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The aggregation of Amyloid-β (Aβ) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ1 receptor chaperone and as σ1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ1 receptor. We report that Amylovis-201 is a potent σ1 agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ1 receptors. Furthermore, we show for the first time that classical σ1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

The aggregation of Amyloid- β (A β) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with A β species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ 1 receptor chaperone and as σ 1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ 1 receptor. We report that Amylovis-201 is a potent σ 1 agonist by several in silico , in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ 1 receptors. Furthermore, we show for the first time that classical σ 1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate A β 25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting A β 25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ 1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD. Amylovis-201, known to interfere with Amyloid- β aggregation, also acts as a sigma-1 agonist in vitro and in vivo. The drug is therefore a dual-acting compound with synergic extracellular and intracellular modes of action. [Display omitted] [ABSTRACT FROM AUTHOR]

Key points Question: Do GluN2B radioligands 11C-NR2B-Me enantiomers show cross-binding with σ1 receptors in brain in vivo? Pertinent findings: 11C-(+)-NR2B-Me, 11C-(−)-NR2B-Me, 11C-(S)-NR2B-SMe, and 11C-(R)-NR2B-SMe give specific signals in whole rat brain that could be pre-blocked and displaced using ligands that specifically target GluN2B receptors, but not by σ1 ligand FTC-146. Implications for patient care: 11C-(−)-NR2B-Me does not show cross-binding with σ1 receptor in rat brain using PET imaging. This radioligand may be promising for human PET imaging.

Introduction: We recently reported 11C-NR2B-SMe ([S-methyl-11C](R,S)-7-thiomethoxy-3-(4-(4-methyl-phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol) and its enantiomers as candidate radioligands for imaging the GluN2B subunit within rat N-methyl-D-aspartate receptors. However, these radioligands gave unexpectedly high and displaceable binding in rat cerebellum, possibly due to cross-reactivity with sigma-1 (σ1) receptors. This study investigated 11C-labeled enantiomers of a close analogue (7-methoxy-3-(4-(p-tolyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol; NR2B-Me) of 11C-NR2B-SMe as new candidate GluN2B radioligands. PET was used to evaluate these radioligands in rats and to assess potential cross-reactivity to σ1 receptors. Methods: NR2B-Me was assayed for binding affinity and selectivity to GluN2B in vitro. 11C-NR2B-Me and its enantiomers were prepared by Pd-mediated treatment of boronic ester precursors with 11C-iodomethane. Brain PET scans were conducted after radioligand intravenous injection into rats. Various ligands for GluN2B receptors or σ1 receptors were administered at set doses in pre-blocking or displacement experiments to assess their impact on imaging data. 18F-FTC146 and enantiomers of 11C-NR2B-SMe were used for comparison. Radiometabolites from brain and plasma were measured ex vivo and in vitro. Results: NR2B-Me enantiomers showed high GluN2B affinity and selectivity in vitro. 11C-NR2B-Me enantiomers gave high early whole rat brain uptake of radioactivity, including high uptake in cerebellum, followed by slower decline. Radioactivity in brain at 30 min ex vivo was virtually all unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. When 11C-(R)-NR2B-Me was used, three high-affinity GluN2B ligands—NR2B-SMe, Ro25-6981, and CO101,244—showed increasing pre-block of whole brain radioactivity retention with increasing dose. Two σ1 receptor antagonists, FTC146 and BD1407, were ineffective pre-blocking agents. Together, these results strongly resemble those obtained with 11C-NR2B-SMe enantiomers, except that 11C-NR2B-Me enantiomers showed faster reversibility of binding. When 18F-FTC146 was used as a radioligand, FTC146 and BD1407 showed strong pre-blocking effects whereas GluN2B ligands showed only weak blocking effects. Conclusion: 11C-NR2B-Me enantiomers showed specific binding to GluN2B receptors in rat brain in vivo. High unexpected specific binding in cerebellum was not due to σ1 receptors. Additional investigation is needed to identify the source of the high specific binding. Key points: Question: Do GluN2B radioligands 11C-NR2B-Me enantiomers show cross-binding with σ1 receptors in brain in vivo? Pertinent findings: 11C-(+)-NR2B-Me, 11C-(−)-NR2B-Me, 11C-(S)-NR2B-SMe, and 11C-(R)-NR2B-SMe give specific signals in whole rat brain that could be pre-blocked and displaced using ligands that specifically target GluN2B receptors, but not by σ1 ligand FTC-146. Implications for patient care: 11C-(−)-NR2B-Me does not show cross-binding with σ1 receptor in rat brain using PET imaging. This radioligand may be promising for human PET imaging. [ABSTRACT FROM AUTHOR]

The σ1 receptor (σ1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of σ1-R's physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-R function, namely the receptor endogenous ligand(s) and the molecular mechanism of ligand access to the binding site, have not yet been unequivocally determined. In this work, we performed molecular dynamics (MD) simulations to help clarify the potential route of access of ligand(s) to the σ1-R binding site, on which discordant results had been reported in the literature. Further, we combined computational and experimental procedures (i.e., virtual screening (VS), electron density map fitting and fluorescence titration experiments) to provide indications about the nature of σ1-R endogenous ligand(s). Our MD simulations on human σ1-R suggested that ligands access the binding site through a cavity that opens on the protein surface in contact with the membrane, in agreement with previous experimental studies on σ1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred σ1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human σ1-R, with significantly higher affinity than the prototypic σ1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological σ1-R ligands. [ABSTRACT FROM AUTHOR]

The σ 1 and σ 2 receptors are enigmatic proteins that have attracted attention for decades due to the chemical diversity and therapeutic potential of their ligands. However, despite ongoing clinical trials with σ receptor ligands for multiple conditions, relatively little is known regarding the molecular function of these receptors. In this review, we revisit past research on σ receptors and discuss the interpretation of these data in light of recent developments. We provide a synthesis of emerging structural and genetic data on the σ 1 receptor and discuss the recent cloning of the σ 2 receptor. Finally, we discuss the major questions that remain in the study of σ receptors. The σ 1 and σ 2 receptors are drug targets for several conditions. However, despite considerable pharmacological interest, relatively little is known about their molecular functions. The prevailing model of σ 1 receptor function is that it is a chaperone protein that acts as a pluripotent modulator of other signaling pathways. This may be true, but current evidence does not rule out other models. Recent structural and biochemical work shows that the σ 1 receptor is a single-pass transmembrane protein that exists in multiple oligomeric states. Ligands differentially modulate these states, and recent crystal structures offer a potential explanation. Novel loss-of-function mutations in the σ 1 receptor that cause neuromuscular disease continue to emerge. Mapping these mutations onto the σ 1 receptor structure reveals structural rationales for their effects. The σ 2 receptor has recently been cloned. It has been identified as TMEM97, a four-pass transmembrane protein possibly involved in cholesterol metabolism. [ABSTRACT FROM AUTHOR]

The sigma-1 (σ 1) receptor is an endoplasmic reticulum (ER) chaperone protein, enriched in mitochondria-associated membranes. Its activation triggers physiological responses to ER stress and modulate Ca2+ mobilization in mitochondria. Small σ 1 agonist molecules activate the protein and act behaviorally as antidepressant, anti-amnesic and neuroprotective agents. Recently, several chemically unrelated molecules were shown to be σ 1 receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a σ 1 PM also shows neuroprotective potentials in pharmacological and genetic models of Alzheimer's disease (AD). For this aim, we describe (±)-2-(3-chlorophenyl)-3,3,5,5-tetramethyl-2-oxo-[1,4,2]-oxazaphosphinane (OZP002) as a novel σ 1 PM. OZP002 does not bind σ 1 sites but induces σ 1 effects in vivo and boosts σ 1 agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the σ 1 antagonist NE-100 or in σ 1 receptor knockout mice. It potentiated the antidepressant effect of the σ 1 agonist igmesine. In mice tested for Y-maze alternation or passive avoidance, OZP002 prevented scopolamine-induced learning deficits, in a NE-100 sensitive manner. Pre-administered IP before an ICV injection of amyloid Aβ 25-35 peptide, a pharmacological model of Alzheimer's disease, OZP002 prevented the learning deficits induced by the peptide after one week in the Y-maze, passive avoidance and novel object tests. Biochemical analyses of the mouse hippocampi showed that OZP002 significantly decreased Aβ 25-35 -induced increases in reactive oxygen species, lipid peroxidation, and increases in Bax, TNFα and IL-6 levels. Immunohistochemically, OZP002 prevented Aβ 25-35 -induced reactive astrogliosis and microgliosis in the hippocampus. It also alleviated Aβ 25-35 -induced decreases in synaptophysin level and choline acetyltransferase activity. Moreover, chronically administered in APPswe mice during 2 months, OZP002 prevented learning deficits (in all tests plus place learning in the water-maze) and increased biochemical markers. This study shows that σ 1 PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dual-ligands σ 1 receptor (σ 1 R) and histone deacetylase (HDAC) have been designed. • Compound 6 showed good affinity for σ 1 R, selectivity over σ 2 R and HDAC inhibition. • Compound 6 strongly reduced the viability of different tumor cell lines. • Compound 6 showed a low toxicity profile in vitro. • Compound 6 demonstrated good stability and ADME profile in silico. Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K i σ 1 R = 38 ± 3.7; K i σ 2 R = 2917 ± 769 and HDACs IC 50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC 50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ 1 R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets. [ABSTRACT FROM AUTHOR]

Mice lacking the σ 1 receptor chaperone (σ 1 R -/- ) are resilient to depressive-like behaviors secondary to neuropathic pain. Examining the resilience's brain mechanisms could help develop conceptually novel therapeutic strategies. We explored the diminished motivation for a natural reinforcer (white chocolate) in the partial sciatic nerve ligation (PSNL) model in wild-type (WT) and σ 1 R -/- mice. In the same mice, we performed a comprehensive reverse transcription quantitative PCR (qPCR) analysis across ten brain regions of seven genes implicated in pain regulation and associated affective disorders, such as anxiety and depression. PSNL induced anhedonic-like behavior in WT but not in σ 1 R -/- mice. In WT mice, PSNL up-regulated dopamine transporter (DAT) and its rate-limiting enzyme, tyrosine hydroxylase (Th), in the ventral tegmental area (VTA) and periaqueductal gray (PAG) as well as the serotonin transporters (SERT) and its rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) in VTA. In addition, μ-opioid receptor (MOR) and σ 1 R were up-regulated in PAG, and MOR was also elevated in the somatosensory cortex (SS) but down-regulated in the striatum (STR). Finally, increased BDNF was found in the medial prefrontal cortex (mPFC) and hypothalamus (HPT). Sham surgery also produced PSNL-like expression changes in VTA, HPT, and STR. Genetic deletion of the σ 1 R in mice submitted to PSNL or sham surgery prevented changes in the expression of most of these genes. σ 1 R is critically involved in the supraspinal gene expression changes produced by PSNL and sham surgery. The changes in gene expression observed in WT mice may be related to pain-related depression, and the absence of these changes observed in σ 1 R -/- mice may be related to resilience.

The σ 1 receptor (S1R) is a ligand-regulated non-opioid intracellular receptor involved in several pathological conditions. The development of S1R-based drugs as therapeutic agents is a challenge due to the lack of simple functional assays to identify and classify S1R ligands. We have developed a novel nanoluciferase binary technology (NanoBiT) assay based on the ability of S1R to heteromerize with the binding immunoglobulin protein (BiP) in living cells. The S1R-BiP heterodimerization biosensor allows for rapid and accurate identification of S1R ligands by monitoring the dynamics of association-dissociation of S1R and BiP. Acute treatment of cells with the S1R agonist PRE-084 produced rapid and transient dissociation of the S1R-BiP heterodimer, which was blocked by haloperidol. The effect of PRE-084 was enhanced by calcium depletion, leading to a higher reduction in heterodimerization even in the presence of haloperidol. Prolonged incubation of cells with S1R antagonists (haloperidol, NE-100, BD-1047, and PD-144418) increased the formation of S1R-BiP heteromers, while agonists (PRE-084, 4-IBP, and pentazocine) did not alter heterodimerization under the same experimental conditions. The newly developed S1R-BiP biosensor is a simple and effective tool for exploring S1R pharmacology in an easy cellular setting. This biosensor is suitable for high-throughput applications and a valuable resource in the researcher's toolkit.

We report the design and synthesis of several 4-phenylpiperidine-4-carbonitrile derivatives as σ1 receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ1 receptors ( Ki(σ1) = 1.22-2.14 nM) and extremely high subtype selectivity ( Ki(σ2) = 830-1710 nM; Ki(σ2)/ Ki(σ1) = 680-887). [18F]9 was prepared in 42-46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic 18F- substitution of the corresponding tosylate precursor. Biodistribution studies in mice demonstrated high initial brain uptakes and high brain-to-blood ratios. Administration of SA4503 or haloperidol 5 min prior to injection of [18F]9 significantly reduced the accumulation of radiotracers in organs known to contain σ1 receptors. Two radioactive metabolites were observed in the brain at 30 min after radiotracer injection. [18F]9 may serve as a lead compound to develop suitable radiotracers for σ1 receptor imaging with positron emission tomography. [ABSTRACT FROM AUTHOR]

We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ40, Aβ42, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ 1 receptor (σ 1 R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K i = 6.5 nΜ; EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro , and exerted powerful analgesic effects in the abdominal constriction test (ED 50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED 50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED 50 = 0.30 mg/kg, in mice). The contributions of MOR and σ 1 R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ 1 R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects—including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion—than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ 1 R ligands as a promising avenue for the development of potent and safe analgesics. [Display omitted] • A series of benzylaminofentanyl derivates were synthesized as bifunctional MOR/σ 1 R ligands to develop safer analgesics. • Compound 68 showed desirable MOR agonism (EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro. • Compound 68 exerted powerful analgesic effects in abdominal constriction test and formalin-induced pain test in rodents. • At equianalgesic doses, compound 68 induced fewer MOR-related side effects than fentanyl in mice. [ABSTRACT FROM AUTHOR]

[Display omitted] The overexpression of σ receptors (σRs) in various types of tumors has prompted a deep investigation of their role in cancer pathophysiology. Consequently, σR ligands have been widely studied in vitro and in vivo for their antiproliferative effects as a novel potential class of chemotherapeutic agents, both alone and in combination with other anticancer drugs. A growing body of evidence highlights that σR ligands can inhibit cancer cells' survival, migration, and proliferation, thanks to the modulation of a wide panel of tumorigenic pathways. In addition to their antitumor activity, σR ligands are gaining momentum as radiotracers for PET and SPECT imaging applications. The purpose of this review is to report on recent advances in the development of σR ligands. In particular, herein, we describe the structure–activity relationships of structurally diverse mixed σ 1 R/σ 2 R ligands that showed promising antitumor profiles towards a variety of cancer cell lines. [ABSTRACT FROM AUTHOR]

Abstract: Aims: We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ1-receptor (σ1R), ameliorates cardiac hypertrophy and dysfunction via σ1R stimulation. Although σ1R on non-cardiomyocytes interacts with the IP3 receptor (IP3R) to promote mitochondrial Ca2+ transport, little is known about its physiological and pathological relevance in cardiomyocytes. Main methods: Here we performed Ca2+ imaging and measured ATP production to define the role of σ1Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca2+ transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy. Key finding: These cardiomyocytes exhibited imbalances in expression levels of σ1R and IP3R and impairments in both phenylephrine-induced mitochondrial Ca2+ mobilization from the SR and ATP production. Interestingly, σ1R stimulation with fluvoxamine rescued impaired mitochondrial Ca2+ mobilization and ATP production, an effect abolished by treatment of cells with the σ1R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ1Rs suppressed intracellular Ca2+ mobilization through IP3Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production. Significance: These results suggest that σ1R stimulation with fluvoxamine promotes SR-mitochondrial Ca2+ transport and mitochondrial ATP production, whereas σ1R stimulation suppresses intracellular Ca2+ overload through IP3Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ1R agonists including fluvoxamine. [Copyright &y& Elsevier]

Abstract: Serotonin (5-HT)1A and σ1 receptors have been implicated in psychiatric disorders. We previously found that combined 5-HT reuptake inhibition and σ1 receptor activation has a synergistic effect on prefrontal dopaminergic transmission in adrenalectomized/castrated mice lacking circulating steroid hormones. In the present study, we examined the mechanisms underlying this neurochemical synergism. Systemic administration of fluvoxamine, a selective 5-HT reuptake inhibitor with agonistic activity towards the σ1 receptor, increased prefrontal dopamine (DA) levels, and adrenalectomy/castration potentiated this fluvoxamine-induced increase in DA. This enhancement of DA release was blocked by WAY100635 (a 5-HT1A receptor antagonist), but not by ritanserin (a 5-HT2 receptor antagonist), azasetron (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist). Individually, osemozotan (a 5-HT1A receptor agonist) and (+)-SKF-10,047 (a σ1 receptor agonist) did not alter prefrontal monoamine levels in adrenalectomized/castrated and sham-operated mice differentially. In contrast, co-administration of these drugs increased prefrontal DA levels to a greater extent in adrenalectomized/castrated mice than in sham-operated animals. Furthermore, co-administration of osemozotan and (+)-SKF-10,047 increased expression of the neuronal activity marker c-Fos in the ventral tegmental area of adrenalectomized/castrated mice, but not in sham-operated animals. These findings suggest that combined activation of 5-HT1A and σ1 receptors has a synergistic effect on prefrontal dopaminergic transmission under circulating steroid deficiency, and that this interaction may play an important role in the regulation of the prefrontal DA system. [Copyright &y& Elsevier]

Although pentazocine binds to σ1-receptor (σ1R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that σ1R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5-1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a σ1R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5-1 μM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO-induced cardiac hypertrophy and rescued hypertrophyinduced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (±dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced σ1R reduction and inositol-1,4,5-trisphosphate (IP3) receptor type 2 (IP3R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that σ1R binds to the ryanodine receptor (RyR) in addition to IP3 receptor (IP3R) in cardiomyocytes. The σ1R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca2+ release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of σ1R by pentazocine rescues cardiac dysfunction by restoring IP3R-mediated mitochondrial ATP production and by suppressing RyR-mediated Ca2+ leak from SR in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The σ1 ligands are considered to be a new class of potential therapeutic agents for several types of central nervous system disorder. Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) was shown to be a promising PET ligand for mapping σ1 receptors, and was applied to measure receptor occupancy with several therapeutic drugs in the living human brain. In this study, we applied this technique for preclinical in vivo screening of novel σ1 selective agonists. Methods: Six newly synthesized piperazine derivatives containing arylalkylamine groups and cyclohexylamine derivatives containing phenyl groups were selected and tested for their in vivo σ1 receptor binding with [11C]SA4503. The test compounds were administered by intravenous co-injection or oral administration. The in vivo receptor binding of [11C]SA4503 was evaluated by a tissue dissection method at a single time point. Results: Our in vivo screen identified the most promising candidate of novel σ1 agonist in the piperazine derivatives. Some correlations between in vitro affinity and in vivo receptor blocking rate were observed when considering oral bioavailability. In vivo receptor blocking of piperazine derivatives after oral administration may be predictable by simple co-injection study. Conclusion: Ligand selection with [11C]SA4503 by the in vivo receptor binding assay was performed successfully. This technique is a practical and high-throughput method that can directly evaluate blood–brain barrier permeability, receptor binding, and bioavailability of drug candidates at the same time. [Copyright &y& Elsevier]

Abstract: Introduction: Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) was shown to be a promising PET ligand for mapping σ1 receptors, and was applied to human subjects. However, an in vitro study indicated that SA4503 also binds to the emopamil binding protein (EBP), vertebral Δ8-Δ7 sterol isomerase. To our knowledge, no information is available about the possibility of [11C]SA4503 binding to EBP in the brain in vivo. Methods: To confirm the selectivity of [11C]SA4503, we carried out an in vivo blocking experiment using high-affinity EBP and σ1 selective blocker. Results: The brain uptake of [11C]SA4503 was dose-dependently decreased by SA4503 and the high-affinity σ1 blockers haloperidol, ifenprodil, and trifluperidol. On the other hand, the effects of the high-affinity EBP blockers tamoxifen and trifluoperazine were negligible. Conclusions: Our results confirmed the σ1-selective binding of [11C]SA4503 in the brain. [Copyright &y& Elsevier]

Abstract: We report the synthesis and evaluation of 4-benzylpiperazine ligands (BP-CH3, BP-F, BP-Br, BP-I, and BP-NO2) as potential σ1 receptor ligands. The X-ray crystal structure of BP-Br, which crystallized with monoclinic space group P21/c, has been determined. In vitro competition binding assays showed that all the five ligands exhibit low nanomolar affinity for σ1 receptors (K i =0.43–0.91nM) and high subtype selectivity (σ2 receptor: K i =40–61nM; K iσ2/K iσ1 =52–94). [125I]BP-I (1-(1,3-benzodioxol-5-ylmethyl)-4-(4-iodobenzyl)piperazine) was prepared in 53±10% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via iododestannylation of the corresponding tributyltin precursor. The log D value of [125I]BP-I was found to be 2.98±0.17, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiolabeled substances in organs known to contain σ1 receptors, including the brain, lung, kidney, heart, and spleen. Administration of haloperidol 5min prior to injection of [125I]BP-I significantly reduced the concentration of radioactivity in the above-mentioned organs. The accumulation of radiolabeled substance in the thyroid was quite low suggesting that [125I]BP-I is relatively stable to in vivo deiodination. These findings suggest that the binding of [125I]BP-I to σ1 receptors in vivo is specific. [Copyright &y& Elsevier]

The acetylcholinesterase (AChE) inhibitor donepezil is also a σ1 receptor agonist. We examined whether donepezil binds to σ1 receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective σ1 receptor ligand [11C]SA4503 was performed to evaluate quantitatively the binding of [11C]SA4503 to σ1 receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [11C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to σ1 receptors in the human brain with occupancies of ∼60% and ∼75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to σ1 receptors in the living human brain at therapeutic doses. Therefore, σ1 receptors may be implicated in the pharmacological mechanism of donepezil in the human brain. [ABSTRACT FROM AUTHOR]

Dimemorfan, an antitussive and a sigma-1 (σ1) receptor agonist, has been reported to display neuroprotective properties. We set up an animal model of ischemic stroke injury by inducing cerebral ischemia (for 1 h) followed by reperfusion (for 24 h) (CI/R) in rats to examine the protective effects and action mechanisms of dimemorfan against stroke-induced damage. Treatment with dimemorfan (1.0 μg/kg and 10 μg/kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative σ1 receptor agonist, PRE084 (10 μg/kg, i.v.), ameliorated the size of the infarct zone by 67–72% or 51–52%, respectively, which was reversed by pre-treatment with the selective σ1 receptor antagonist, BD1047 (20 μg/kg, i.v.). Major pathological mechanisms leading to CI/R injury including excitotoxicity, oxidative/nitrosative stress, inflammation, and apoptosis are all downstream events initiated by excessive accumulation of extracellular glutamate. Dimemorfan treatment (10 μg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1β, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammation-related signals (p38 mitogen-activated protein kinase, nuclear factor-κB, and signal transducer and activator of transcription-1), expression of neuronal and inducible nitric oxide synthase, oxidative/nitrosative tissue damage (lipid peroxidation, protein nitrosylation, and 8-hydroxy-guanine formation), and apoptosis in the ipsilateral cortex after CI/R injury. Dimemorfan treatment at the time of reperfusion, although did not prevent an early rise of glutamate level, significantly prevented subsequent glutamate accumulation after reperfusion. This inhibitory effect was lasted for more than 4 h and was reversed by pre-treatment with BD1047. These results suggest that dimemorfan activates the σ1 receptor to reduce glutamate accumulation and then suppresses initiation of inflammation-related events and signals as well as induction of oxidative and nitrosative stresses, leading to reductions in tissue damage and cell death. In conclusion, our results demonstrate for the first time that dimemorfan exhibits protective effects against ischemic stroke in CI/R rats probably through modulation of σ1 receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events. [ABSTRACT FROM AUTHOR]

Abstract: We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for σ1 receptors, but a low affinity for σ2 receptors. In addition, we found that DM has a higher affinity than DX for σ1 sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the σ1 receptor antagonist BD 1047, but not by the σ2 receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the σ1 receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via σ1 receptor stimulation. [Copyright &y& Elsevier]

Background and purpose:The acetylcholinesterase inhibitor, donepezil, is also a high affinity σ1 receptor agonist. We examined the involvement of σ1 receptors in its anti-amnesic and neuroprotective properties against amyloid β25-35 peptide-induced toxicity in mice.Experimental approach:Mice were given an intracerebroventricular (i.c.v.) injection of Aβ25-35 peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Aβ25-35 injection to evaluate oxidative stress. Donepezil, the σ1 agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Aβ25-35 injection, or 24 h after Aβ25-35 injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively.Key results:All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the σ1 antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors.Conclusions and implications.The potent anti-amnesic and neuroprotective effects of donepezil against Aβ25-35-induced toxicity involve both its cholinergic and σ1 agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.British Journal of Pharmacology (2006) 149, 998–1012. doi:10.1038/sj.bjp.0706927; published online 23 October 2006 [ABSTRACT FROM AUTHOR]

The present series of experiments examined the involvement of the σ1 receptor and related neuroactive steroids in the memory state induced by a very low dose of cocaine. Using a modified passive avoidance procedure in mice, we examined whether cocaine induces state-dependent (StD) learning. Animals trained and tested with saline or the same dose of cocaine (0.1 or 0.3 mg/kg) showed correct retention, measured using two independent parameters: the retention latency and a ratio between the retention latency and the last training latency. Animals trained with cocaine (0.1 mg/kg) and tested with saline or cocaine (0.03, 0.3 mg/kg), or trained with saline and tested with cocaine, showed altered retention parameters, demonstrating that StD occurred. Therefore, cocaine administered before training produced a chemical state used as an endogenous cue to insure optimal retention. Since σ1 receptor activation is an important event during the acquisition of cocaine reward, we tested several σ1 ligands and related neurosteroids. The σ1 agonist igmesine or antagonist BD1047 failed to produce StD, but modified the cocaine state. Among neuroactive steroids, pregnanolone and allopregnanolone, positive modulators of the γ-aminobutyric acid type A (GABAA) receptor, produced StD. However, steroids also acting as σ1 agonists, dehydroepiandrosterone (3β-hydroxy-5α-androsten-17-one (DHEA)), pregnenolone, or antagonist, progesterone, failed to induce StD but modified the cocaine state. Furthermore, optimal retention was observed with mice trained with (igmesine or DHEA)+cocaine and tested with a higher dose of cocaine, or with mice trained with (BD1047 or progesterone)+cocaine and tested with vehicle. This study demonstrated that: (i) low doses of cocaine induce a chemical state/memory trace sustaining StD; (ii) modulation of the σ1 receptor activation, although insufficient to provoke StD, modulates the cocaine state; (iii) neuroactive steroids exert a unique role in state-dependent vs state-independent learning, via GABAA or σ1 receptor modulation, and are able to affect the cocaine-induced mnesic trace at low brain concentrations.Neuropsychopharmacology (2006) 31, 1431–1443. doi:10.1038/sj.npp.1300885; published online 31 August 2005 [ABSTRACT FROM AUTHOR]

It has been hypothesized that σ1 receptors (σ1Rs) are involved in the effects of cocaine abuse. Many in vitro and in vivo studies have already indicated an influence of σ1R ligands on dopaminergic transmission; however, the direct effect on the brain is poorly understood. Herein we describe the effects of cocaine and the selective dopamine-1 receptor (D1R) agonist, (+)-SKF38393, on gene expression of the σ 1R in a human fetal a strocyte cell line (SVG cells). This study provides the first evidence for the expression of σ1 mRNA in these cells. Our results show that treatment of SVG cells with various cocaine concentrations for several time durations showed no significant alternations in σ 1R gene expression, as detected by real-time quantitative RT-PCR, whereas treating cells for 24 h with (+)-SKF38393 caused a significant down-regulation in σ1 transcrits. This (+)-SKF38393-induced effect was blocked by the D1R selective antagonist (+)-SCH23390. These results suggest that the effect of cocaine on σ2 gene expression in the brain might be indirect and mediated through D1R. [ABSTRACT FROM AUTHOR]

Abstract: Chronic alcohol consumption (CAC) provokes intense neurobiological alterations, which lead, notably, to an important abstinence syndrome upon withdrawal with deleterious cognitive consequences. We here examined the effect of activation or inactivation of the σ1 receptor during CAC withdrawal on the cognitive abilities of Swiss mice. Animals consumed an alcohol 10%/sucrose 30g/l solution during 4 months. Control groups consumed only the sucrose vehicle solution. Then, animals experienced a progressive, 16 days long, CAC withdrawal, during which they were administered once daily with saline, igmesine (10mg/kgi.p.), a σ1 receptor agonist, or BD1047 (10mg/kgi.p.), a σ1 antagonist. Mice were then tested using an object exploration task, to evaluate their locomotor and exploratory activities and reactions to object habituation, spatial change or novel object presentation. CAC-treated animals showed augmentation of locomotion, anxiety and object exploration, which impeded correct reaction to object habituation, spatial change or novelty. Treatment with the σ1 ligands, ineffective in control groups, resulted in decrease of the hyper-responsiveness and restored habituation. However, correct reactions to spatial change and novelty were only produced by the σ1 agonist treatment. Moreover, the σ1 receptor hippocampal expression was increased in CAC-treated mice. Treatments with both σ1 ligands regulated its expression, but subcellular fractionation experiments revealed that the agonist treatment increased [3H](+)-pentazocine binding to σ1 sites in the plasma membrane fraction, while the antagonist maintained it only in the microsomal, putatively endoplasmic reticulum, fraction. In conclusion, CAC increased the σ1 receptor expression in the hippocampus of mice. Regulation of its expression during withdrawal, notably using a selective agonist, allowed not only to attenuate the CAC-induced hyper-responsiveness, but also to restore correct cognitive abilities. [Copyright &y& Elsevier]

Alzheimer’s disease (AD) is the most common dementia occurring in elderly. We report herein the neuroprotective properties of procaine and other anesthetic agents against β-amyloid-induced neurotoxicity. Procaine displayed strong neuroprotective properties against the amyloid peptide Aβ1–42 and preserved Aβ1–42-induced ATP depletion on rat pheochromocytoma PC12 cells. Procaine also inhibited the neurotoxic effect that glutamate displayed on PC12 cells, suggesting that the reduction of glutamate-induced neurotoxicity may be the mechanism by which these compounds exert their ‘antiamyloid’ effects. In search of a mechanism of action we observed that procaine is a ligand for the σ1 receptor, a protein which ligands have been shown to protect mitochondrial function and to exert antidepressant properties. Procaine binds also to muscarinic receptors but the true meaning of this feature needs to be clarified. In conclusion, these data suggest that procaine exerts neuroprotective properties and may serve either as a treatment for AD or as a starting point for the development of novel therapies for AD. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present paper studied the effect and mechanism of neurosteroid pregnenolone sulfate (PREGS) on spontaneous glutamate release using electrophysiological and biochemical methods combined with a pharmacological approach. The results suggested that PREGS had a selective enhancing effect on spontaneous glutamate release in the prelimbic cortex and the hippocampus but not in the striatum. The effect of PREGS in the prelimbic cortex appeared to be via modulation of a1-adrenergic and s1 receptors, but in the hippocampus it might be dependent on s1 receptors only. The activation of a1-adrenergic receptors synergized s1 receptor activation in the prelimbic cortex. Intracellular calcium released from the endoplasmic reticulum, protein kinase C, adenylyl cyclase and protein kinase A played a key role in the effect of PREGS. Intracellular calcium, protein kinase C and adenylyl cyclase might be upstream events in the activation of protein kinase A after PREGS. [ABSTRACT FROM AUTHOR]

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects.Dextromethorphan and dimemorfan are high-affinity ligands ats1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan.Kainate (KA) administration (10?mg?kg-1, i.p.) produced robust convulsions lasting 4-6?h in rats. Pre-treatment with dimemorfan (12 or 24?mg?kg-1) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan.The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selectives1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related tos1 receptor-activated modulation of AP-1 transcription factors.We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects.Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.British Journal of Pharmacology (2005) 144, 908-918. doi:10.1038/sj.bjp.0705998 [ABSTRACT FROM AUTHOR]

In utero cocaine (IUC) exposure results in offspring rats in complex neurochemical and behavioral alterations, particularly affecting learning and memory processes. We examined here the impact of IUC exposure on memory functions in male and female offspring rats and report that selective sigma1 (σ1) receptor agonists are effective in reversing the deficits. Dams received a daily cocaine, 20 mg/kg ip, injection between gestational days E17 to E20. Learning was examined in offspring between day P30 and P41 using delayed alternation in the T-maze, water-maze learning and passive avoidance. Both male and female rats prenatally exposed to cocaine showed delayed alternation deficits and impairments of acquisition of a fixed platform position in the water maze, as shown by higher acquisition latencies and diminutions of time spent in the training quadrant during the probe test. The acquisition of a daily changing platform position also demonstrated impaired working memory. Finally, passive avoidance deficits were observed. Pretreatment with the synthetic σ1 agonist igmesine (0.1–1 mg/kg ip) or the neuroactive steroid dehydroepiandrosterone (DHEA 10–40 mg/kg ip) reversed the prenatal cocaine-induced learning deficits in offspring rats for each test. The σ1 antagonist BD1063 (1 mg/kg ip) failed to affect performances alone but blocked the igmesine and DHEA effects, confirming the involvement of the σ1 receptor. IUC exposure thus results in marked memory deficits, affecting spatial and nonspatial short- and long-term memories in juvenile male and female offspring rats. The activation of the σ1 neuromodulatory receptor allows a complete behavioral recovery of the memory functions in prenatally cocaine-exposed rats. [Copyright &y& Elsevier]

1: Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma1 (s1) receptor agonist, igmesine, in alleviating the observed deficits. 2: Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using spontaneous alternation in the Y-maze, delayed alternation in the T-maze, water-maze learning and passive avoidance. 3: Both male and female PS rats showed impairments of spontaneous and delayed alternation performances. Acquisition of a fixed platform position in the water-maze was unchanged in PS rats, but the probe test revealed a diminution of time spent in the training quadrant. Acquisition of a daily changing platform position demonstrated impaired working memory for male and female PS rats. Finally, passive avoidance deficits were observed. 4: Pretreatment with the selective s1 agonist igmesine (1-10?mg?kg-1 i.p.) reversed the PS-induced learning deficits in offspring rats for each test. The s1 antagonist BD1063 failed to affect performances alone but blocked the igmesine effect, confirming the involvement of the s1 receptor. 5: PS thus induces delayed memory deficits, affecting spatial and nonspatial, short- and long-term memories in juvenile male and female offspring rats. Activation of the s1 neuromodulatory receptor allows a significant recovery of the memory functions in PS rats.British Journal of Pharmacology (2004) 142, 689-700. doi:10.1038/sj.bjp.0705835 [ABSTRACT FROM AUTHOR]

Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective σ1 receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the σ1 receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the β-amyloid-(1–40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in β-amyloid-(40–1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in β-amyloid-(1–40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in β-amyloid-(1–40)-treated rats. Neurosteroid levels were measured in several brain structures after β-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of β-amyloid-(1–40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the β-amyloid infusion. The σ1 receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the β-amyloid toxicity. The present study suggests that σ1 receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer''s disease-associated depressive symptoms. [Copyright &y& Elsevier]

Abstract The sigma1 (σ1 ) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the σ1 receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in σ1 receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either σ1 receptor expression or steroid levels. The σ1 -receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo [3 H](+)-SKF-10 047 binding to σ1 receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [3 H](+)-SKF-10 047 binding only in Swiss. The behavioural efficacy of the selective σ1 agonists igmesine and PRE-084 – reversion of the scopolamine-induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test – were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous σ1 antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of σ1 -receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the σ1 receptor. [ABSTRACT FROM AUTHOR]