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BackgroundThere is a bidirectional link between sleep and migraine, however causality is difficult to determine. Previous studies rely on retrospective questionnaires, and small samples to support their findings. This study aimed to overcome this by teasing apart this relationship using sleep assessment and concomitant migraine data collected from a smartphone application using Bayesian modelling.MethodsAnonymized self-reported data on sleep and migraine from 11,166 global users (aged 18-81 years, mean: 41.21, standard deviation: 11.49) were collected from the Migraine Buddy application (Healint Pte. Ltd.) between 30thJune and 31stDecember 2021. Measures included: demographics, start and end times of each sleep episode and migraine attack, and the pain intensity for each migraine attack (visual analogue scale 0-10). Bayesian regression models were used to predict occurrence of a migraine attack the next day based on users’ deviations from mean monthly sleep, number of sleep interruptions, and hours slept the night before in those reporting ≥ 4 and ResultsOnce exclusion criteria were applied, there were 724 users (129 males, 412 females, 183 unknown) with an average age of 41.88 years (SD= 11.63), with a mean monthly number of attacks of 9.94. A greater number of sleep interruptions (95% Highest Density Interval (95% HDI [0.112 – 0.205]) and deviation from a user’s mean sleep the night before (95% HDI [0.040 – 0.080]) were significant predictors of a next day migraine attack. Total hours slept was not a significant predictor (95% HDI [-0.04 – 0.04]). Pain intensity, but not attack occurrence was a positive predictor of hours slept.DiscussionSleep fragmentation and deviation from typical sleep are the main drivers of the relationship between sleep and migraine, whereas overall sleep duration is not. Conversely, simply having a migraine attack does not predict sleep duration, it is the pain associated with an attack which alters sleep. This study has shed light on the causal mechanisms of sleep and migraine and highlights sleep hygiene as crucial in migraine management.

Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREB(S142A) mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREB(S142A) mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREB(S142A) mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms.

Cytokine-dependent mechanisms in the CNS have been implicated in the pathogenesis of depression. Interleukin-6 is upregulated in depressed patients and dowregulated by antidepressants. It is, however, unknown whether IL-6 is involved in the pathogenesis of depression. We subjected IL-6-deficient mice (IL-6(-/-)) to depression-related tests (learned helplessness, forced swimming, tail suspension, sucrose preference). We also investigated IL-6 in the hippocampus of stressed wild-type mice. IL-6(-/-) mice showed reduced despair in the forced swim, and tail suspension test, and enhanced hedonic behavior. Moreover, IL-6(-/-) mice exhibited resistance to helplessness. This resistance may be caused by the lack of IL-6, because stress increased IL-6 expression in wild-type hippocampi. This suggests that IL-6 is a component in molecular mechanisms in the pathogenesis of depression. IL-6(-/-) mice represent tools to study IL-6-dependent signaling pathways in the pathophysiology of depression in vivo. Moreover, these mice may support the screening of compounds for depression by altering cytokine-mediated signaling.

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/-mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/-mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/-mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

Learning and memory, like most physiological processes, seem to be under the control of circadian rhythm. The recently cloned mPer1 and mPer2 genes play an important role in the regulation of the circadian rhythm. In this study, we tested mPer1 and mPer2 mutant mice in two different learning and memory paradigms, a water-maze place navigation task and contextual fear conditioning. In both learning tests, the hippocampus is critically involved. None of these learning types were affected by the mutations, suggesting that mPer1 and mPer2 do not play a major role in the regulation of hippocampus- dependent learning and memory.

The olfactory bulbectomy syndrome is thought to represent a rodent model for psychomotor agitated depression. While this model has been extensively characterized in rats, fewer studies have been conducted with mice. Therefore, the present study aimed at extending the characterization of the OBX-induced behavioral syndrome in mice, using tests like open field, novel object exploration, novel cage and T-maze learning. OBX mice exhibited hyperactivity in a brightly illuminated open field, and also in a novel home cage as well as in the T-maze. Furthermore, OBX mice demonstrated increased exploratory behavior in the novel object test and in the T-maze. The complex alterations described here with respect to locomotion and exploration are robust and can be achieved by relatively simple test procedures. The extended behavioral characterization of the murine OBX model may contribute in particular to the increasing need to test transgenic mice for the presence of depression-like behaviors.

Depression is a multifactorial and multigenetic disease. At present, three main theories try to conceptualize its molecular and biochemical mechanisms, namely the monoamine-, the hypothalamus-pituitary-adrenal- (HPA-) system- and the neurotrophin-hypotheses. One way to explore, validate or falsify these hypotheses is to alter the expression of genes that are involved in these systems and study their respective role in animal behavior and neuroendocrinological parameters. Following an introduction in which we briefly describe each hypothesis, we review here the different mouse lines generated to study the respective molecular pathways. Among the many mutant lines generated, only a few can be regarded as genetic depression models or as models of predisposition for a depressive syndrome after stress exposure. However, this is likely to reflect the human situation where depressive syndromes are complex, can vary to a great extent with respect to their symptomatology, and may be influenced by a variety of environmental factors. Mice with mutations of candidate genes showing depression-like features on behavioral or neurochemical levels may help to define a complex molecular framework underlying depressive syndromes. Because it is conceivable that manipulation of one single genetic function may be necessary but not sufficient to cause complex behavioral alterations, strategies for improving genetic modeling of depression-like syndromes in animals possibly require a simultaneous targeted dysregulation of several genes involved in the pathogenesis of depression. This approach would correspond to the new concept of 'endophenotypes' in human depression research trying to identify behavioral traits which are thought to be encoded by a limited set of genes.

Dysregulations and dysfunctions of corticosteroids and their receptors have been implicated in the pathogenesis of stress-related disorders, in particular in depression. It is currently under debate, however, whether corticosteroid imbalances are a cause or rather a consequence of affective disorders. Corticosteroids exert their effects mainly by two receptors: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). We present here analyses made on several strains of mice with targeted mutations of corticosteroid receptors. The results help to understand how corticosteroid receptors regulate the hypothalamic-pituitary-adrenal (HPA) system. Furthermore, first behavioral analyses have indicated that corticosteroid receptor mutant mice show alterations in their emotional behavior. Certain mouse strains with specific alterations of GR or MR expression may represent genetic models of depression or at least have a predisposition to develop a depressive or a depression-resistant state upon exposure to stress. The corticosteroid receptor-regulated target genes to be identified in these models may code for proteins that could represent new drug-targets for the treatment of affective disorders.

Based on clinical and experimental observations, the neurotrophin hypothesis of depression as conceptualized originally, made the following predictions: (i) reduced activity of the CREB–BDNF–TrkB pathway is implicated in the pathogenesis of depression; (ii) activation of the CREB–BDNF–TrkB pathway is part of the molecular mechanisms of antidepressive therapy. This concept has recently been challenged, at least in part, by studies with transgenic mice. According to the neurotrophin hypothesis, mice with genetical disruptions of any part of the CREB–BDNF–TrKB pathway would be expected to display depression-like behaviors. However, none of several mouse strains investigated so far have exhibited such a behavior, some of them being even less ‘depressive’ than the controls. Despite some possible explanations for the lack of a depression-like phenotype, the present findings challenge the hypothesis that this signaling pathway plays a major role in the pathogenesis of depression. However, mice with impaired CREB signaling show reduced BDNF inducibility. Moreover, mice with impaired BDNF-TrkB signaling have a decreased behavioral response to antidepressants. Thus, despite the conflicting results on the role of the CREB–BDNF–TrkB pathway in the pathogenesis of depression, this signaling cascade seems to be directly involved in the mechanisms of antidepressive therapy. Therefore, pharmacological strategies should be developed to generate small-molecule agents that increase the expression and promote the release of BDNF more specifically and more efficiently than currently available antidepressants.

The sigma(1) (sigma(1)) receptor represents a unique intracellular neuronal protein modulating several neurotransmitter responses with relevant effects on cognitive functions. We examined here its expression and behavioral efficacy during aging. The sigma(1) receptor expression was examined in young (2 months old) and aged (24 months old) C57BL/6 mouse brain using comparative RT-PCR and immunohistochemistry. The promnesic effect of PRE-084, a selective sigma(1) agonist, was assessed using a water-maze procedure. The sigma(1) mRNA expression was not affected during aging in the olfactory bulb, hippocampus, hypothalamus, cortex or cerebellum. The sigma(1) immunolabeling was intense in the olfactory bulb, hippocampus, hypothalamus and midbrain of the young mouse and the distribution appeared unchanged in the aged. The subcellular localization was similar in aged and younger animals, the protein being present on nuclear, mitochondrial, endoplasmic reticular and plasmic membranes. At the behavioral level, aged C57BL/6 mice showed deficits in the invisible platform learning, but not when the platform was visible. Animals subjected to a transfer test under repeated treatment with saline or PRE-084 significantly learned the new platform location. This study shows that sigma(1) receptor expression is preserved in aged animals and demonstrates the efficacy of a selective sigma(1) agonist against age-related memory deficits. Targeting this unique receptor may offer an original drug strategy during aging.

The sigma(1) (sigma(1)) 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 sigma(1) 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 sigma(1) receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either sigma(1) receptor expression or steroid levels. The sigma(1)-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 sigma(1) 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 sigma( 1) 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 sigma(1) 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 sigma(1)-receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the sigma(1) receptor.

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

The neuroactive steroids pregnenolone (3beta-hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (DHEA, 3alpha-hydroxy-5-androstene-17-one) are negative allosteric modulators of the GABA(A) receptors and positive modulators of acetylcholine, NMDA and sigma(1) receptors. Pregnenolone was recently shown to potentiate the neuronal damage induced by excessive glutamate in cell culture models, whereas dehydroepiandrosterone was reported to present some neuroprotective activity. The in vivo relevance of these effects was investigated in mice submitted to an hypoxic insult, the repeated exposure to carbon monoxide (CO) gas, a model that leads to neurodegeneration in the CA(1) hippocampal area and learning deficits. Recording spontaneous alternation behaviour in the Y-maze assessed short-term memory and long-term memory was examined using a passive avoidance task. After exposure to CO, mice showed a progressive deterioration of their learning ability, reaching significance after 3 days and being maximal after 7 days. Pregnenolone administered before CO significantly facilitated the hypoxia-related deficits, which could be measured 1 day after CO and appeared maximal after 3 days. Dizocilpine blocked the deficits in vehicle- and pregnenolone-treated CO-exposed animals, showing that pregnenolone selectively facilitated the NMDA receptor-dependent excitotoxicity. Dehydroepiandrosterone blocked the appearance of the CO-induced deficits, even after 7 days. Interestingly, the sigma(1) receptor antagonist N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) failed to affect the dehydroepiandrosterone-induced protection, showing the lack of involvement of sigma(1) receptors. Cresyl violet-stained sections of the mouse hippocampal formation showed that the neurodegeneration observed in the CA(1) area after exposure to CO was augmented by pregnenolone and blocked by dehydroepiandrosterone. These results show that pregnenolone and dehydroepiandrosterone, although being similarly involved in modulating the excitatory/inhibitory balance in the brain, do not equally affect the extent of excitotoxic insults.

The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial. During this acquisition session, the mouse was stressed by the presence of a pair of rats under the grid floor of the apparatus. One hour later, it was placed again in the environment with the known and a novel object, but in the absence of the rats. While non-exposed mice spent more time exploring the new object, mice that had been exposed to the rats during acquisition failed to discriminate between the known and the new object during retrieval. This cognitive impairment in stressed mice was prevented by the administration of SSR149415 (10 mg/kg, ip), SSR125543 (10 mg/kg, ip) and the selective serotonin reuptake inhibitor, fluoxetine (10 mg/kg, ip). Under similar conditions, the cognitive enhancer donepezil (1 mg/kg, ip) failed to reverse object recognition deficit. These results indicate that the effects of SSR149415 and SSR125543 in the modified object recognition test, in stressed mice, involve the ability of mice to cope with stress rather than an effect on cognition per se. Together, these data suggest that SSR149415 and SSR125543 may be of interest to reduce the cognitive deficits following exposure to stress-related events, such as acute stress disorder.

Trilostane is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), which notably converts pregnenolone into progesterone or dehydroepiandrosterone into androstenedione. Trilostane shows antidepressant-like properties in the forced swimming test (FST). The compound, however, induced only moderate effects on neuroactive steroid levels that could be related to its behavioral efficacy. We compared the behavioral effect of trilostane with the other 3β-HSD inhibitor, cyanoketone, and analyzed the putative involvement of the β-type estrogen receptor (ERβ) in its antidepressant effect. Trilostane reduced immobility in the FST significantly at 12.5 and 25 mg/kg subcutaneously (s.c.), whereas cyanoketone (0–100 mg/kg s.c.) was ineffective. The negative ER modulator fulvestrant (ICI 182780) dose-dependently blocked the effect of trilostane (25 mg/kg). Trilostane increased circulating estradiol levels in the 12.5–50 mg/kg dose-range, and this effect was unaffected by stress and not shared by cyanoketone (25 mg/kg). The trilostane (25 mg/kg) treatment increased the ERβ mRNA expression in adrenals (+100%) and centrally, in the hippocampus (+330%). Stress and cyanoketone failed to affect ERβ mRNA levels in periphery or in the brain. These data demonstrate that the antidepressant-like potential of trilostane is not due to its 3β-HSD inhibiting activity, since it is not shared by cyanoketone, but rather to its estrogenic activity. The compound, which releases estradiol and up-regulates ERβ receptors, could be used as a therapeutic tool to allow an estrogenic facilitation of antidepressant efficacy.

Although it has been postulated that adult neurogenesis, i.e. the generation of functional neurons from progenitor cells in the mammalian brain, is involved in both the pathogenesis of depressive disorders and the therapeutic effect of antidepressant drugs, its regulation is still poorly understood. Nitric oxide, a gaseous messenger molecule, represents a possible modulating agent as it is involved in learning and memory formation as well as synapto- and morphogenesis. Here we investigated whether adult neurogenesis is altered in mice lacking endothelial nitric oxide synthase (NOS-III). Compared to wild-type littermates, NOS-III-deficient mice showed a significant reduction in neuronal progenitor cell proliferation in the dentate gyrus, suggesting a role for NOS-III in the stimulation of neuroneogenesis. NeuN, beta-III-tubulin and GFAP double-immunolabelling demonstrated that proliferating progenitor cells differentiate preferentially into neurons but not into astrocytes. However, when the survival rate of newly formed cells was examined no difference between wild-type and NOS-III knockout mice was found, suggesting that NOS-III selectively exerts its effects on the proliferation of progenitor cells. This might be mediated by a decrease in vascular endothelial growth factor (VEGF) transcripts in the hippocampus of knockout animals. At the behavioural level, while NOS-III knockout mice displayed better and faster learning in a learned helplessness paradigm, no depression-like behaviours were observed. In conclusion, our results indicated that NOS-III is involved in the proliferation of neuronal progenitor cells, although behavioural analysis does not provide evidence for a pro-depressive effect of reduced neuroneogenesis.

Dysregulations and dysfunctions of corticosteroids and their receptors have been implicated in the pathogenesis of stress-related disorders, in particular in depression. It is currently under debate, however, whether corticosteroid imbalances are a cause or rather a consequence of affective disorders. Corticosteroids exert their effects mainly by two receptors: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). We present here analyses made on several strains of mice with targeted mutations of corticosteroid receptors. The results help to understand how corticosteroid receptors regulate the hypothalamic-pituitary-adrenal (HPA) system. Furthermore, first behavioral analyses have indicated that corticosteroid receptor mutant mice show alterations in their emotional behavior. Certain mouse strains with specific alterations of GR or MR expression may represent genetic models of depression or at least have a predisposition to develop a depressive or a depression-resistant state upon exposure to stress. The corticosteroid receptor-regulated target genes to be identified in these models may code for proteins that could represent new drug-targets for the treatment of affective disorders.

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 sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-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 beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.

This study examined the antidepressant efficacy of the selective sigma(1) receptor agonists igmesine or PRE-084 in mice injected intracerebroventricularly (i.c.v.) with beta(25-35)-amyloid peptide and submitted to the forced swim test. Beta(25-35) peptide-injected animals developed memory deficits after 8 days contrarily to controls injected with scrambled beta(25-35) peptide or vehicle solution. In the forced swim test, the i.c.v. treatment failed to affect the immobility duration, but the antidepressant effect of the sigma(1) agonists was facilitated in beta(25-35) animals. Igmesine reduced immobility duration at 30 versus 60 mg/kg in control groups. PRE-084 decreased immobility duration at 30 and 60 mg/kg only in beta(25-35) animals. Desipramine reduced the immobility duration similarly among groups and fluoxetine appeared less potent in beta(25-35) animals. The beta(25-35) animals exhibited decreased progesterone levels in the hippocampus (-47%). The behavioural efficacy of sigma(1) agonists is known to depend on neuro(active)steroids levels synthesised by glial cells and neurones, which are affected by the beta-amyloid toxicity. This behavioural study suggests that sigma(1) agonists, due to their enhanced efficacy, may allow to alleviate the depressive symptoms associated with Alzheimer's disease.

The sigma(1) (sigma(1)) 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 sigma(1) 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 sigma(1) receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either sigma(1) receptor expression or steroid levels. The sigma(1)-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 sigma(1) 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 sigma( 1) 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 sigma(1) 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 sigma(1)-receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the sigma(1) receptor.

Steroids, synthesized in peripheral glands or centrally in the brain--the latter being named neurosteroids--exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA(A), NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the sigma(1) protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, sigma1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the sigma1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as sigma1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective sigma1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.

Activation of the neuronal sigma(1) (sigma(1)) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, sigma(1) agonists modulate learning, response to stress and depression. In particular, the selective sigma(1) agonist igmesine reduced immobility in the forced swimming test.We investigated the effect of modulators of Ca(2+) influx and mobilization, administered intracerebroventricularly at doses ineffective alone, on the igmesine effect. The tricyclic antidepressant desipramine was also studied for comparison.The calcium chelator EGTA blocked both igmesine and desipramine-induced decreases of immobility duration, indicating the importance of extracellular Ca(2+) influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the sigma(1) agonist effect. Verapamil, an L-type VDCC antagonist or omega-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (-)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca(2+) stores is involved selectively in the effect mediated by the sigma(1) receptor, since the membrane permeable intracellular Ca(2+) chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP(3)) receptor-sensitive Ca(2+) pools appeared primarily involved, rather than Ca(2+)/caffeine-sensitive Ca(2+) pools. Indeed, the InsP(3) receptor positive modulator bradykinin potentiated, whereas the InsP(3) receptor antagonist xestospongin C blocked the igmesine effect. The ryanodine receptor agonist caffeine failed to affect the efficacy of igmesine, whereas the antagonist ryanodine reduced it.The sigma(1) receptor-mediated behavioral effect is dependent not only on rapid Ca(2+) influx, as observed for a classical antidepressant, but also on intracellular Ca(2+) mobilization.

Neurosteroids have been reported to modulate learning and memory processes in aged animals and in pharmacological models of amnesia. We report here the effects of dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate (PREGS), and progesterone (PROG) on the learning impairment induced in mice by the muscarinic acetylcholine receptor antagonist, scopolamine. Spatial working memory was examined using the spontaneous alternation behavior in a Y-maze and long-term memory using place learning in a rectangular water-maze adapted for mice. Both DHEAS and PREGS (5-20 mg/kg, s.c.) prevented dose-dependently and significantly the scopolamine (2 mg/kg, s.c.)-induced alternation deficits. PROG (2-20 mg/kg, s.c.) failed to affect the scopolamine-induced deficits, but blocked, at 20 mg/kg, the beneficial effects induced by DHEAS or PREGS. In the water-maze, DHEAS (20 mg/kg) attenuated significantly the scopolamine-induced deficits, as observed during the acquisition sessions or the retention test. PROG (2, 20 mg/kg) did not affect the control or scopolamine-treated group performances, but blocked the ameliorating effect of DHEAS. Furthermore, in both tests, the selective sigma1 (sigma1) receptor antagonist NE-100 (1 mg/kg, i.p.) failed to affect the behaviors showed by the control or scopolamine-treated groups, but it blocked the ameliorating effects induced by DHEAS or PREGS. These results confirm the modulating role of neurosteroids in learning and memory processes and demonstrate that their modulation of the cholinergic systems involves an interaction with sigma1 receptors.