the biological effects of steroids in the rimcazole, potently inhibited [ H]progesterone binding in

central and peripheral nervous systems have been exten- rat liver microsomal membrane preparations and in porcinesively studied. Neuroactive steroids include both steroids liver-solubilized fractions [83,139]. Systemic administra-from the periphery which are transported through the tion of steroids dose-dependently inhibited the in vivo

3blood–brain barrier and act within the brain, and locally binding of [ H](1)-SKF-10,047 to s sites [75]. Proges-1

synthesized neurosteroids. Their physiological actions, terone was also found to be the most potent inhibitor, withdemonstrated from embryogenic through adult life, involve a significant inhibition at 10 mg/kg. Pregnenolone sulfateboth some genomic actions mediated by nuclear steroid and DHEA sulfate gave significant effects at 40 mg/kg,receptors and non-genomic neuromodulatory actions af- which were unrelated to their in vitro affinity. In addition,

3fecting several neurotransmitters and second messenger binding levels of [ H](1)-SKF-10,047 were significantlysystems. Neuroactive steroids include the neurosteroids reduced in pregnant female mice as compared to non-pregnenolone, dehydroepiandrosterone, their sulfate esters, pregnant ones or males [75]. It was also observed thatprogesterone, allopregnanolone, plus steroids not synthes- modulation of endogenous steroid levels affected in vivo

3ized centrally, such as testosterone, 17b-estradiol, corticos- [ H](1)-SKF-10,047 binding-parameters [97]. Suppres-terone, and their metabolites. Evidence is now accumulat- sion of peripheral steroids by adrenalectomy/castration

3ing to show that they are allosteric modulators of GABA , enhanced [ H](1)-SKF-10,047 binding. Finasteride, anA

NMDA, cholinergic and s receptors. The non-genomic inhibitor of 5a-reductase that catalyzes the conversion of1

actions of neuroactive steroids and their physiopathological progesterone to 5a-pregnane-3,20-dione, was used toconsequences have been reviewed augment progesterone levels. Treatment of surrenalectom-

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 123

ized /castrated mice with finasteride led to a significant that they could improve cholinergic-dependent memory3decrease of in vivo [ H](1)-SKF-10,047 binding-levels processes either during the acquisition, consolidation, or

[97]. Thus, neuroactive steroids directly interact with s the retention phase [64]. Another very selective s re-1 1

sites, progesterone appearing to be the most efficient ceptor agonist, SA4503, reversed scopolamine-inducedinhibitor. Its K value might be expected to be reached in amnesia and attenuated the learning impairments in ratsi

local physiological concentrations, suggesting a functional with cortical cholinergic dysfunction, such as ibotenicinteraction with s receptors in the brain. Pregnenolone acid-induced lesions of the basal forebrain, in the passive1

and DHEA sulfate, which are inefficient in vitro, affected avoidance test, and in the Morris water-maze test [63,113].in vivo binding, suggesting that under physiological con- Similarly, DTG or PRE-084 reduced learning impairmentsditions, these steroids could also interact with s receptors. induced by scopolamine or mecamylamine in mice [66,76].1

The physiological tests used to describe s pharma- Scopolamine-induced amnesia was not affected, but1

cology also allow demonstration of neuroactive steroid /s mecamylamine-induced amnesia was significantly at-1

receptor interactions. Monnet and co-workers [85] reported tenuated, indicating that s receptor ligands may also13that the NMDA-evoked [ H]norepinephrine release from potently modulate nicotinic cholinergic receptor-mediated

preloaded rat hippocampal slices was potentiated by behaviors [66,76]. This result was in accordance with theDHEA sulfate and inhibited by pregnenolone sulfate. neuromodulatory effect exerted by s receptor ligands on1

These effects were blocked by the s antagonists halo- the nicotinic receptor.1

peridol and BD1063, or by progesterone. Bergeron and In addition, s receptor ligands show anti-amnesic1

co-workers [8] reported that the excitatory electrophysio- effects against impairments induced after blockade of thelogical response of rat CA hippocampal pyramidal neu- NMDA receptor. High affinity s receptor ligands, such as3 1

rons to microiontophoretic applications of NMDA could be DTG, (1)-SKF10,047, (1)-pentazocine, PRE-084, andpotentiated by DHEA. This effect was also sensitive to the SA4503 attenuated learning impairments induced in mices antagonists haloperidol and NE-100, or to progesterone. by dizocilpine in various behavioral tests [66,74,76,141].1

The above results were the first demonstration of the The involvement of hippocampal NMDA receptors wasphysiological importance of the s receptor as a target for clearly demonstrated by showing that intra-hippocampal1

neuroactive steroids. In addition, both in vitro and in vivo administration of (1)-SKF-10,047, ineffective by itself,effects of DHEA or pregnenolone were blocked by pertus- prevented the dizocilpine-induced increase in the numbersis toxin, indicating that the s receptor, although unre- of working errors in a three-panel runway task in rats [89].1

lated to classical seven transmembrane domains receptors,may be in some way coupled to G proteins.i / o

3.2. Neuroactive steroids /s receptor interaction in1

learning and memory

3. Differential involvement of the s receptor in the Neuroactive steroids have been shown to affect memory1

mnesic effects of neuroactive steroids performances by themselves and to alleviate several phar-macological models of amnesia. Pregnenolone, DHEA and

3.1. Anti-amnesic effects of s receptor agonists their sulfate esters, enhanced memory retention in an active1

avoidance learning task in mice after central administrationThe s receptor agonists have not yet been reported to [20]. Pregnenolone sulfate was the most potent of these1

affect memory capacities by themselves, but have been compounds. Its long-duration effect, still observable 1demonstrated to have beneficial properties in several week after administration, suggested to these authors thatmodels of amnesia (Table 1) (for reviews, see Refs. pregnenolone was serving as a precursor of other steroids,[68,73]). Earley and co-workers [17] initially demonstrated which ensured a near-optimal modulation of transcriptionthat several s receptor ligands reversed, in a dose-depen- of immediate-early genes required for the facilitation of the1

dent manner, amnesia induced by scopolamine in the rat. plastic changes in memory processes [20]. PregnenoloneDTG, (1)-3-PPP and igmesine prevented scopolamine- sulfate also enhanced memory formation when adminis-induced amnesia in the step-through type passive avoid- tered after the first session of training in a spontaneousance task, whereas (1)-SKF-10,047 and rimcazole were alternation task in rats [78], or in an appetitive reinforcedinactive. The s receptor agonists, (1)-SKF-10,047, (6)- Go–No Go visual discrimination task in mice [84]. These1

pentazocine, DTG, (1)-3-PPP, also prevented amnesia results suggest that pregnenolone sulfate might have ainduced by cholinergic dysfunction, using scopolamine or specific effect on memory consolidation processes, ratherthe serotonin depleter p-chloroamphetamine, in a step- than acquisition. DHEA, and its sulfate ester, improveddown type passive avoidance task in mice [64,65]. Interest- age-related deficits in a footshock active avoidance trainingingly, effects on p-chloroamphetamine-induced amnesia in aged mice. DHEA administered centrally prevented thewere observed when s receptor agonists were adminis- amnesia induced by administration of the vehicle di-1

tered before training as well as before retention, indicating methylsulfoxide (DMSO) alone. DHEA sulfate, adminis-

124 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

tered systemically or centrally immediately after training, that had been treated centrally with b -amyloid related25–35

or given in the drinking water for 2 weeks, facilitated peptide [77]. The b -amyloid peptide-induced amnesia25–35

memory retention in a step-down passive avoidance test in is sensitive to cholinomimetics or NMDA/glycinemice, but did not improve acquisition [21,22]. The benefi- modulatory site agonists [69,70]. The s receptor agonists,1

cial effects of neuroactive steroids were also tested in (1)-pentazocine, PRE-084 or SA4503, attenuated, in aexperimental models of amnesia. Pregnenolone sulfate dose-dependent and bell-shaped manner, the b -25–35

counteracted deficits induced by different NMDA receptor amyloid peptide-induced deficits in the spontaneous al-antagonists. Administration of this steroid dose-dependen- ternation task and step-down passive avoidance tests [77].tly reduced the learning deficit and motor impairment All effects were blocked by BMY-14,802 and haloperidol.induced by pretraining-administration of the competitive In parallel, DHEA, pregnenolone, and their sulfate esters,antagonist 3-((6)-2-carboxypiperazin-4-yl)-propyl-1-phos- also dose-dependently reduced b -amyloid peptide-in-25–35

phonic acid (CPP), in a step-through passive avoidance duced deficits. Progesterone behaved as an antagonist,task in the rat [108]. Limited effect of pregnenolone sulfate blocking the beneficial effects of both the active steroidsalone on passive avoidance response were observed, and the s receptor agonists. Conversely, haloperidol1

suggesting that the potent reduction of CPP-induced blocked the effects induced by the active steroids, showingimpairments by this neuroactive steroid is not due to a clear crossed pharmacology between s receptor ligands1

intrinsic memory enhancement properties, but rather to its and steroids on memory processes [77].positive pharmacological action on NMDA receptors [57]. These observations strongly suggest that part of theThe steroid also blocked the impairments induced by anti-amnesic properties of neuroactive steroids on NMDA-D-AP5 in an active avoidance test in mice [58]. In and acetylcholine-dependent learning and memory pro-addition, administration of pregnenolone sulfate in rats cesses implicates, beside direct effects on these neuro-prevented the cognition deficits induced by dizocilpine, a transmitter receptors and their interaction with thenon-competitive NMDA receptor antagonist [110]. Pre- GABAergic systems, an interaction with s systems.1

gnenolone sulfate infusion in adrenalectomized/castrated However, from these studies, no specificity of actions wererats prevented the learning deficits induced by dizocilpine observed between pregnenolone or DHEA, both steroids[12]. Interestingly, blockade of 5a-reductase activity led to acting as potent anti-amnesic agents.the disappearance of the pregnenolone sulfate effect,leading the authors to suggest that an increase in allopreg- 3.3. Results using in vivo antisense strategynanolone could mediate the pregnenolone sulfate effect.

The interaction between neuroactive steroids and s Following cloning of the protein, the implication of the1

receptors was shown in learning and memory processes, s receptor in learning and memory processes could be1

initially using crossed pharmacology studies with selective firmly established using an in vivo antisense strategy [72]antagonists. The memory enhancing effect of DHEA (Maurice et al., submitted). A phosphorothioate-modifiedsulfate against dizocilpine-induced learning impairments antisense oligodeoxynucleotide, targeting s receptor1

could be blocked by preadministration of the s receptor DNA, was administered in mice intracerebroventricularly1

antagonist BMY-14,802 [67]. The anti-amnesic effects of for 3 days. This treatment led to a 58–60% reduction ofSA4503 against learning impairments induced by diz- the number of s sites in the ipsilateral hippocampus, and1

vocilpine or N -nitro-L-arginine methyl ester (L-NAME), to a 33–38% reduction in the cortex, as assessed usingthe nitric oxide synthase inhibitor, could be blocked by Scatchard analyses of in vitro binding experiments [72]progesterone, in a similar manner as that of haloperidol (Maurice et al., submitted). The anti-amnesic effects of[74]. The interaction between s receptor ligands and PRE-084 or SA4503, observed against the learning impair-1

neuroactive steroids appears to also be of critical relevance ments induced by dizocilpine or scopolamine, wereto cholinergic-associated memory mechanisms [126]. In- blocked after administration of s antisense oligodeoxy-1

deed, the beneficial effects of DHEA sulfate and pre- nucleotide, but not after a saline- or a control s mismatch1

gnenolone sulfate against scopolamine-induced learning oligodeoxynucleotide-treatment. These observationsimpairments in mice could be blocked by NE-100. Recent- showed that: (i) the s receptor is not obligatory for1

ly, the pro-mnesic effects of pregnenolone and DHEA optimal learning capacities in control animals; (ii) thesulfates were directly evaluated in a modified passive receptor is neither necessary for NMDA-mediated learningavoidance task in mice [106]. Both steroids facilitated processes in control conditions, nor for the establishmentretention when given either pre- or post-training, but not of the deficits induced by dizocilpine; (iii) the cloned s1

before the retention test. These effects could be antagon- receptor is likely to represent the subtype of receptorized by haloperidol [106]. The anti-amnesic potencies of mediating the anti-amnesic effects of s agonist, providing1

s receptor agonists and neuroactive steroids were also a molecular basis for the involvement of the s receptor in1 1

evaluated in a basic model of Alzheimer’s disease-type memory processes [72].amnesia, where learning deficits were produced in mice Surprisingly, the in vivo antisense strategy revealed

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 125

some discrepancies for the anti-amnesic effects induced by 4. s Receptor /neuroactive steroids interaction in1

neuroactive steroids (Maurice et al., submitted). Antisense depressionoligodeoxynucleotide treatment directed against the s1

receptor led to a complete blockade of the anti-amnesic 4.1. s Receptor agonists and neuroactive steroids show1

effects mediated by DHEA sulfate, confirming that the antidepressant potentialssteroid effects involve primarily an interaction with s1

receptors. Conversely, pregnenolone sulfate still induced a Neuroactive steroids and s ligands have independentlypotent anti-amnesic effect in s receptor antisense-treated been suggested to play an important role in depression.1

animals, data suggested that it interacted more directly and Indeed, both modulate noradrenergic and glutamatergicefficiently with GABA receptors and/or NMDA recep- neurotransmissions which play important roles in be-A

tors, to mediate its behavioral effects. Indeed, pre- havioral despair [11,124]. Consequently, s receptor agon-1

gnenolone is known to effectively positively modulate the ists [44,48,62,88,123,125,128] and some neuroactive ster-activation of NMDA receptor complexes. In particular, this oids [98,105,128] show efficacious antidepressant-likesteroid-augmented NMDA receptor-mediated increase in effects in several animal models (Table 1).

21intracellular Ca in hippocampal neuronal cultures Several clinical studies suggest a link between the[10,36,134], and increased the convulsant potency of endogenous levels of neuroactive steroids and the depres-NMDA [52]. The steroid may be acting through a specific sive state. Pregnenolone level in the cerebrospinal fluid isextracellularly directed modulatory site located on the decreased in subjects with an affective illness, particularlyreceptor complex, which is distinct from either the sper- during episodes of active depression [24]. Fluoxetine, a

21mine, glycine, phencyclidine, arachidonic acid, Mg and selective serotonin reuptake inhibitor, induced the level ofredox sites [95]. Interestingly, some other steroid sulfates, allopregnanolone in the cortex and hippocampus of the rat,like pregnanolone sulfate or epipregnanolone sulfate in- probably by acting directly on 3a-hydroxysteroid oxido-hibited the NMDA response, through a similar direct reductase activity [129]. During depression, there was aaction on the NMDA receptors, which may involve a significant decrease in allopregnanolone and pregnanolonedistinct site on the complex [94,95]. DHEA or its sulfate concentrations in human plasma [111]. After successfulester is also considered to be an excitatory steroid. It acts treatment with antidepressants, allopregnanolone and pre-as a negative allosteric modulator of the GABA receptor gnanolone levels were increased in the cerebrospinal fluidA

[54]. It potentiates several responses to NMDA in vitro and of treated patients. In contrast, when treatment failed, thein vivo [8,85]. However, the latter effect is unlikely to be level of allopregnanolone and pregnanolone failed torelated to the effect of pregnenolone effect on NMDA increase [130]. A correlation was observed between thereceptors, since DHEA sulfate did not interact directly levels of pregnenolone, and its sulfate, and symptomwith the NMDA receptor [46,94]. In addition, DHEA has severity in premenstrual syndrome, which was opposite tobeen reported to attenuate the neurodegeneration in pri- that for 5a-dihydroprogesterone and allopregnanolonemary hippocampal cultures exposed to glutamate, NMDA, whose levels increased when symptom severity decreaseda-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [133]. In alcoholic subjects, the levels of plasma allopreg-(AMPA) or kainic acid [46,55,133]. On the other hand, nanolone and allotetrahydrodeoxycorticosterone werepregnenolone sulfate was found to potentiate NMDA- markedly lower than those of control subjects during theinduced neurodegeneration in cell cultures or on the early withdrawal phase, when anxiety and depressionisolated retina treated with glutamate [27,135]. Such scores were the highest [109]. Depression ratings indifference were also observed in vivo, with pregnenolone abstinent alcoholic patients were negatively correlated withprecipitating appearance of learning deficits observed in plasma levels of DHEA and DHEA sulfate [32]. Thesemice exposed to an hypoxic insult by repetitive inhalation observations together suggest the clinical importance ofof carbon monoxide, whereas DHEA completely protected neuroactive steroid in the physiopathology of mood dis-the animals [71]. Indeed, the direct and efficient action of orders. Moreover, in an open trial, DHEA administered topregnenolone is consistent with its ability to enhance the depressive patients with low DHEA levels significantlyNMDA-induced toxicity. As established through the anti- reduced depression ratings [137]. A double-blind studysense studies, DHEA or its sulfate ester potentiates the confirmed this result [136].NMDA-evoked responses through its interaction with the The s agonists had antidepressant-like effects in sever-1

s receptor. Pregnenolone was reported to act as an al animal models. Igmesine (see Fig. 3A,B), SA4503,1

inverse agonist on the s receptor in vitro [85] but (1)-pentazocine, DTG or OPC14523 reduced immobility1

inefficient in vivo [8]. Agonists of the s receptor exert a in swim test [62,117,123] and in the tail suspension test1

bell-shaped concentration dependency, since at low dosage [48,125]. (1)-SKF-10,047, dextrometorphan and igmesinethey allow a limited facilitation of NMDA receptor activa- reduced the stress-induced colonic activity and the con-tion and at higher doses become inefficient or inhibit the ditioned fear stress [44,140]. Interestingly, maximumNMDA-mediated responses [8,68,71,85]. response of OPC14523 was higher than to either fluoxetine

126 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

Fig. 3. The antidepressant-like effect of the selective s receptor agonist igmesine in the forced swimming test. Each mouse was placed in a glass cylinder1

(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 6min on day 2. The duration of immobility during the last 5 min was measured. The mouse was considered as immobile when it stopped struggling andmoved 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 inhibitorthat 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 replacedby saccharose 1%, NaCl 0.9% solution. Animals were used for behavioral experiments 6 days after surgery. (A) Dose–response effect of igmesine incontrol Swiss mice. (B) Antagonism of the igmesine-induced effect by the selective s receptor antagonist BD1047. (C) Crossed pharmacology:1

antagonism of the igmesine-induced effect by the steroid progesterone. (D) Dose–response effect of igmesine in AdX/CX animals and attenuating effect offinasteride 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 weight, unlike classic antidepressants such as desipraminethan fluoxetine or imipramine [123]. The antidepressant or fluoxetine [125]. St John’s wort (hypericum perfor-effect observed after chronic treatment with s agonists atum), a well-known natural antidepressant, has compo-1

was not accompanied by side effects like decrease in body nents with significant affinity for the s receptor [104].1

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 127

3Hypericum perforatum extract was shown to provide a [42,43]. The in vivo [ H](1)-SKF-10,047 binding levels tobeneficial effect on behavioral despair in rats through an s sites in the mouse forebrain appeared significantly1

activation of the s receptor [93]. Even though no clinical increased in AdX/CX mice and further increased after1

study has yet been published, these results suggest that s trilostane-treatment. Conversely, finasteride-treatment led1

receptor agonists could be used as novel antidepressants to a significant decrease of binding as compared to AdX/with significant clinical efficacy. CX animals [97]. Thus, s sites are directly and tonically1

The interaction between neuroactive steroids and s inhibited by endogenous steroids. Among neuroactive1

receptor, and the resultant crossed pharmacology, has also steroids, progesterone appeared to be the most importantbeen shown in the model of behavioral despair. In par- modulator because of the high affinity of the steroid forticular, DHEA and pregnenolone sulfates significantly these sites, and because of the significant inverse-correla-reduced the immobility time observed in the forced swim tion observed between progesterone levels after treatmenttest. This effect was blocked by the selective s antago- and the binding levels.1

nists NE-100 [105] and BD1047 (Urani et al., submitted). Swim stress induced an increase in the level of proges-3A similar result was observed in the model of conditioned- terone and a decrease in [ H](1)-SKF-10,047 binding to

fear–stress where the sulfates of pregnenolone and DHEA the s receptor in the hippocampus of control animals1

attenuated, in a NE-100-sensitive manner, the motor [127]. These effects were enhanced in AdX/CX mice, butsuppression induced by previous electric footshock [88]. In completely blocked following treatment with trilostane. Aparallel, progesterone blocked the antidepressant-like ef- significant inverse-correlation was observed between pro-fect in the forced swim test induced by the s agonist gesterone increase and the inhibition of in vivo binding to1

igmesine [128] (see Fig. 3C) or (1)-SKF-10,047 [88]. At s sites after stress [127]. These observations confirmed1

doses where neither (1)-SKF-10,047, nor DHEAS where that some neurosteroids modulate the efficacy of s1

efficient, an additive effect could be observed, since receptor agonists in the response to stress and depression,combination of both drugs induced a significant reduction as was previously observed in learning and memoryof the stress-induced motor suppression in the conditioned processes [97]. Furthermore, the reverse correlation be-fear stress [88]. This result, in parallel to the clear crossed tween progesterone levels and the binding to s receptors1

pharmacology, suggests that these neuroactive steroids and suggests that progesterone could be an endogenous s1

s agonists both act through the same target. receptor ligand.1

Several experiments suggest a common mechanism ofaction between some neuroactive steroids and s ligands1

in mood disorders linked to stress. Such a neuroactive 5. Therapeutic potentialsteroid /s receptor interaction might lead to a novel1

therapy which included s ligands and neuroactive ster- As described in this review, selective s receptor1 1

oids. Such as therapeutic approach might be used for agonists show potent anti-amnesic and anti-depressanttreatment-resistant depression. One of the principal inter- properties. Clinical development for these compounds canests of such therapy might be the lack of side-effects, be anticipated, particularly taking into account their lack ofcontrarily to what is observed with classical antidepres- effects in control animals and the absence of reportedsants. side-effects [73]. However, the results and literature de-

tailed above indicates that in control animals with normal4.2. Endocrine manipulations levels of neuroactive steroids the efficacy of s receptor1

agonists may be limited, particularly against depressiveStress has been shown to affect levels of several states. Conversely, it is expected that these compounds

neuroactive steroid. Swim stress induced an increase in might present a preserved, if not enhanced, efficacy inallopregnanolone and allotetrahydrodeoxycorticosterone in steroid-depleted subjects [128]. In particular, cognitivethe cortex of rats [100]. Electric footshock induced an deficits or depressive states may constitute a suitableincrease in pregnenolone, progesterone, allopregnanolone therapeutic indication for selective s receptor agonists1

and allotetrahydrodeoxycorticosterone in the brain of adult [96].or aged rat [2–5]. It was thus expected that physiological A comparative study of the immunohistochemical label-modulation of neuroactive steroids levels during stress or ing of the s receptor between young adult (2 months old)1

acute depressive state may affect the efficacy of s and aged (24 months old) C57Bl /6 mice revealed a1

receptor agonists in vivo. This question was addressed remarkable preservation of labeling [96] (Phan et al.,through selective endocrine manipulations. submitted). The structures presenting high or moderate

In AdX/CX animals deprived of circulating steroids, levels of immunolabeling, olfactory bulbs, hippocampus,treatment with trilostane, an inhibitor of the 3b-hydroxy- cortex, hypothalamus, midbrain, etc., showed a similarsteroid dehydrogenase, decreases progesterone levels, labeling in aged and young adults animals, as illustrated inwhereas treatment with finasteride, a 5a-reductase inhib- Fig. 4A.itor, leads to an accumulation of progesterone in the brain The importance of decrease in some decrease levels

128 T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132

Fig. 4. The therapeutic interest of selective s receptor agonists against the aging-related cognitive deficits. (A) Comparison of the s receptor1 1

immunohistochemical distribution in the 2- and 24-month-old C57Bl /6 mouse. Sagittal sections showing the highly preserved distribution of theimmunolabeling throughout the whole brain. (B) Comparison of the neurosteroidal levels in the 2- and 24-month-old C57Bl /6 mouse. Measurements ofprogesterone, 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, lateralsuperior 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 observed in young mice [21]. Furthermore, this neuroac-behavior is presently being investigated. Some steroid tive steroid plays a physiological role in preserving and/orlevels decrease markedly during aging [91]. For example, enhancing cognitive abilities in old animals, possibly viaabout 60% decreases were observed in the levels of some an interaction with central cholinergic systems. Suchfree neuroactive steroids measured in the brain of aged observations suggests that the neuromodulatory action ofC57Bl /6 mice as compared to young adults (Fig. 4B). The pregnenolone sulfate and/or DHEA sulfate reinforcesubstantial age-related decrease of plasma or central levels neurotransmitter systems. Furthermore, since their levelsof these steroids that occurs concurrently with involution decrease in blood with age, neuroactive steroids could beof the zona reticularis indicates that these steroids might important endogenous substrates for effective memoryplay a role in the incidence of age-related cognitive capacities [91,108].deficits. Indeed, correlation between hippocampal pre- A therapeutic interest in selective s receptor agonists is1

gnenolone sulfate levels and the learning ability of aged thus suggested from concomitant observations in agedrats and memory performances in a water-maze and a animals (Fig. 4): (i) preservation of s receptor-immuno-1

two-trial recognition task was observed in aged rats. labeling [96], and (ii) significant decrease of brain levelsAnimals with better performances had greater levels of of progesterone. A preliminary study was recently per-pregnenolone sulfate [107,131]. Furthermore, pre- formed in order to determine whether a selective s1

gnenolone sulfate administered into the hippocampus receptor agonist (PRE-084) could ameliorate the spatialtemporarily corrected the memory deficits of aged rats learning in aged animals, using a water-maze procedurewhen given immediately after acquisition trial [131]. In [96]. Aged C57Bl /6 mice, 2 or 24 months old, wereparallel, a single systemic injection of DHEA sulfate trained to locate a visible platform and then an invisibleimmediately after training improved the impairment of platform. Finally, a transfer test under saline or PRE-084memory in middle-aged and old mice submitted to a treatment was performed. Aged, but not young adultfootshock active avoidance test, bringing it back to levels animals showed learning deficits unrelated to visual im-

T. Maurice et al. / Brain Research Reviews 37 (2001) 116 –132 129

Characterization and measurement of dehydroepiandrosterone sul-pairment. PRE-084 treatment allowed aged mice to learnfate in rat brain, Proc. Natl. Acad. Sci. USA 78 (1981) 4704–4707.the new platform location, in terms of decreased latencies

´[16] C. Corpechot, M. Synguelakis, S. Talha, M. Axelson, J. Sjovall, R.to the platform during training and increased presence in Vihko, E.E. Baulieu, P. Robel, Pregnenolone and its sulfate ester inthe platform quadrant during retention. These experiments the rat brain, Brain Res. 270 (1983) 119–125.demonstrate the efficacy of a selective s agonist to [17] B. Earley, M. Burke, B.E. Leonard, C.J. Gouret, J.L. Junien,1

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