University of Groningen Sigma-1 Receptor Imaging in the Brain

University of Groningen

Sigma-1 Receptor Imaging in the Brain Kuzhuppilly Ramakrishnan, Nisha

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2014

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Kuzhuppilly Ramakrishnan, N. (2014). Sigma-1 Receptor Imaging in the Brain: Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503. s.n.

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 27-09-2021

The cholinergic system, sigma-1 receptors and cognition

Aren van Waarde1, Nisha K. Ramakrishnan1, Anna A. Rybczynska1, Philip H.Elsinga1, Kiichi Ishiwata2, Ingrid M. Nijholt3, Paul G.M.Luiten4 and Rudi A. Dierckx1,5

1 Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 2 9713 GZ Groningen, The Netherlands Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 3 1-1 Naka-cho, Itabashi-ku, Tokyo, 173-0022, Japan Neurosciences, Section Functional Anatomy, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 4 9713 AV Groningen, The Netherlands Molecular Neurobiology, University of Groningen, Kerklaan 30, 5 9751 NN Haren, The Netherlands Department of Nuclear Medicine, University Hospital Gent, De Pintelaan 185, 9000 Gent Belgium

Behav Brain Res. 2011 Aug 10;221(2):543-54

2 30

ABSTRACT

This article provides an overview of present knowledge regarding the relationship 2 between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of ß-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxicKeywords: compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress. Acetylcholine, cholinergic system, cognition, sigma-1 receptors, memory, anti-amnesic effects, sigma-1 agonists, neurodegenerative disease THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 31

INTRODUCTION

Cholinergic neurotransmission is a crucial process underlying memory 2 and cognitive function. Cholinergic basal forebrain neurons in the nucleus(1) (2) basalis magnocellularis innervate the cerebral cortex, amygdaloid complex,, or hippocampus and are essential for learning and memory formation . Some cortical cholinergic activity is lost in normal aging. Patients suffering from AD or related dementias display a severe degeneration(3) (4)of cholinergic(5) neurons and a corresponding loss of cortical cholinergic neurotransmission,, , which is one of the factors underlying their memory deficits . Administration of an anticholinergic drug, such as the muscarinic antagonist(6) scopolamine, to experimental animals or healthy volunteers results in striking impairments of memory function which resemble Alzheimer dementia . On the other hand, acetylcholinesterase (AChE) inhibitors such as tacrine, physostigmine, rivastigmine and galantamine which suppress(7) breakdown of the neurotransmitter acetylcholine, can temporarily improve memory function in some demented patients and(8) in animal(9) models of amnesia . The sigma-1, receptor,(10) a unique(11) orphan(12) (13) receptor, is strongly expressed(14) in neurons and in glia . Neurosteroids,, , i.e., steroid hormones which are synthesized within the brain itself , and sphingolipids interact (15) with sigma-1 sites which are now considered(16) as ligand-regulated molecular chaperones modulating the activity (17)of voltage-regulated(18) (19) and ligand-gated(20) ion channels , intracellular calcium signaling, , , and the release of various neurotransmitters including acetylcholine and glutamate . Occupancy of sigma-1 receptors by agonists causes translocation (21) of the(22) receptor protein from the endoplasmatic reticulum to the cell membrane where,(23) (24)the receptor can regulate(25) (26)ion channels and neurotransmitter(27) (28) release , (Figure 1). The(29) sigma-1, receptor is implicated in , cellular differentiation , neuroplasticity , neuroprotection , and cognitive functioning of the brain . As both the cholinergic system and sigma-1 receptors are implied in cognition, we will in this article present an overview of current knowledge regarding the relationship between these neuronal pathways, and discuss potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. ACETYLCHOLINE AND SIGMA-1 RECEPTOR FUNCTION n vitro in vivo ofSigma-1 receptor agonists are potent modulators of acetylcholine release, both i 3 and . Igmesine and (+)SKF(18) 10,047 potentiate the KCl-evoked release H-acetylcholine from rat hippocampal slices, and this effect can be blocked by the sigma antagonist haloperidol . The sigma-1 receptor(17) 3agonist SA4503 dose-dependently increases the electrically evoked release of H-acetylcholine from hippocampal but not striatal slices isolated from rat brain . 32 (194). ,

2 efflux from the 2+ or NMDA-receptor associated receptors (red square). After 3 + to its receptor and Ca 3 Under baseline (resting) conditions, sigma-1 receptors Left: efflux by sigma-1 receptor agonists. After (193) 2+ Sigma-1receptoragonists inducedissociation translocationandsigma-1 receptors of Right: receptor complex. As a result, both the binding of IP 3 release when given alone, but they impede the potentiation of Ca 2+ Two schemes illustrating the hypothetical function of sigma-1 receptors. ), probably by directprotein-proteinprobablyby), interactions. 2+ agonist stimulation, sigma-1 receptors translocate to the plasmalemma where they can regulate ion channels (K ER are increased. Sigma-1 antagonists induce dissociation of only sigma-1 receptors dofrom not affectthe complex,Ca ankyrin remaining in place. Antagonists Figure 1. (black oval) largely reside at the endoplasmatic reticulum (ER), in association with ankyrin (green oval) and IP Ca plus ankyrin from the sigma-1 receptor-ankyrin-IP THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 33

Using in vivo

microdialysis in freely moving rats, extracellular acetylcholine levels in the frontal cortex were found to be acutely and dose-dependently increased upon administration of the sigma-1 receptor agonists(30) (31)(+)-SKF 10,047, (+)-3-PPP, 2 (±)-pentazocine and DTG. The effect of SKF 10,047 was , stereoselective and it could be reversed by the sigma antagonist haloperidol . In later experiments, (+)-SKF 10,047(32) was shown to also increase extracellular acetylcholine in the hippocampus in a stereoselective fashion and this effect could also be blocked by haloperidol . Regional differences in the stimulation of acetylcholine release by sigma-1 receptor agonists were subsequently observed. (+)-SKF 10,047 and (33)DTG increased the release of acetylcholine in hippocampus and frontal cortex, but in the rat striatum, DTG had no and (+)-SKF 10,047 had only a marginal effect . Acetylcholine release in the(19) hippocampus(34) and frontal cortex was also strongly increased by the sigma-1 agonist, SA4503, whereas acetylcholine release in the striatum was not affected (see Figure 2). The absence of an increase of striatal acetylcholine levels after administration of sigma-1 receptor agonists may

Figure 2. Upper panel: The sigma-1 receptor agonist SA4503 (10 mg/kg, per os, administered at time zero) increases extracellular acetylcholine levels in the frontal cortex but not in the striatum of freely moving rats. Lower panel: The effect of SA4503 on acetylcholine release is counteracted by the sigma-1 receptor antagonist NE-100 (0.5 mg/kg, co-administered with SA4503). After (19), (34). 34

be the reason why such drugs do not display some undesired side effects which are frequently seen after administration of acetylcholinesterase (AChE) inhibitors (19). Since selective sigma-1 receptor agonists can facilitate the activity of cholinergic systems by stimulating acetylcholine release, particularly in the 2 cortex and hippocampus, such drugs have the potential to ameliorate the memory impairments resulting from cholinergic dysfunction. However, the capability of sigma-1 receptor agonists to ameliorate such impairments appears to be not solely due to modulation of residual acetylcholine release. In a recent study involving the potent and selective sigma-1 agonist (±)-

PPCC (Ki at muscarinic receptors > 10,000 nM) and cholinergic lesions of varying severity, it was noted that the anti-amnesic effects of the sigma receptor agonist occur even in animals with complete cholinergic depletion, i.e. a total absence of cholinergic neurons in the basal forebrain nuclei (35). Pretreatment of animals with the sigma-1 receptor antagonist BD1047 blocked the anti-amnesic effects of (±)-PPCC (36). Thus, PPCC appears to improve cognition through sigma-1 receptors via additional, other mechanisms than stimulation of acetylcholine release. Some possible mechanisms are discussed in subsequent sections of this paper.

CHANGES OF SIGMA RECEPTOR DENSITY IN AGING AND NEURODEGENERATIVE DISEASE When sigma-1 receptor density in the brain of aged (20-28 years old) and young adult (4-8 years old) monkeys was compared using the radioligand 11C-SA4503

was observed in aged animals (37). In a similar PET study in humans, 11C-SA4503 bindingand PET, was a highly found significant to be unchanged increase in the(160-210%) human brain of the during binding healthy potential aging (38)(BP). This contrasts strikingly with the age-dependent loss of cholinergic, glutamatergic and dopaminergic receptors which occurs in primates (Figure 3). Using autoradiography and the non-subtype-selective sigma ligand 3H-DTG, e region of the hippocampus of Alzheimer’s disease (AD) patients as compared a significant, 26% loss of binding sites was noted in the CA1 stratum pyramidal pyramidal cells (39). These preliminary results suggested that sigma receptors are preferentiallyto healthy controls. located This on pyramidalloss of sigma cells receptors in the CA1 correlated region of thewith hippocampus. a 29% loss of In later PET studies, a loss of sigma-1 receptors from the brain of patients with AD was indeed observed (40). The BP of the sigma-1 ligand 11C-SA4503 was

cerebellum and thalamus of early AD patients as compared to healthy controls, butsignificantly not in the reduced hippocampus (by 44 (41) to 60%). in the frontal, temporal, and occipital lobe, Two genetic variants of the sigma-1 receptor gene could affect the susceptibility of humans to AD, i.e. G-241T/C-240T (rs. 1799729) in the proximal promoter

region and A61C (resulting in an amino acid substitution Q2P) in the first exon THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 35

A B 2

Figure 3. Age-related increases of sigma-1 receptor density in rhesus monkey brain (upper left) compared to the decreases of muscarinic M1/M4, serotonin-2A (5-HT2A), and dopamine D2/D3 receptor numbers with aging in human brain. Data from (195), (196), (197), and (198), respectively.

(42)

. The haplotype TT-C has been suggested to provide protection against AD. However, in a later study in a group of Polish patients (219 subjects with late-onset AD, 97 subjects with mild cognitive impairment and 308 nondemented subjects),(43) no significant differences for the sigma-1 receptor allele, genotype, haplotype, and diplotype distributions were observed between the studied groups .

11 In a small group of patients with early Parkinson’s disease (n = 6), the BP of C-SA4503 was found to be significantly(44) lower on the more affected than the less affected side of the anterior putamen, although there was no significant difference in BP between patients and controls . These data suggest that Parkinson’s disease may be associated with a loss of sigma-1 receptors from the putamen, although the decrease is less striking than that observed in the cerebral cortex in AD. In the rodent brain, sigma-1 receptor density was generally found to be preserved during aging. In a recent study involving healthy controls and senescent-accelerated mice (SAM), no differences between 6-, 9- and 12-month old rodents regarding the sigma-1 receptor density of various brain regions were observed, 3 neither at the level of mRNA nor at the protein level (histochemistry, binding of H-(+)-SKF 36

10,047). However, in aged (12-mo) SAM, the antidepressant efficacy of the sigma-1 agonist igmesine was increased. This(45) augmented response may be due to decreased 2 levels of neurosteroids in these animals, particularly progesterone, a steroid with sigma-1 receptor antagonist action . The efficacy of sigma-1 receptor agonists is known to be inversely correlated to brain progesterone levels. In rats treated with chronic intracerebroventricular infusion of beta-amyloid(1-40) protein, or in beta- amyloid(25-35) peptide-treated(46), (47) mice, a significant decrease of cerebral progesterone levels is accompanied by a corresponding increase of the antidepressant activity of sigma-1 receptor agonists . In another study on murine(48) ageing,. no differences in cerebral sigma-1 receptor density were observed between 2-mo and 24-mo old C57/BL6 mice, neither at the mRNA nor at the protein level

Changes of sigma-1 and sigma-2 receptors3 in aging3 rat brain have been

examined3 as well, by applying the radioligands H-SA4503, H-(+)pentazocine and H-DTG for binding studies in brain homogenates of 1.5 mo, 6-, 12- and 24-mo old Fisher-344 rats. The number of binding sites increased with aging, but the binding affinity of all ligands was decreased. Apparently, increases of receptor density (49)(over)compensate for a reduced affinity of the receptor proteins to agonists in this rodent strain, and as a consequence, ligand binding is increased at old age

3 , particularly at ages greater than 12 months. In an older study which used H-haloperidol (in combination with 50 nM unlabeled spiperone) to(50) quantify. sigma-1 plus sigma-2 receptors, receptor density in the brain of Fisher-344 rats was found to be unaltered between postnatal day 1 and age 12 months reportedThese findings to have offewer a preserved receptor density may perhaps not be generalized to all rat strains, since middle-aged Sprague-Dawley rats (5-6 mo old) were

3 sigma binding sites and sites with lower affinity for (51)H-DTG than young adult animals (2-3 mo old). The older animals also exhibited a decreased behavioral response to sigma ligands3 injected into the substantia nigra . Another research group which used H-(+)-PPP(52) confirmed. that the binding sites for this ligand in the brain of Sprague-Dawley rats are present at high density during the perinatal period, and decline thereafter SIGMA LIGANDS IMPROVE COGNITION IN ANIMAL MODELS OF COGNITIVE IMPAIRMENT

Sigma-1 agonists (applied systemically) have shown anti-amnesic efficacy in several animal models of cognitive impairment. Both pharmacological and pathological models of amnesia have been examined (see Table 1 for an overview). These include: (i) cholinergic deficits (either induced by muscarinic antagonists or by lesions of the forebrain or the nucleus basalis resulting in a selective loss of cholinergic neurons); (ii) pathology induced by direct administration of ß-amyloid(25-35) peptide to the rodent CNS, an animal model of Alzheimer’s THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 37

disease; (iii) aging-induced losses of memory function, both in normal mice and SAM; (iv) neurodegeneration caused by exposure of animals to CO gas, or to trimethyltin; (v) prenatal stress (restraint, or exposure to cocaine), and (vi) 2 glutamatergic, serotonergic, or calcium channel deficits induced by various drugs The beneficial effects of sigma-1 receptor agonists on cognitive performance were detected in many different cognitive tests assessing short-term (working memory), long-term (reference memory), contextual or spatial memory processes. For example, the sigma-1 receptor agonists (+)-SKF 10,047, pentazocine, DTG, (+)-3-PPP, igmesine and SA4503 prevented the scopolamine-induced amnesia of mice and rats in passive avoidance tasks, and the beneficial action of these compounds was blocked by sigma-1 receptor antagonists like NE-100. The (34)anti-amnesic(53) (54) effects(55) (56) of SA4503 were blocked after sigma-1 receptor antisense administration,, , , but, not after administration of a mismatch oligodeoxynucleotide . Thus, activation of the sigma-1 receptor is involved in the improvement of cognition, and sigma-1 agonists have potential for the treatment of amnesia resulting from cholinergic dysfunction. Sigma-1 receptor agonists such as (+)-SKF 10,047, (+)-pentazocine, DTG, PRE-084 and SA4503 also showed a potent anti-amnesic action against the cognitive deficits induced by NMDA-receptor blockade in mice and rats, e.g. treatment of animals with the non-competitive NMDA receptor antagonist dizocilpine before the learning test. These beneficial effects were stereoselective and were blocked by pretreatment of animals with sigma-1 antagonists such as BMY 14802, haloperidol or NE-100 (see Table 1 for references). Neurotoxicity models of cognitive impairment which have been employed for testing cognitive enhancement by sigma-1 receptor agonists include repeated exposure of mice to CO gas(57) and trimethyltin administration to rats. The former model results after 5 to 7 days in neuronal death that remains restricted(58) (59) to the CA1 area of the hippocampus . Trimethyltin administration results in, damage of selective neural populations from limbic structures of the brain . In such neurotoxicity models, similar findings were obtained as in the pharmacological models of amnesia, i.e. sigma-1 receptor agonists improved cognitive performance and this improvement could be blocked by sigma-1 receptor antagonists. However, in contrast to the scopolamine or dizocilpine-induced amnesia, cognitive impairments after exposure of animals to CO or trimethyltin were alleviated not only by sigma-1 agonists but also by sigma-2 receptor agonists. In most behavioral tests, sigma-1 receptor agonists doin not vivo facilitate and sigma-1 receptor antagonists do not impede the learning of healthy control animals. testDownregulation (60) (61) of sigma-1 receptor expression using an antisense approach also does , not affect the learning ability of healthy mice submitted to a passive avoidance . However, sigma-1 receptor agonists improve the performance of pharmacologically or pathologically lesioned animals in standard learning tests, and this improvement in lesioned rodents can be blocked by sigma-1 receptor antagonists. 38

Table 1.

AmnesiaAnimal model models in which sigma-1Species agonists have shown anti-amnesicσ1 agonists properties σ1 antagonists Other drugs used Behavioral tests Reference Cholinergic deficit 2

Scopolamine Rat Igmesine, (+)-3-PPP, DTG None Piracetam Passive avoidance (151) Scopolamine Mouse (+)-SKF 10,047, (±)-pentazocine None Ritanserin, mian-serin, Passive avoidance (54) tacrine, physostigmine Scopolamine, Ibotenic Rat SA4503 Haloperidol, NE-100 None Passive avoidance (152) acid forebrain lesion Scopolamine Mouse (+)-SKF 10,047 Haloperidol,none NE-100 (-)SKF 10,047, Passive avoidance (56) physostigmine Ibotenic acid forebrain lesion Rat SA4503 None Morris water maze (153) Scopolamine Mouse DHEA-S, PREG-S Progesterone NE-100 None Y-maze, water maze (154) Scopolamine Mouse PRE084, SA4503 Antisense mismatch antisense Y-maze, passive avoidance (155) Scopolamine Rat OPC-14523 NE-100 None Morris water maze (156) (158) (159) Nucleus basalis lesion Rat Fluoxetine None None Active avoidance (157) Scopolamine Mouse (+)-pentazocine, (+)-SKF 10,047 antisense, NE-100 (-)pentazocine, Y-maze U-50,488H (160) Scopolamine Mouse ANAVEX1-41 antisense, BD1047 None Y-maze, passive avoidance, water (161) maze, forced swimming test Scopolamine Mouse Dimemorfan Haloperidol None Passive avoidance Water maze (162) 192IgG-saporin induced Rat (±)-PPCC BD1047 None Morris water maze (163) lesions, Atropine sulfate Amyloid-inducedL-NAME 7-nitroindazole neurodegenerationMouse (+)-SKF 10,047(+)-pentazocine NE-100 None Y-maze (164)

ß-amyloid(25-35) peptide Mouse (+)-pentazocine, PRE084, SA4503, Haloperidol, BMY14802, None Y-maze, passive avoidance (165) PREG-S, DHEA-S progesterone ß-amyloid(25-35) peptide Mouse Donepezil, PRE084 BD1047 Tacrine, rivastigmine, Y-maze, passive avoidance (166) galantamine ß-amyloid(25-35) peptide Mouse ANAVEX1-41 BD1047 Scopolamine Y-maze, passive avoidance, (75) radial arm maze Aging-relatedß-amyloid(25-35) memory peptide loss Mouse Dimemorfan Haloperidol None Passive avoidance Water maze (167)

Senescence-accelerated mouse Mouse Igmesine, PRE084 BMY14802none JO1783 Y-maze, water maze, passive (168) avoidance, open field Normal aging Rat PRE084 None Water maze (169) none Normal aging Rat OPC-14523 NE-100 None Morris water maze (170) Hypoxia-inducedNormal aging neurodegenerationMouse PRE084 None Morris water maze (171)

Repeated CO exposure Mouse (+)-SKF 10,047, DTG BMY14802 None Y-maze, passive avoidance (172) Repeated CO exposure Mouse PRE084, DTG, BD1008 NE-100, haloperidol None Passive avoidance (173)

Repeated CO exposure Mouse DHEA Pregnelone, NE-100 None Y-maze, passive avoidance (174) Repeated CO exposure Mouse Donepezil, igmesine BD1047 Tacrine, rivastigmine, Y-maze, passive avoidance (175) galantamine THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 39

Table 1.

AmnesiaAnimal model models in which sigma-1Species agonists have shown anti-amnesicσ1 agonists properties σ1 antagonists Other drugs used Behavioral tests Reference Cholinergic deficit 2

Repeated CO exposure Mouse (+)-SKF 10,047, DTG BMY14802 None Y-maze, passive avoidance (172) Repeated CO exposure Mouse PRE084, DTG, BD1008 NE-100, haloperidol None Passive avoidance (173)

Table 1. Continued

Amnesia model Species σ1 agonists σ1 antagonists Other drugs used Behavioral tests Reference Toxin-induced neurodegeneration (aspecific) 2 none Trimethyltin Rat Igmesine None passive avoidance, (176) radial arm maze PrenatalTrimethyltin stress Mouse PRE084, DTG, BD1008 NE-100, haloperidol None Passive avoidance (177)

Prenatal restraint Rat Igmesine BD1063 None Y-maze, T-maze, water (178)

maze, passive avoidance Prenatal cocaine exposure Rat Igmesine, DHEA BD1063 None T-maze, water maze, (179) NMDA-receptor deficit passive avoidance

Dizocilpine Mouse (+)-SKF 10,047, (+)-pentazocine, DTG BMY14802, NE-100 (-)SKF 10,047, Y-maze, passive avoidance, (180) (-)pentazocine elevated plus maze

Dizocilpine Rat (+)-SKF 10,047 (-)SKF 10,047 Three-panel runway task (181) Dizocilpine Mouse DHEA-S BMY14802, haloperidol Y-maze, passive avoidance (182) Dizocilpine Mouse SA4503 Haloperidol, progesterone L-NAME Y-maze, passive avoidance (183) Dizocilpine Rat (+)-SKF 10,047, SA4503 NE-100 None Radial arm maze (184) Dizocilpine Rat SA4503, DHEA-S, PREG-S Progesterone, NE-100 None Radial arm maze (185) Dizocilpine Mouse PRE084, SA4503 Antisense Mismatch antisense Y-maze, passive avoidance (186) Dizocilpine Mouse PRE084, DHEA-S, PREG-S Antisense Mismatch antisense Y-maze, passive avoidance (187) Phencyclidine, dizocilpine Mouse SA4503, (+)-pentazocine, (+)-SKF 10,047 NE-100 D-cycloserine, L-NAME One-trial water-finding task (188) Dizocilpine Mouse Donepezil, igmesine Antisense, BD1047 Rivastigmine, tacrine Y-maze, passive avoidance (189) Phencyclidine Mouse Fluvoxamine, SA4503, DHEA-S NE-100 Paroxetine Novel object recognition task (190) SerotonergicPhencyclidine deficit Mouse Donepezil NE-100 Physostigmine Novel object recognition task (191) p- none

chloroamphe-tamine Mouse (+)-SKF 10,047, (±)-pentazocine Ritanserin, mianserin, Passive avoidance (54) p none tacrine, physostigmine -chloroamphetamine Mouse (+)-SKF 10,047, DTG, (+)-3-PPP (-)SKF 10,047, Passive avoidance (53) Ca2+ channel deficit hemicholinium-3

nimodipine Mouse PRE084 BMY14802 None Y-maze, passive avoidance, (129) Sigma receptor deficit water maze none

CDEP Mouse (+)-SKF 10,047, DTG, (+)-3-PPP None Passive avoidance (192) THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 41

Table 1. Continued

Amnesia model Species σ1 agonists σ1 antagonists Other drugs used Behavioral tests Reference Toxin-induced neurodegeneration (aspecific) none 2 Trimethyltin Rat Igmesine None passive avoidance, (176) radial arm maze PrenatalTrimethyltin stress Mouse PRE084, DTG, BD1008 NE-100, haloperidol None Passive avoidance (177)

Prenatal restraint Rat Igmesine BD1063 None Y-maze, T-maze, water (178)

maze, passive avoidance Prenatal cocaine exposure Rat Igmesine, DHEA BD1063 None T-maze, water maze, (179) NMDA-receptor deficit passive avoidance

Dizocilpine Mouse (+)-SKF 10,047, (+)-pentazocine, DTG BMY14802, NE-100 (-)SKF 10,047, Y-maze, passive avoidance, (180) (-)pentazocine elevated plus maze

CDEP Mouse (+)-SKF 10,047, DTG, (+)-3-PPP None Passive avoidance (192) 42

Neuroactive steroids (such as DHEA-S or pregnenolone sulfate) have similar effects as non-steroid sigma-1 receptor agonists, whereas progesterone behaves as a sigma-1 receptor antagonist. These observations suggest that sigma-1 receptors are not directly involved in learning or memory, but sigma-1 receptor agonists can modulate 2 neural processes underlying cognition, particularly under pathological conditions. However, in some publications pro-mnesic effects of sigma-1 receptor agonists have been reported. For example, the neurosteroids DHEA-S and PREG-S, when

learning task in mice in a dose-dependent manner with a bell-shaped dose- responsegiven either curve. pre- Thisor post-training, action of the were neurosteroids found to facilitate appears retention to be dependent of a modified on their interaction with sigma-1 receptors, since it can be blocked by concurrent administration of the sigma antagonist haloperidol (62). Long-term potentiation (LTP) in rat hippocampus, a process thought to be crucial for learning and memory, is facilitated after chronic (7 d) administration of the neurosteroid DHEA-S. This potentiation appears to be based on alterations in postsynaptic neurons since no changes were observed in presynaptic glutamate release. DHEA-S appears to act through sigma-1 receptors, since the potentiating effect is absent when sigma-1 receptor antagonists (NE-100, haloperidol) are co-administered with the neurosteroid (63). Another neurosteroid with sigma-1 receptor agonist action, PREG-S, has also been reported to facilitate LTP in the rodent hippocampus by a mechanism involving sigma-1 receptors and L-type calcium channels (64). The non-sulfated forms of the neurosteroids which lack the sigma-1 receptor agonist action (DHEA and PREG) do not potentiate LTP (65), (64). Paired-pulse facilitation in hippocampal neurons from adult rats, a short-term increase of the postsynaptic potential, is also potentiated by PREG-S and this potentiation is abolished after co-administration of sigma-1 receptor antagonists (66).

IMPROVEMENT OF COGNITIVE FUNCTION IN HUMANS Fluvoxamine has been reported to be effective in improving cognitive impairments in an animal model of schizophrenia, in contrast to paroxetine (67).

of concentration, poor memory, slowness of mind, and poor executive function in a patientInterestingly, with schizophrenia fluvoxamine but (68) not paroxetine was also found to improve the lack is more than 50 times higher than that of paroxetine, although both compounds are potent selective serotonin reuptake. The affinity inhibitors of fluvoxamine (SSRIs) (69)for sigma-1. High occupancy receptors (up to 60%) of sigma-1 receptors in the human brain was observed with 11C- (70) (see Figure 4 for a similar occupancy study). These data suggest that sigma-1 receptor agonists SA4503 PET after a single oral dose of 200 mg fluvoxamine be candidates for treating cognitive impairments in schizophrenia. including SSRIs with sigma-1 receptor agonist action, such as fluvoxamine, may 43

THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION

Figure 4. PET scans of the brain of a human volunteer, made with the sigma-1 receptor ligand 11C-SA4503, at baseline (left) and after oral administration of an antipsychotic drug, interval 3 h (middle) and 10 h (right), respectively. The binding of 11C-SA4503 was considerably reduced after occupancy of sigma-1 receptors by the antipsychotic drug. Data from our own group, not previously published.

receptor agonism exist as well, e.g. donepezil. A recent paper reported that therapeutic Compounds which combine acetylcholinesterase (AChE) inhibition with sigma-1 brain (71) doses of donepezil result in considerable sigma-1 receptor occupancy in human . Sigma-1 receptor agonists may have potential for treating AD since the amyloidcompounds toxicity are not (see only (72) capable of alleviating cognitive deficits in animal models of cognitive impairment (see above)in vitro butexperiments they can alsoin cultured provide cortical neuroprotection neurons (73) against and by in vivo studies in rodents for (74) a review), (75) . Evidence for such neuroprotective activity has been provided both by (76). Such compounds may . Recently, it was found that sigma-1 receptor agonists can powerfully suppress microglial activation depression,therefore attenuate anxiety, the psychosis, inflammatory substance component abuse, in neurodegenerative stroke and neuropathic diseases. pain More applications of sigma-1 receptor(77) , (78) agonists,, (79), (80) e.g. , (29) in the, (81) treatment. Companies of are discussed in several recent reviews (78) involved in the development of drugs for such indications include M’s Science, AGY Therapeutics, Otsuka American Pharmaceutical, and Sanofi-Aventis MODULATION OF GLUTAMATE RELEASE BY SIGMA-1 AGONISTS

memoryBesides the (82) well-known. It is thus ofdeficits interest of acetylcholine,that sigma ligands the neurotransmitter are capable of modulating glutamate can be reduced in AD. Both neurotransmitters are supposed to play vital roles in glutamate release in various areas of the brain. 44

The neurosteroid PREGS (which is supposed to act as a sigma-1 receptor agonist) and the sigma-1 receptor agonist (+)-pentazocine, but not the (-)-enantiomers of PREGS and pentazocine, or the inactive steroid isopregnanolone enhance the spontaneous release of glutamate in cultured hippocampal neurons. 2 The sigma receptor antagonists haloperidol and BD1063 and a membrane- permeable calcium chelator block this effect of PREGS. These results suggest that hippocampal glutamate release can be enhanced via activation of presynaptic sigma-1 receptors and an elevation of the levels of intracellular Ca2+ (83). Later

glutamate is enhanced by PREGS both in the hippocampus and in prelimbic cortex, butstudies not byin the another striatum. research The effect group of confirmed PREGS in thatthe prelimbic the spontaneous cortex appears release to of be mediated via alpha-1 adrenergic and sigma-1 receptors, whereas the effect in the hippocampus is dependent on sigma-1 receptors only. Intracellular calcium released from the endoplasmatic reticulum plays a key role in the enhancement of glutamate release (84). DHEA-S, another neurosteroid with sigma-1 receptor agonist action, also enhances the spontaneous release of glutamate in prelimbic cortex and hippocampus. The effect of this compound in the prelimbic cortex

appears to be mediated via dopamine D1 and sigma-1 receptors, whereas that in the hippocampus occurs only via sigma-1 receptors (85). Brain-derived neurotrophic factor (BDNF)-induced glutamate release in cultured cortical neurons is potentiated by antidepressants with sigma-1 receptor

blocked by the sigma-1 receptor antagonist BD1047. Not only pharmacological agonistactivation activity but also such overexpression as fluvoxamine of and the imipramine, sigma-1 receptor and this enhances potentiation BDNF- is enhanced glutamate release. The sigma-1 receptor appears to play an important role in BDNF signaling leading to the release of glutamate, and the enhancement 2+ of glutamate release seems to occur via the PLC-gamma/IP3/Ca pathway (86). Thus, sigma ligands represent a strategy for modulating glutamatergic activity within the mammalian brain, and such modulation could be an additional mechanism underlying the anti-amnesic action of sigma-1 receptor agonists.

MODULATION OF THE NMDA RESPONSE BY SIGMA-1 AGONISTS NMDA receptors mediate the induction of LTP and long-term depression in various brain areas (i.e. long-lasting improvements and impairments of synaptic transmission) (87), (88), (89), (90). Such forms of synaptic plasticity are considered as important cellular mechanisms underlying learning and memory (91), (92), (93). Pharmacological inhibition of NMDA receptor function, by administration of NMDA antagonists either directly into the brain or by systemic administration of compounds which can cross the blood-brain barrier, results in impaired spatial learning and nonspatial passive avoidance learning in rodents (94), (95), (96), THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 45

(97)

. Knockout(98) mice lacking the NMDA receptor 1 gene in CA1 pyramidal cells of the hippocampus exhibit impaired spatial learning but unimpaired nonspatial learning . Apparently, NMDA-dependent strengthening of CA1 synapses is 2 essential for the acquisition and storage of spatial memory. In many studies, sigma-1 receptor agonists were shown to modulate responses induced by NMDA receptor activation in various brain areas such as the hippocampus and prefrontal cortex. Some responses are potentiated and others inhibited by sigma-1 receptor agonists. Sigma-1 receptor antagonists when administered alone are without any effect, but these compounds block the agonist-induced modulation. For example, the electrophysiological response of pyramidal neurons in the CA3 region of the rat dorsal hippocampus to NMDA (excitatory activation) is potentiated by sigma-1 receptor agonists such as (+)pentazocine, DTG, BD737, igmesine, L687,384, or DHEA and therapeutic drugs with significant sigma-1 receptor agonist affinity (the SSRI sertraline and the monoamine oxidase inhibitor(99) (100) clorgyline),(101) (102)whereas(103) this(104) potentiation(105) is reversed by sigma-1 receptor antagonists, such, as, haloperidol,, , BMY14802,, NE-100, progesterone and testosterone . The potentiation persists for at least 60 minutes(99) and can be sustained by prolonged microiontophoretic application of a sigma-1 receptor agonist, indicating that sigma-1 receptors do not rapidly desensitize . Steroid hormones with antagonist action such as progesterone and testosterone produce a tonic dampening of the function of sigma-1 receptors and, consequently, of NMDA-mediated responses. Pregnancy reduces sigma-1 receptor function in the brain, since a tenfold higher dose(106) of sigma-1 receptor agonists is required to potentiate the NMDA-response of pyramidal neurons in pregnant female rats than in non-pregnant control animals . In an electrophysiological study in which animals were unilaterally lesioned by local injection of colchicine into the mossy fiber system (an afferent system to CA3 pyramidal neurons), the potentiating effect of (+)-pentazocine(107) on the NMDA-response was found to persist on the lesioned side, but the potentiating effects of DTG and igmesine were abolished after lesioning . These data were interpreted as suggesting that the test drugs were acting on two different subtypes(107) of sigma receptors, and that the receptors for DTG and igmesine are located on the mossy fiber terminals, in contrast to the receptors for (+)-pentazocine . In a later study, the effect of the sigma-2 subtype-selective ligand siramesine was tested on the neuronal response to NMDA in the CA3 region of the rat dorsal hippocampus. Siramesine was found to potentiate the NMDA response dose- dependently with a bell-shaped(108) curve, but the effect of siramesine could - in contrast to the effect of sigma-1 receptor agonists - not be reversed by NE-100, haloperidol or progesterone . Thus, not only sigma-1 but also sigma-2 receptors appear to be involved in modulation of the NMDA response. Bell-shaped dose-response curves are a common finding in studies regarding the effect of sigma-1 receptor agonists. At low doses the NMDA response is 46

(99) (109) (110) (103) , , , potentiated but at higher dose the potentiation is reversed . For example, the sigma-1 receptor agonist SR 31742A increases NMDA-induced 2 inward currents of pyramidal(111) cells in slices of rat medial prefrontal cortex at doses ranging from 10 to 100 nM (EC50 23 nM), but at doses greater than 100 nM an inhibition is observed . The potentiaton of NMDA-receptor mediated neurotransmission by SR 31742A may account for the antipsychotic and(112) cognition- enhancing properties of the drug, whereas the inhibition of NMDA responses at higher drug concentrations may account for its neuroprotective effect . Recently, a molecular mechanism has been proposed which may explain how sigma-1 receptor ligands increase the NMDA response. Calcium ions entering the cells

through NMDA-receptor-related channels+ normally activate a potassium current via small-conductance calcium-activated K channels (SK channels). This current (113)shunts the NMDA receptor responses. Sigma-1 subtype-selective receptor agonists prevent SK channel opening, and consequently increase the NMDA receptor response . MODULATION OF CALCIUM HOMEOSTASIS

(114) (115)The intracellular(116) (117) (118) localization of sigma-1 receptors (mainly in endoplasmatic, reticulum,, but, also, in nuclear and plasma membranes and on mitochondria ) suggests that these binding sites could be involved in the regulation of calcium mobilization. Indeed, sigma-1 receptor activation has been shown (119) to affect calcium homeostasis. Sigma-1 receptor agonists increased contractility, beating(120) rate and calcium influx in cultured cardiac myocytes from neonatal rats . Intracellular levels of inositol triphosphate in these cells were increased as well . In NG108 (neuroblastoma-glioma) cells, various sigma-1 receptor agonists enhanced the bradykinin-induced increases in cytosolic free calcium with bell-shaped dose- response curves whereas this effect (121) could be blocked by a sigma-1 receptor antisense oligonucleotide,2+ suggesting that sigma-1 receptor activation facilitates IP3-receptor-mediated Ca signaling . In SH-SY5Y (neuroblastoma) cells, the sigma-1 receptor agonist (+)-pentazocine2+ and various neurosteroids(122) also potentiated the bradykinin-induced Ca response, and this potentiation was blocked by the sigma receptor antagonists haloperidol and progesterone . By expression of either complete sigma-1 receptors or the N- or C-terminal segment of the sigma-1 receptor protein in MCF-7 breast cancer cells (which normally express few sigma-1 receptors), proof was obtained that sigma-1 receptor overexpression results in an enhancement of bradykinin-, vasopressin- or ATP-induced calcium(123) release, and that the C-terminal segment of the sigma-1 receptor is involved in the interaction with the inositol triphosphate receptor-ankyrin-B 220 complex . Experiments in adult guinea pig isolated brainstem(124) preparations have indicated that sigma-1 receptor activation leads to activation of phospholipase C and the beta-1 and beta-2 isoforms of protein kinase C . In isolated rat hippocampal 47

THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION

(125). However, in rat frontal cortical neurons, receptor activation leads to a potentiationreduce of NMDA-receptor-mediated2+ increases of free intracellular calcium neurons, sigma receptor ligands were found to 2+ the NMDA-induced Ca 2 influx. Sigma-1-subtype-selective compounds (igmesine, (+)-pentazocine) particularly affected the sustained phase of the Ca response to NMDA, whereas non-subtype-selective compounds (DTG, haloperidol) reduced the initial and sustained phases to the same degree. The inhibition of the sustained phase was Cadirectly2+ related to the affinity(126) of the ligands to sigma-1 receptors. Thus, in frontal cortical neurons, sigma-1 receptors appear to facilitate the desensitization of the response to NMDA . Attenuation of NMDA-induced calcium responses by sigma ligands in frontal cortical neurons(127) was. also observed in a later study, and that study confirmed that sigma ligands shifted the NMDA response from a sustained to a biphasic or transient event In an interesting study on the sigma-1 receptor agonist igmesine, the effect of intracerebroventricularly administered modulators of calcium influx and mobilization was examined on the reduction of immobilization time caused by igmesine in the forced swimming test. Using chelators of extracellular and intracellular calcium, L- and N-type voltage-dependent2+ calcium channel antagonists and agonists, evidence was obtained2+ that the antidepressant(128). effect of igmesine is dependent not only on rapid Ca influx (like that of classical antidepressants), but also on intracellular Ca mobilization Antagonists of voltage-dependent calcium channels such as nimodipine impair the cognitive performance of rodents in various learning tests. Such impairments could be attenuated by pre-administration of the sigma-1 receptor agonists PRE- 084, and this attenuation could be completely prevented by co-administration of the sigma-1 receptor antagonist BMY-14802. Thus, calcium fluxes are implied in memory processes and (129) an impairment of calcium influx through voltage- dependent calcium channels can,2+ at least partially, be overcome by administration andof a sigma-1Ca2+ receptor agonist . Potentiation or attenuation of calcium signaling via sigma-1 receptors (both Ca entry at the plasma membrane level via channels mobilization from intracellular stores) may explain why selective(130) sigma-1. receptor agonists can modulate a wide variety of neuronal responses, and be the key mechanism by which sigma-1 receptors affect learning and memory INVOLVEMENT OF SIGMA-1 RECEPTORS IN NEURONAL DIFFERENTIATION AND NEUROPLASTICITY

(131), (132) Sigma-1 receptors are expressed not only in neurons but also in astrocytes and oligodendrocytes within the brain . Overexpression of sigma-1 receptors potentiates nerve growth factor (NGF)-induced neurite outgrowth in PC-12 cells, and 48

(133)

this effect can be blocked by(134) sigma-1 receptor antisense . Sigma-1 receptors are strongly upregulated(135) in the corpus callosum of (136)developing brains, particularly in the 2 phase of active myelination . A high expression of these binding sites is observed in oligodendrocytes and Schwann cells , suggesting involvement of the sigma-1 receptor(137) in myelination. Knockdown of these receptors by siRNA results in complete inhibition of the differentiation(26) and myelination of oligodendrocyte progenitor cells and prevention of the formation of mature dendritic spines in hippocampal primary neurons . Eliprodil, a neuroprotective drug with a high affinity agonist action at sigma receptors, strongly promotes myelination in neuron- oligodendrocyte cocultures. These data suggest that upregulation of sigma-1 receptors is an important prerequisite(138) for neuronal differentiation, and that sigma-1 receptor agonists like eloprodil may be of therapeutic interest in demyelinating diseases such as multiple sclerosis . Overexpression of sigma-1 receptors promotes (139) lipid (140) reconstitution(141) (142) in the plasma membrane and potentiates raft-residing neurotrophic, , factors, receptors and signal transduction (NGF, EGF, BNDF) . These neurotrophic factor signaling pathways may therefore be involved in the differentiation-promoting effects of sigma-1 receptors. When PC-12 cells are treated with(143) NGF and verbenachalcone, a differentiation enhancer, the sigma-1 receptor belongs to the 10 (out of 10,000) genes showing the strongest upregulation . Since a very high(144) expression of sigma-1 receptors has been noticed in the ventricular zone of young rat brains, where active proliferation and differentiation of cells occurs , sigma-1 receptors may not only play an important role in neuroplasticity but may also be involved in neurogenesis. An involvement of sigma-1 receptors in neurogenesis is suggested by the observation that continuous administration of the sigma-1 agonist SA4503 dose-dependently enhances the number of bromodeoxyuridine-positive cells in the subgranular zone of the adult rat hippocampus (by 48% at 3 mg/kg/d and by 94% at 10 mg/ kg/d, respectively, after a treatment period of 3 days), indicating an increased cellular proliferation. Since SA4503 causes parallel(145) increases of hippocampal 5-HT neurotransmission and cell proliferation, the neurotransmitter serotonin may play a central role in the proliferation process . Not only sigma-1 receptor overexpression, but also drug-induced sigma-1 receptor activation results in potentiation(146) of NGF-induced neurite outgrowth. Donepezil, a combined sigma-1 receptor ligand and AChE inhibitor (IC50 values 14.6 nM and 21.5 nM, respectively ), potentiates NGF-induced neurite outgrowth in PC12 cells, and(147) this effect of donepezil can be blocked by the sigma-1 receptor antagonist NE-100 or the inositol 1,4.5-triphosphate (IP3)-receptor (148)antagonist xestospongin C , but is not affected by cholinoceptor antagonists (mecamylamine, scopolamine) or cholinomimetic(149) drugs (nicotine, carbachol) . Physostigmine, an AChE inhibitor without sigma-1 receptor affinity, does not alter NGF-induced neurite outgrowth . The SSRI fluvoxamine (but not THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 49

the SSRIs sertraline or paroxetine) and the sigma-1 receptor agonists SA4503, PPBP and DHEA-sulfate likewise(150) potentiate neurite outgrowth in PC12 cells in a concentration-dependent manner,(69) and the effect of these drugs can also be blocked 2 by NE-100 or xestospongin C . Since sertraline and fluvoxamine have similar affinities to sigma-1 receptors(150) but only fluvoxamine promotes outgrowth, these data may indicate that sertraline is a sigma-1 receptor antagonist and fluvoxamine a sigma-1 receptor agonist . Specific inhibitors of phospholipase C (PLC), phosphatidyl inositol 3-kinase (PI3K), p38 mitogen-activated protein kinase (p38MAPK), c-Jun(150) terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase signaling pathways block the potentiation of NGF-induced neurite outgrowth as well . Apparently, both sigma-1 receptors and IP3-receptors are involved in the potentiation of neurite outgrowth by the test drugs, besides the PLC, PI3K, p38MAPK, JNK and the Ras/Raf/MAPk signaling pathways. CONCLUSION

Because of the neuromodulatory role of sigma-1 receptors, ligands for these binding sites can affect a large variety of cerebral processes. Modification of calcium transients (both by affecting calcium release from intracellular stores and influx of extracellular calcium) and modulation of potassium channel activity via direct protein-protein interaction appear to be key processes underlying the action of sigma-1 receptor ligands. Probably via these mechanisms, several neurotransmitter systems are modulated, particularly the cholinergic and glutamatergic (NMDA- receptor) pathways. The modulatory role of sigma-1 receptors explains why sigma-1 receptor ligands are usually devoid of an effect under control conditions but have striking effects when the normal homeostasis of the organism has agonists been disturbed, e.g. by disease or by a pharmacological challenge. Data from preclinical studies in a large variety of animal models suggests that sigma-1 receptor are promising compounds for the treatment of cognitive dysfunction. 50

REFERENCES 1. Aigner TG. Pharmacology of memory: function: behavioral consequences and cholinergic-glutamatergic interactions. therapeutic opportunities. Brain Res Curr Opin Neurobiol. 1995;5(2):155-160. Brain Res Rev. 2001;37(1-3):116-132. 2 2. Gallagher M, Colombo PJ. Ageing: the 13. Su TP, London ED, Jaffe JH. Steroid cholinergic hypothesis of cognitive binding at sigma receptors suggests decline. Curr Opin Neurobiol. a link between endocrine, nervous, 1995;5(2):161-168. and immune systems [see comments]. . 1988;240(4849):219-221. 3. Bartus RT, Dean RL, III, Beer B, Lippa Science AS. The cholinergic hypothesis of 14. Ramachandran S, Chu UB, Mavlyutov geriatric memory dysfunction. Science. TA, Pal A, Pyne S, Ruoho AE. The sigma1 1982;217(4558):408-414. receptor interacts with N-alkyl amines and endogenous sphingolipids. Eur J 4. Coyle JT, Price DL, DeLong MR. Pharmacol. 2009;609(1-3):19-26. Alzheimer’s disease: a disorder of cortical cholinergic innervation. 15. Maurice T, Su TP. The pharmacology of Science. 1983;219(4589):1184-1190. sigma-1 receptors. Pharmacol Ther. 2009. 5. Davies P, Maloney AJ. Selective loss of 16. Hayashi T, Su TP. Sigma-1 receptor central cholinergic neurons in Alzheimer’s chaperones at the ER-mitochondrion disease. Lancet. 1976;2(8000):1403. interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131(3):596-610. 6. Patel S, Tariot PN. Pharmacologic models of Alzheimer’s disease. Psychiatr 17. Horan B, Gifford AN, Matsuno K, Clin North Am. 1991;14(2):287-308. Mita S, Ashby CR. Effect of SA4503 on the electrically evoked release of 7. Krall WJ, Sramek JJ, Cutler NR. 3H-acetylcholine from striatal and Cholinesterase inhibitors: a therapeutic hippocampal rat brain slices. Synapse. strategy for Alzheimer disease. Ann 2002;46(1):1-3. Pharmacother. 1999;33(4):441-450. 18. Junien JL, Roman FJ, Brunelle G, Pascaud 8. Hayashi T, Su T. The sigma receptor: X. JO1784, a novel sigma ligand, evolution of the concept in potentiates [3H]acetylcholine release neuropsychopharmacology. Curr from rat hippocampal slices. Eur J Neuropharmacol. 2005;3(4):267-280. Pharmacol. 1991;200(2-3):343-345. 9. Hayashi T, Su TP. Sigma-1 receptors 19. Kobayashi T, Matsuno K, Nakata K, Mita at galactosylceramide-enriched lipid S. Enhancement of acetylcholine release microdomains regulate oligodendrocyte by SA4503, a novel sigma 1 receptor differentiation. Proc Natl Acad Sci U S A. agonist, in the rat brain. J Pharmacol Exp 2004;101(41):14949-14954. Ther. 1996;279(1):106-113. 10. Maurice T. Neurosteroids and sigma1 20. Meyer DA, Carta M, Partridge LD, receptors, biochemical and behavioral Covey DF, Valenzuela CF. Neurosteroids relevance. Pharmacopsychiatry. enhance spontaneous glutamate release 2004;37 Suppl 3:S171-S182. in hippocampal neurons - Possible role of 11. Maurice T, Phan VL, Urani A, Kamei metabotropic sigma(1)-like receptors. J H, Noda Y, Nabeshima T. Neuroactive Biol Chem. 2002;277(32):28725-28732. neurosteroids as endogenous 21. Hayashi T, Su TP. Intracellular dynamics effectors for the sigma1 (sigma1) of sigma-1 receptors (sigma(1) binding receptor: pharmacological evidence sites) in NG108-15 cells. J Pharmacol and therapeutic opportunities. Jpn J Exp Ther. 2003;306(2):726-733. Pharmacol. 1999;81(2):125-155. 22. Hayashi T, Su TP. Sigma-1 receptor 12. Maurice T, Urani A, Phan VL, Romieu P. chaperones at the ER-mitochondrion The interaction between neuroactive interface regulate Ca(2+) signaling and steroids and the sigma1 receptor cell survival. Cell. 2007;131(3):596-610. THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 51

23. Hayashi T, Su TP. Sigma-1 receptors (+)-N-allylnormetazocine-Brain Res stimulated at galactosylceramide-enrichedProc Natl Acad Sci U lipid S A hippocampal cholinergic functions in microdomains regulate oligodendrocyte rats. . 1995;690(2):200-206. differentiation. . 33. Kobayashi T, Matsuno K, Mita S. Regional 2 2004;101(41):14949-14954. differences of the effectJ Neural of Transm sigma 24. Hayashi T, Su TP. An update on Genreceptor Sect ligands on the acetylcholine the development of drugsExpert for release in the rat brain. Opinneuropsychiatric Ther Targets disorders: focusing . 1996;103(6):661-669. on the sigma(1) receptor ligand. 34. Matsuno K, Senda T, Kobayashi T, . 2008;12(1):45-58. Okamoto K, Nakata K, Mita S. SA4503,Behav a 25. Takebayashi M, Hayashi T, Su TP. A Brainnovel Rescognitive enhancer, with sigma-1 perspective on the Pharmacopsychiatry new mechanism of receptor agonistic properties. antidepressants: neuritogenesis through . 1997;83:221-224. sigma-1 receptors. . 35. Antonini V, Prezzavento O, Coradazzi 2004;37 Suppl 3:S208-S213. M et al. Anti-amnesic properties of 26. Tsai SY, Hayashi T, Su TP. Hippocampal (+/-)-PPCC, a novel sigma receptorJ dendritogenesis and associated Neurochemligand, on cognitive dysfunction induced anchoring ofInt NMDA J Neuropsychopharmacol and AMPA receptors by selective cholinergic lesion in rats. are controlled by sigma-1 receptors . 2009;109(3):744-754. [abstract]. . 36. Antonini V, Prezzavento O, Coradazzi 2006;9(Suppl 1):S213. M et al. Anti-amnesic properties of 27. Marrazzo A, Caraci F, Salinaro ET, (+/-)-PPCC, a novel sigma receptorJ Su TP, Copani A, Ronsisvalle G. Neurochemligand, on cognitive dysfunction induced Neuroprotective effects Neuroreport of sigma-1 by selective cholinergic lesion in rats. receptor agonists against beta- . 2009;109(3):744-754. amyloid-induced toxicity. . 37. Kawamura K, Kimura Y,Neurobiol Tsukada H Aging et al. 2005;16(11):1223-1226. An increase of sigma receptors in the 28. Maurice T, Lockhart BP. NeuroprotectiveProg aged monkey brain. . Neuropsychopharmacoland anti-amnesic potentialsBiol Psychiatry of 2003;24(5):745-752. sigma receptor ligands. 38. Ishii K, Kimura Y, Kawamura K, Oda K, . Sasaki T, Ishiwata K. Mapping of sigma1 1997;21:69-102. receptors Neuroimage by 11C-SA4503-distribution 29. Maurice T. Cognitive effectsSigma Receptors:of sigma- and aging effect in normal human brain. Chemistry,receptor ligands. Cell Biology In: Matsumoto and Clinical RR, [abstract]. . 2002;16(3):S31. ImplicationsBowen WD, Su TP, eds. 39. Jansen KL, Faull RL, Storey P, Leslie RA. Loss of sigma binding sites in the CA1 . New York: Springer; area of the anterior hippocampusBrain Res in 2007:237-271. Alzheimer’s disease correlates with 30. Matsuno K, Matsunaga K, Mita S. CA1 pyramidal cell loss. . Increase of extracellular acetylcholine 1993;623(2):299-302. level in rat frontal cortex inducedBrain Res by 40. Mishina M, Ohyama M, IshiiAnn K Nucl et al. MedLow (+)N-allylnormetazocine as measured density of sigma1 receptors in early by brain microdialysis. . Alzheimer’s disease. . 1992;575(2):315-319. 2008;22(3):151-156. 31. Matsuno K, Matsunaga K, Senda 41. Mishina M, Ohyama M, IshiiAnn K Nucl et al. MedLow T, Mita S. IncreaseJ Pharmacol in extracellular Exp Ther density of sigma1 receptors in early acetylcholine level by sigma ligands in Alzheimer’s disease. . rat frontal cortex. . 2008;22(3):151-156. 1993;265(2):851-859. 42. Uchida N, Ujike H, Tanaka Y et al. A 32. Matsuno K, Senda T, Kobayashi T, Mita variant of the sigma receptor type-1 S. Involvement of sigma 1 receptor in gene is a protective factor for Alzheimer 52

Am J Geriatr Psychiatry Brain Res Dev Brain Res

disease. . brain. . 2005;13(12):1062-1066. 1990;51(2):147-152. 43. Maruszak A, Safranow K, Gacia M et al. 53. Matsuno K, Senda T, Matsunaga K, Mita 2 Sigma receptor type 1 gene variation S. Ameliorating effects of sigma receptor in a group ofDement polish Geriatrpatients Cogn with ligands on the impairment of passive DisordAlzheimer’s disease and mild cognitive Euravoidance J Pharmacol tasks in mice: involvement impairment. in the central acetylcholinergic system. . 2007;23(6):432-438. . 1994;261(1-2):43-51. 44. Mishina M, IshiwataActa K, Neurol Ishii K Scand et al. 54. Matsuno K, Senda T, Matsunaga K, Mita S, Function of sigma1 receptors in Kaneto H. Similar ameliorating effects of Parkinson’s disease. . benzomorphans and 5-HT2 antagonists 2005;112(2):103-107. on drug-induced impairment of 45. Phan VL, Miyamoto Y, Nabeshima T, passive avoidancePsychopharmacology response in mice: Berl Maurice T. Age-related expression of comparison with acetylcholinesterase sigma1 receptors and antidepressant inhibitors. . Jefficacy Neurosci of Res a selective agonist in the 1993;112(1):134-141. senescence-accelerated (SAM) mouse. 55. Maurice T, Phan VL, Privat A. The anti- . 2005;79(4):561-572. amnesic effects of sigma1 (sigma1)Brain 46. Urani A, Romieu P, Roman FJ, Maurice Resreceptor agonists confirmed by in vivo T. Enhanced antidepressant effect antisense strategy in the mouse. of sigma(1) (sigma(1))Behav Brain receptor Res . 2001;898(1):113-121. agonists in beta(25-35)-amyloid 56. Senda T, Matsuno K, Kobayashi T, Mita S. peptide-treated mice. . Reduction of the scopolamine-induced 2002;134(1-2):239-247. impairmentPhysiol of Behav passive- avoidance 47. Urani A, Romieu P, Roman FJ et al. performance by sigma receptor agonist Enhanced antidepressant efficacy in mice. . 1997;61(2):257- of sigma1 receptor agonists in rats 264. Eurafter J Pharmacol chronic intracerebroventricular 57. Nabeshima T, Katoh A, Ishimaru H et infusion of beta-amyloid-(1-40) protein. al. Carbon monoxide-induced delayed . 2004;486(2):151-161. amnesia, delayedJ Pharmacol neuronal Exp death Ther and 48. Phan VL, Urani A, Sandillon F, Privat A, change in acetylcholine concentration Maurice T. Preserved sigma1 (sigma1) in mice. . Neurobiolreceptor Aging expression and behavioral 1991;256(1):378-384. efficacy in the aged C57BL/6 mouse. 58. Brown AW, Aldridge WN, Street BW, . 2003;24(6):865-881. Verschoyle RD. The behavioral andAm 49. Ishiwata K, Kobayashi T, Kawamura Jneuropathologic Pathol sequelae of intoxication K, Matsuno K. Age-related changesAnn Nucl of by trimethyltin compounds in the rat. Medthe binding of [3h]SA4503 to sigma1 . 1979;97(1):59-82. receptors in the rat brain. 59. Chang LW,Neurobehav Dyer RS. A time-course Toxicol Teratol study . 2003;17(1):73-77. of trimethyltin induced neuropathology 50. Majewska MD, Parameswaran S, Vu in rats. . T, London ED. Brain Divergent Res Dev ontogeny Brain Res of 1983;5(4):443-459. sigma and phencyclidine binding sites 60. Maurice T, Phan VL, Privat A. The anti- in the rat brain. . amnesic effects of sigma1 (sigma1)Brain 1989;47(1):13-18. Resreceptor agonists confirmed by in vivo 51. Matsumoto RR, Bowen WD, Walker antisense strategy in the mouse. JM. Age-relatedBrain Res differences in the . 2001;898(1):113-121. sensitivity of rats to a selective sigma 61. Maurice T, Phan VL, Urani A, Guillemain ligand. . 1989;504:145-148. I. Differential involvement of the 52. Paleos GA, Yang ZW, Byrd JC. Ontogeny sigma(1) (sigma(1)) receptor in the of PCP and sigma receptors in rat anti-amnesic effect of neuroactive THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 53

Br Eur Jsteroids, Pharmacol as demonstrated using an in Jserotonin Pharmacol reuptake inhibitors with vivo antisense strategy in the mouse. subtypes of s receptors in rat brain. . 2001;134(8):1731-1741. . 1996;307:117-119. 62. Reddy DS, Kulkarni SK. The effects 70. Ishikawa M, Ishiwata K, Ishii K et al. 2 of neurosteroids on acquisitionBrain and High Occupancy of Sigma-1 Receptors Resretention of a modified passive- in the Human Brain after Single Oral avoidance learning task in mice. Administration of Fluvoxamine:Biol Psychiatry A . 1998;791(1-2):108-116. Positron Emission Tomography Study 63. Chen L, Dai XN, Sokabe M. Chronic Using [(11)C]SA4503. . administration of dehydroepia- 2007;62(8):878-883. ndrosterone sulfate (DHEAS) primes 71. Ishikawa M, Sakata M, Ishii K et al. for facilitated induction of long-term High occupancy of sigma1 receptors potentiation via sigmaNeuropharmacology 1 (sigma1) in the human brain after single oral receptor: optical imaging study in rat administrationInt J Neuropsychopharmacolof donepezil: a positron hippocampal slices. . emission tomography study using [11C] 2006;50(3):380-392. SA4503. . 64. Sabeti J, Nelson TE, Purdy RH, Gruol DL. 2009;12(8):1127-1131. Steroid pregnenolone sulfate enhances 72. Maurice T. Improving Alzheimer’sDrug News NMDA-receptor-independent long- PerspectDisease-Related Cognitive Deficits with term potentiation at hippocampal sigma1 Receptor Agonists. HippocampusCA1 synapses: role for L-type calcium . 2002;15(10):617-625. channels and sigma-receptors. . 2007;17(5):349-369. 73. Marrazzo A, Caraci F, Salinaro ET, Su TP, Copani A, Ronsisvalle G. Neuroprotective 65. Chen L, Dai XN, Sokabe M. Chronic Neuroreporteffects of sigma-1 receptor agonists administration of dehydroepia- against beta-amyloid-induced toxicity. ndrosterone sulfate (DHEAS) primes . 2005;16(11):1223-1226. for facilitated induction of long-term potentiation via sigmaNeuropharmacology 1 (sigma1) 74. Meunier J, Ieni J, Maurice T. The receptor: optical imaging study in rat anti-amnesic and neuroprotective hippocampal slices. . effects of donepezil against amyloid 2006;50(3):380-392. beta(25-35) peptide-inducedBr J Pharmacol toxicity in mice involve an interaction with 66. Schiess AR, Partridge LD. Pregnenolone the sigma(1) receptor. . sulfate acts through a G-protein- 2006;149(8):998-1012. coupled sigma1-like Eur receptor J Pharmacol to enhance short term facilitation in adult 75. Villard V, Espallergues J, Keller E et hippocampal neurons. . al. Antiamnesic and Neuroprotective 2005;518(1):22-29. Effects of the Aminotetrahydrofuran Derivative Neuropsychopharmacology ANAVEX1-41 Against 67. Hashimoto K, Fujita Y, Iyo M. Amyloid beta(25-35)-Induced Toxicity Phencyclidine-induced cognitive in Mice. . deficits in mice are improved by 2009;34(6):1552-1566. subsequentNeuropsychopharmacology subchronic administration of fluvoxamine: role of sigma-1 76. Hall AA, Herrera Y, Ajmo CT, Jr., Cuevas receptors. . J, PennypackerGlia KR. Sigma receptors 2007;32(3):514-521. suppress multiple aspects of microglial activation. . 2008;57(7):744-754. 68. Iyo M, Shirayama Y, Watanabe H et al. Fluvoxamine as a sigma-1 receptorProg 77. Cobos EJ, Entrena JM, Nieto FR, Cendan Neuropsychopharmacolagonist improved cognitive Biol impairments Psychiatry CM, Del Pozo E.Curr Pharmacology Neuropharmacol and in a patient with schizophrenia. therapeutic potential of sigma(1) . receptor ligands. . 2008;32:1072-1073. 2008;6(4):344-366. 69. Narita N, Hashimoto K, Tomitaka S, 78. Collier TL, Waterhouse RN, Kassiou M. Minabe Y. Interactions of selective Imaging sigma receptors: applications 54

Curr Pharm Des

in drug development. . 89. Harris EW, Ganong AH, Cotman 2007;13(1):51-72. CW. Long-term potentiation inBrain the 79. Hashimoto K, Ishiwata K. Sigma Reshippocampus involves activation of N- methyl-D-aspartate receptors. 2 receptor ligands: possibleCurr applicationPharm Des as therapeutic drugs and as . 1984;323(1):132-137.Trends Pharmacol Sci radiopharmaceuticals. . 90. Izquierdo I. Role of NMDA receptors 2006;12(30):3857-3876. in memory. . 1991;12(4):128-129. 80. Hayashi T, Su TP. An update on the development of drugsExpert for 91. Bliss TV, Collingridge GL. A synapticNature Opinneuropsychiatric Ther Targets disorders: focusing model of memory: long-term on the sigma(1) receptor ligand. potentiation in the hippocampus. . . 2008;12(1):45-58. 1993;361(6407):31-39. Pharmacol Ther Physiol Rev 81. Maurice T, Su TP. The pharmacology of 92. Lynch MA. Long-term potentiation and sigma-1 receptors. . 2009. memory. Int J Neurol. 2004;84(1):87-136. 82. CurrAigner Opin TG. Neurobiol Pharmacology of memory: 93. Teyler TJ. Long-term potentiation and cholinergic-glutamatergic interactions. memory. . 1987;21-22:163- . 1995;5(2):155-160. 171. 83. Meyer DA, Carta M, Partridge LD, 94. Cory-Slechta DA. The Psychopharmacolimpact of NMDA Covey DF, Valenzuela CF. Neurosteroids Bullreceptor antagonists on learning and enhance spontaneous glutamate memory functions. release in hippocampalJ Biol neurons Chem . 1994;30(4):601-612. - Possible role of metabotropic 95. Morris RG, Anderson E, Lynch GS, sigma(1)-like receptors. . Baudry M. Selective impairment of 2002;277(32):28725-28732. learning and blockade of long-term 84. Dong Y, Fu YM, Sun JL, Zhu YH, Sun Naturepotentiation by an N-methyl-D- FY, Zheng P. Neurosteroid enhances aspartate receptor antagonist, AP5. glutamate release in rat prelimbicCell . 1986;319(6056):774-776. Molcortex Life Sci via activation of alpha1- 96. Parada-Turska J, Turski WA. Excitatory adrenergic and sigma1 receptors. amino acid antagonists and memory: . 2005;62(9):1003-1014. effect of drugs actingNeuropharmacology at N-methyl-D- 85. Dong LY, Cheng ZX, Fu YM et al. aspartate receptors in learning and Neurosteroid dehydroepiandrosterone memory tasks. . sulfate enhances spontaneous 1990;29(12):1111-1116. glutamate release inNeuropharmacology rat prelimbic cortex 97. Venable N, Kelly PH. Effects of NMDA through activation of dopamine D1 and receptor Psychopharmacology antagonists on passive (Berl) sigma-1 receptor. . avoidance learning and retrieval in rats 2007;52(3):966-974. and mice. . 86. Yagasaki Y, Numakawa T, Kumamaru 1990;100(2):215-221. E, Hayashi T, Su TP, Kunugi H. Chronic 98. Tsien JZ, Huerta PT, Tonegawa S. The antidepressants potentiate via essential role of hippocampal CA1Cell sigma-1 receptors the brain-derivedJ Biol Chem NMDA receptor-dependent synaptic neurotrophic factor-induced signaling plasticity in spatial memory. . for glutamate release. . 1996;87(7):1327-1338. 2006;281(18):12941-12949. 99. Bergeron R, de Montigny C, Debonnel 87. NatureArtola A, Singer W. Long-term potentiation G. BiphasicNaunyn effects Schmiedebergsof sigma ligands Arch on and NMDA receptors in rat visual cortex. Pharmacolthe neuronal response to N- methyl-D- . 1987;330(6149):649-652. aspartate. 88. CollingridgeNature G. Synaptic plasticity. The . 1995;351(3):252-260. role of NMDA receptors in learning and 100. Bergeron R, de Montigny C, Debonnel G. memory. . 1987;330(6149):604- Potentiation of neuronal NMDA response 605. induced by dehydroepiandrosterone THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 55

Eur J Pharmacol J Neurosciand its suppression by progesterone: sigma receptor ligands. . effects mediated via sigma receptors. 1993;240(2-3):319-323. . 1996;16:1193-1202. 110. Monnet FP, de Costa BR, Bowen WD. 101. Bergeron R, Debonnel G, de Montigny Differentiation of sigma ligand-activated 2 C. Modification of theEur N-methyl-D-J Pharmacol receptor subtypes that modulateBr J Pharmacol NMDA- aspartate response by antidepressant evoked [3H]-noradrenaline release in sigma receptor ligands. . rat hippocampal slices. . 1993;240(2-3):319-323. 1996;119(1):65-72. 102. Debonnel G, Bergeron R, de Montigny C. 111. Liang X, Wang RY. Biphasic modulatory Potentiation by dehydroepiandrosterone action of the selective sigma receptor of the neuronal response to N-methyl- ligand SR 31742A on N-methyl-D-Brain Res D-aspartate in the CA3 regionJ Endocrinol of the rat aspartate-induced neuronal responses dorsal hippocampus: an effect mediated in the frontal cortex. . via sigma receptors. . 1998;807(1-2):208-213. 1996;150 Suppl:S33-42. 112. Liang X, Wang RY. Biphasic modulatory 103. Monnet FP, Debonnel G, de Montigny C. action of the selective sigma receptor In vivo electrophysiological evidence for ligand SR 31742A on N-methyl-D-Brain Res a selective modulation of N-methyl-D- aspartate-induced neuronal responses aspartate-inducedJ Pharmacol neuronal Expactivation Ther in the frontal cortex. . in rat CA3 dorsal hippocampus by 1998;807(1-2):208-213. sigma ligands. . 113. Martina M, Turcotte ME, Halman S, 1992;261(1):123-130. Bergeron R. The sigma-1 receptor 104. Monnet FP, Debonnel G, Fournier A, de modulates NMDA receptor J synaptic Physiol Montigny C. Neuropeptide Y potentiates transmission and plasticity via SK the N-methyl-D-aspartate responseJ Pharmacol in the channels in rat hippocampus. . ExpCA3 Ther dorsal hippocampus. II. Involvement 2007;578(Pt 1):143-157. of a subtype of sigma receptor. 114. Itzhak Y, Stein I, Zhang SH, Kassim CO, . 1992;263(3):1219-1225. Cristante D. Binding of sigma-ligands 105. Monnet FP, Debonnel G, Junien JL, de to C57BL/6 mouse brain membranes: Montigny C. N-methyl-D-aspartate-Eur J effects of monoamine oxidase Pharmacolinduced neuronal activation is selectively inhibitors and subcellularJ Pharmacol distribution Exp modulated by sigma receptors. Therstudies suggest the existence of sigma- . 1990;179(3):441-445. receptor subtypes. . 1991;257(1):141-148. 106. Bergeron R, de MontignyBr J C, Pharmacol Debonnel G. Pregnancy reduces brain sigma 115. Jiang G, Mysona B, Dun Y et al. receptor function. . Expression, subcellularInvest localization,Ophthalmol 1999;127(8):1769-1776. Visand Sci regulation of sigma receptor in 107. Debonnel G, Bergeron R, Monnet FP, de retinal muller cells. Montigny C. Differential effects of sigma . 2006;47(12):5576-5582. ligands on the N-methyl-D- aspartate 116. McCann DJ, Su TP. Haloperidol-sensitive response in the CA1 andNeuroscience CA3 regions (+)[3H]SKF-10,047 binding sites (sigmaEur J of the dorsal hippocampus: effect of Pharmacolsites) exhibit a unique distribution in mossy fiber lesioning. . rat brain subcellular fractions. 1996;71(4):977-987. . 1990;188(4-5):211-218. 108. Couture S, Debonnel G. Modulation of 117. Phan VL, Urani A, Sandillon F, Privat A, Synapsethe neuronal response to N-methyl-D- Maurice T. Preserved sigma1 (sigma1) aspartate by selective sigma2 ligands. Neurobiolreceptor Aging expression and behavioral . 1998;29(1):62-71. efficacy in the aged C57BL/6 mouse. 109. Bergeron R, Debonnel G, de Montigny . 2003;24(6):865-881. C. Modification of the N-methyl-D- 118. Samovilova NN, Vinogradov VA. aspartate response by antidepressant Subcellular distribution of (+)-[3H]SKF 56

Eur J Pharmacol 10,047 binding sites in rat liver. 127. Klette KL, Lin Y, Clapp LE, DeCoster MA, . 1992;225(1):69-74. Moreton JE, Tortella FC. Neuroprotective 119. Ela C, Barg J, Vogel Z, Hasin Y, Eilam sigma ligands attenuate NMDABrain Resand 2 Y. Sigma receptor ligandsJ Pharmacol modulate trans-ACPD- induced calcium signaling Expcontractility, Ther Ca++ influx and beating rate in rat primary neurons. . in cultured cardiac myocytes. 1997;756(1-2):231-240. . 1994;269(3):1300-1309. 128. Urani A, Romieu P, Portales- 120. Novakova M, Ela C, Bowen WD, Hasin Casamar E, Roman FJ, Maurice T. The Y, Eilam Y. Highly selective sigma antidepressant-like effect induced receptor ligands Eur elevate J Pharmacol inositol by the sigma(1) (sigma(1)) receptor 1,4,5- trisphosphate production in rat Psychopharmacologyagonist igmesine involves modulation (Berl) cardiac myocytes. . of intracellular calcium mobilization. 1998;353(2-3):315-327. . 2002;163(1):26-35. 121. Hayashi T, Maurice T, Su TP. Ca(2+) signaling via sigma(1)-receptors:J 129. Maurice T, Su TP, Parish DW, Privat A. Pharmacolnovel regulatory Exp Ther mechanism affecting Prevention of nimodipine-inducedJ Neural Transm intracellular Ca(2+) concentration. Genimpairment Sect of learning by the selective . 2000;293(3):788- sigma ligand PRE-084. 798. . 1995;102:1-18. 122. Hong W, Nuwayhid SJ, Werling LL. 130. Monnet FP. Sigma-1 receptor as Modulation of bradykinin-induced Biolregulator Cell of neuronal intracellular calcium changes in SH-SY5Y cells by Ca2+: clinical and therapeutic relevance. Synapseneurosteroids and sigma receptor . 2005;97(12):873-883. ligands via a shared mechanism. 131. Hayashi T, Su T. The sigma receptor:Curr . 2004;54(2):102-110. Neuropharmacolevolution of the concept in 123. Wu Z, Bowen WD. Role of sigma-1 neuropsychopharmacology. receptor C-terminal segment in IP3 . 2005;3(4):267-280. receptor activation: J Constitutive Biol Chem 132. Hayashi T, Su TP. Sigma-1 receptors enhancement of calcium signaling at galactosylceramide-enrichedProc Natl Acad Sci U lipid S A in MCF-7 tumor cells. . microdomains regulate oligodendrocyte 2008;283:28198-28215. differentiation. . 124. Morin-Surun MP, Collin T, Denavit- 2004;101(41):14949-14954. Saubie M, Baulieu EE, Monnet FP. 133. Takebayashi M, Hayashi T, Su TP. Intracellular sigma(1) receptor Nerve growth factor-induced neurite modulates phospholipase C and protein Proceedings of the National Academy of sprouting in PC12J Pharmacol cells Exp involves Ther Scienceskinase C of activities the United in States the of brainstem. America sigma-1 receptors: implications for antidepressants. . . 2002;303(3):1227-1237. 1999;96(14):8196-8199. 134. Hayashi T, Su TP. Sigma-1 receptors 125. Monnet FP, Morin-Surun MP, Leger at galactosylceramide-enrichedProc Natl Acad Sci U lipid S A J, Combettes L. Protein kinase C- microdomains regulate oligodendrocyte dependent potentiation of intracellularJ differentiation. . Pharmacolcalcium influx Exp Ther by sigma1 receptor 2004;101(41):14949-14954. agonists in rat hippocampal neurons. . 2003;307(2):705- 135. Palacios G, Muro A, Vela JM et al. 712. Immunohistochemical localizationBrain of the sigma1-receptor in oligodendrocytes 126. Hayashi T, Kagaya A, Takebayashi M Res et al. Modulation by sigma ligands of in the rat central nervous system. . 2003;961(1):92-99. intracellular free Ca++ mobilizationJ Pharmacol by N- Expmethyl-D-aspartate Ther in primary culture of 136. Palacios G, Muro A, Verdu E, Pumarola rat frontal cortical neurons. M, Vela JM. Immunohistochemical . 1995;275(1):207-214. localization of the sigma1 receptor in THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 57

Brain Res Schwann cells of rat sciatic nerve. 146. Kato K, Hayako H, Ishihara Y, Marui S, . 2004;1007(1-2):65-70. Iwane M, Miyamoto M. TAK-147, an 137. Hayashi T, Su TP. Sigma-1 receptors acetylcholinesterase inhibitor, increases Neuroscicholine Lett acetyltransferase activity in at galactosylceramide-enrichedProc Natl Acad Sci U lipid S A 2 microdomains regulate oligodendrocyte cultured rat septal cholinergic neurons. . 1999;260(1):5-8. differentiation. . 2004;101(41):14949-14954. 147. Ishima T, Nishimura T, Iyo M, Hashimoto K. Potentiation of nerve growth factor- 138. Demerens C, Stankoff B, Zalc B, Lubetzki induced neurite outgrowth in PC12Prog NeurologyC. Eliprodil stimulates CNS myelination: Neuropsychopharmacolcells by donepezil: Role Biol ofPsychiatry sigma-1 new prospects for multiple sclerosis? receptors and IP(3) receptors. . 1999;52(2):346-350. . 139. Hayashi T, Su TP. The potential role of 2008;32:1656-1659. sigma-1 receptors in lipid transport Life 148. Oda T, Kume T, Katsuki H, Niidome and lipid raft reconstitution in the Sci T, Sugimoto H, Akaike A. DonepezilJ brain: implication for drug abuse. Pharmacolpotentiates Sci nerve growth factor-induced . 2005;77(14):1612-1624. neurite outgrowth in PC12 cells. 140. Takebayashi M, Hayashi T, Su TP. A . 2007;104(4):349-354. perspective on the Pharmacopsychiatry new mechanism of 149. Ishima T, Nishimura T, Iyo M, Hashimoto antidepressants: neuritogenesis through K. Potentiation of nerve growth factor- sigma-1 receptors. . induced neurite outgrowth in PC12Prog 2004;37 Suppl 3:S208-S213. Neuropsychopharmacolcells by donepezil: Role Biol ofPsychiatry sigma-1 141. Takebayashi M, Hayashi T, Su TP. receptors and IP(3) receptors. sigma-1 receptors potentiate epidermal . growth factor signaling towards 2008;32:1656-1659. Synapseneuritogenesis in PC12 cells: Potential 150. Nishimura T, Ishima T, Iyo M, Hashimoto relation to lipid raft reconstitution. K. Potentiation of nerve growth . 2004;53(2):90-103. factor-induced neurite outgrowth by 142. Yagasaki Y, Numakawa T, Kumamaru fluvoxamine:PLoS role ONE of sigma-1 receptors, E, Hayashi T, Su TP, Kunugi H. Chronic IP3 receptors and cellular signaling antidepressants potentiate via pathways. . 2008;3(7):e2558. sigma-1 receptors the brain-derivedJ Biol Chem 151. Earley B, Burke M, Leonard BE, Gouret CJ, neurotrophic factor-induced signaling Junien JL. Evidence for an anti-amnesic for glutamate release. . Braineffect Resof JO 1784 in the rat: a potent and 2006;281(18):12941-12949. selective ligand for the sigma receptor. 143. Yeh LA, Padmanaban D, Ho P et al. Effects . 1991;546(2):282-286. of a verbenachalcone derivativeBioorg on 152. Senda T, Matsuno K, Okamoto K, Kobayashi Medneurite Chem outgrowth, Lett inhibition of caspase T, Nakata K, Mita S. Ameliorating effect of induction and gene expression. SA4503, a novel sigma 1 receptor agonist,Eur J . 2005;15(4):1193-1196. Pharmacolon memory impairments induced by 144. Hayashi T, Su TP. Sigma-1 receptors cholinergic dysfunction in rats. at galactosylceramide-enrichedProc Natl Acad Sci U lipid S A . 1996;315(1):1-10. microdomains regulate oligodendrocyte 153. Senda T, Matsuno K, Kobayashi differentiation. . T, Nakazawa M, Nakata K, Mita S. 2004;101(41):14949-14954. Ameliorative effect of SA4503, a novel 145. Lucas G, Rymar VV, Sadikot AF, Debonnel cognitive enhancer, on the basalPharmacol forebrain G. Further evidence for an antidepressant Biochemlesion-induced Behav impairment of the spatial potential of the selective sigma1 learning performance in rats. agonist SAInt 4503: J Neuropsychopharmacol electrophysiological, . 1998;59(1):129-134. morphological and behavioural 154. Urani A, Privat A, Maurice T. The studies. . modulation by neurosteroids of 2008;11(4):485-495. the scopolamine-induced learning 58

impairmentBrain in Res mice involves an (+/-)-PPCC, a novel sigma receptorJ interaction with sigma1 (sigma1) Neurochemligand, on cognitive dysfunction induced receptors. . 1998;799(1):64-77. by selective cholinergic lesion in rats. 2 155. Maurice T, Phan VL, Privat A. The anti- . 2009;109(3):744-754. amnesic effects of sigma1 (sigma1)Brain 164. Mamiya T, Noda Y, Noda A et al. Resreceptor agonists confirmed by in vivo Effects of sigma receptor agonists antisense strategy in the mouse. on the impairment of spontaneous . 2001;898(1):113-121. alternation behavior and decrease of cyclic GMP levelNeuropharmacology induced by nitric 156. Tottori K, Nakai M, Uwahodo Y et al. oxide synthase inhibitors in mice [In Attenuation of scopolamine-induced and Process Citation]. . age-associated memory impairments by 2000;39(12):2391-2398. the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 165. Maurice T, Su TP, Privat A. Sigma1 (1-[3-[4-(3-chlorophenyl)-1- (sigma 1) receptor agonists and piperazinyl]propyl]-5-methoxy-3,4-J Pharmacol neurosteroids attenuate B25-35- Expdihydro-2[1H]-quinolinone Ther Neuroscienceamyloid peptide-induced amnesia in monomethanesulfonate). mice through a common mechanism. . 2002;301(1):249-257. . 1998;83(2):413-428. 157. Ivkovic M, Damjanovic A, Jasovic- 166. Meunier J, Ieni J, Maurice T. The Gasic M, Paunovic VR. The effects of anti-amnesic and neuroprotective Psychiatrfluoxetine Danub on cognitive functions in effects of donepezil against amyloid animal model of Alzheimer’s disease. beta(25-35) peptide-inducedBr J Pharmacol toxicity . 2004;16(1-2):15-20. in mice involve an interaction with the sigma(1) receptor. . 158. Hiramatsu M, Hoshino T, Kameyama T, 2006;149(8):998-1012. Nabeshima T. InvolvementEur J Pharmacol of kappa- opioid and sigma receptors in short- 167. Wang HH, Chien JW, Br Chou J Pharmacol YC, Liao term memory in mice. . JF, Chen CF. Anti-amnesic effect of 2002;453(1):91-98. dimemorfan in mice. . 2003;138(5):941-949. 159. Hiramatsu M, Hoshino T. Involvement of kappa-opioid receptors and 168. Maurice T, Roman FJ, Su TP, Privat A. Brainsigma Res receptors in memory function Beneficial effects of sigma agonists on demonstrated using an antisense strategy. the age-relatedBrain Res learning impairment . 2004;1030(2):247-255. in the senescence-accelerated mouse (SAM). . 1996;733(2):219-230. 160. Hiramatsu M, Hoshino T. Improvement 169. Maurice T. Beneficial effect of the of memory impairment byBrain (+)- Resand (-)-pentazocine via sigma, but not sigma(1) receptor Eur agonist J Pharmacol PRE- kappa opioid receptors. . 084 against the spatial learning 2005;1057(1-2):72-80. deficits in aged rats. . 2001;431(2):223-227. 161. Espallergues J, Lapalud P, Christopoulos 170. Tottori K, Nakai M, Uwahodo Y et al. A et al. Involvement of the sigma1 Attenuation of scopolamine-induced and (sigma1) receptor in the anti-amnesic, age-associated memory impairments by but not antidepressant-like, effects of Br J Pharmacol the sigma and 5-hydroxytryptamine(1A) the aminotetrahydrofuran derivative receptor agonist OPC-14523 ANAVEX1-41. . (1-[3-[4-(3-chlorophenyl)-1- 2007;152(2):267-279. piperazinyl]propyl]-5-methoxy-3,4-J Pharmacol 162. Wang HH, Chien JW, Br Chou J Pharmacol YC, Liao Expdihydro-2[1H]-quinolinone Ther JF, Chen CF. Anti-amnesic effect of monomethanesulfonate). dimemorfan in mice. . . 2002;301(1):249-257. 2003;138(5):941-949. 171. Phan VL, Urani A, Sandillon F, Privat A, 163. Antonini V, Prezzavento O, Coradazzi Maurice T. Preserved sigma1 (sigma1) M et al. Anti-amnesic properties of receptor expression and behavioral THE CHOLINERGIC SYSTEM, SIGMA-1 RECEPTORS AND COGNITION 59

Neurobiol Aging efficacy in the aged C57BL/6 mouse. 180. Maurice T, Hiramatsu M, Itoh J, . 2003;24(6):865-881. Kameyama T, Hasegawa T, Nabeshima 172. Maurice T, Hiramatsu M, Kameyama T, T. Behavioral evidence for a modulating Hasegawa T, Nabeshima T. Behavioral role of sigma ligands in Brain memory Res 2 evidence for a modulating role of processes. I. Attenuation of dizocilpine sigma ligandsBrain in Res memory processes. II. (MK-801)-induced amnesia. . Reversion of carbon monoxide-induced 1994;647(1):44-56. amnesia. . 1994;647(1):57-64. 181. Ohno M, Watanabe S. Intrahippocampal 173. Maurice T, Phan VL, Noda Y, Yamada K, administration of (+)-SKF 10,047, a Privat A, Nabeshima T. The attenuation Brainsigma Res ligand, reverses MK-801-induced of learning impairments induced after impairment of working memory in rats. exposure to CO or trimethyltin in mice . 1995;684:237-242. Brby J Pharmacol sigma (sigma) receptor ligands 182. Maurice T, Junien JL, Privat A. involves both sigma1 and sigma2 sites. Dehydroepiandrosterone sulfate . 1999;127(2):335-342. Behavattenuates Brain dizocilipine-induced Res learning 174. Maurice T, Phan V, Sandillon F, impairment in mice via sigma-1 receptors. Urani A. Differential effect of . 1997;83:159-164. dehydroepiandrosterone and its steroid 183. Maurice T, Privat A. SA4503, a novel Eurprecursor J Pharmacol pregnenolone against the cognitive enhancer with sigma1 behavioural deficits in CO-exposed mice. receptorEur agonistJ Pharmacol properties, facilitates . 2000;390(1-2):145- NMDA-receptor-dependent learning in 155. mice. . 1997;328:9-18. 175. Meunier J, Ieni J, Maurice T. Antiamnesic 184. Zou LB, Yamada K, Nabeshima T. Sigma and neuroprotective effects of receptor ligands (+)-SKF10,047 Eur and J donepezil againstJ learning Pharmacol impairments Exp Ther PharmacolSA4503 improve dizocilpine- induced induced in mice by exposure to carbon spatial memory deficits in rats. monoxide gas. . . 1998;355(1):1-10. 2006;317(3):1307-1319. 185. Zou L, Yamada K, Sasa M, Nakata Y, 176. O’Connell AW, Earley B, Leonard BE. Nabeshima T. Effects of sigma(1) The sigma ligand JO 1784 prevents receptor agonist SA4503 and Pharmacoltrimethyltin-induced Toxicol behavioural and neuroactive steroidsNeuropharmacology on performance sigma-receptor dysfunction in the rat. in a radial arm maze task in rats [In . 1996;78(5):296-302. Process Citation]. . 177. Maurice T, Phan VL, Noda Y, Yamada K, 2000;39(9):1617-1627. Privat A, Nabeshima T. The attenuation 186. Maurice T, Phan VL, Privat A. The anti- of learning impairments induced after amnesic effects of sigma1 (sigma1)Brain exposure to CO or trimethyltin in mice Resreceptor agonists confirmed by in vivo Brby J Pharmacol sigma (sigma) receptor ligands antisense strategy in the mouse. involves both sigma1 and sigma2 sites. . 2001;898(1):113-121. . 1999;127(2):335-342. 187. Maurice T, Phan VL, Urani A, Guillemain 178. Meunier J, Gue M, Recasens M, Maurice I. Differential involvement of the T. Attenuation by a sigma1 (sigma1) sigma(1) (sigma(1)) receptor in the receptor agonist of the learning Br and J anti-amnesic effect of neuroactiveBr Pharmacolmemory deficits induced by a prenatal Jsteroids, Pharmacol as demonstrated using an in restraint stress in juvenile rats. vivo antisense strategy in the mouse. . 2004;142(4):689-700. . 2001;134(8):1731-1741. 179. Meunier J, Maurice T. Beneficial effects of 188. Noda A, Noda Y, Kamei H et al. the sigma1 receptor agonists igmesine Phencyclidine impairs latent and dehydroepiandrosteroneNeurotoxicol Teratol against learning in Neuropsychopharmacologymice: interaction between learning impairments in rats prenatally glutamatergic systems and sigma(1) exposed to cocaine. . receptors. . 2004;26(6):783-797. 2001;24(4):451-460. 60

Curr Neuropharmacol 189. Maurice T, Meunier J, Feng B, Ieni therapeutic potential of sigma(1) J, Monaghan DT. Interaction with receptor ligands. . sigma(1) protein, but not N-methyl-D-J 2008;6(4):344-366. 2 Pharmacolaspartate receptor,Exp Ther is involved in the 194. Hayashi T, Su TP. An update on pharmacological activity of donepezil. the development of drugsExpert for . 2006;317(2):606- Opinneuropsychiatric Ther Targets disorders: focusing 614. on the sigma(1) receptor ligand. 190. Hashimoto K, Fujita Y, Iyo M. . 2008;12(1):45-58. Phencyclidine-induced cognitive 195. Kawamura K, Kimura Y,Neurobiol Tsukada H Aging et al. deficits in mice are improved by An increase of sigma receptors in the subsequentNeuropsychopharmacology subchronic administration aged monkey brain. . of fluvoxamine: role of sigma-1 2003;24(5):745-752. receptors. . 2007;32(3):514-521. 196. Norbury R, Travis MJ, Erlandsson K et al. In vivo imaging of muscarinic 191. Kunitachi S, Fujita Y, Ishima T et al. receptors in the aging femaleExp brain Gerontol with Phencyclidine-induced cognitive (R,R)[123I]-I-QNB and single photon deficits in mice are ameliorated by emission tomography. . Brainsubsequent Res subchronic administration 2005;40(3):137-145. of donepezil: Role of sigma-1 receptors. . 2009. 197. Sheline YI, Mintun MA, Moerlein SM,Am JSnyder Psychiatry AZ. Greater loss of 5-HT(2A) 192. Matsuno K, Senda T, Kobayashi T, Murai receptors in midlife than in late life. M, Mita S. Reduction of 4-cyclohexyl-1- . 2002;159(3):430-435. [(1R)-1,2-diphenylethyl]-piperazine- induced memory impairmentMethods of passive Find 198. Inoue M, Suhara T, Sudo Y et al. Age- Expavoidance Clin Pharmacol performance by sigma 1 relatedLife Sci reduction of extrastriatal receptor agonists in mice. dopamine D2 receptor measured by . 1998;20(7):575-580. PET. . 2001;69(9):1079-1084. 193. Cobos EJ, Entrena JM, Nieto FR, Cendan CM, Del Pozo E. Pharmacology and