Posted by desolationrower on January 25, 2009, at 21:51:54
In reply to Re: * Seroquel - Why does it help so many conditions? » desolationrower, posted by SLS on January 25, 2009, at 13:58:35
> > quetiapine is also a pretty strong alpha2 antagonist. it might interact with the sigma receptor as well. and 5ht6 and some other receptors not well understood.
>
>
> I know nothing about sigma receptors.
>
>
> - Scottits probably worth looking into...
Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders.
The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed.Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of sigma-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that sigma-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.
PMID: 15089113
Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors.
This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.
PMID: 16495935
[Sigma-receptor ligands and anti-stress actions]
[Article in Japanese]Noda Y, Kamei H, Nabeshima T.
Department of Neuropsychopharmacology, Nagoya University Graduate School of Medicine, Japan.
The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoin-sensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma1 receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.
PMID: 10562964
(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites.
Kamei H, Kameyama T, Nabeshima T.Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Mice exhibited a marked suppression of motility when they were replaced in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by (+)-N-allylnormetazocine ((+)-SKF-10,047) and by dextromethorphan, putative sigma receptor agonists, but not by other sigma receptor ligands, (+)-pentazocine and 1,3-di-(2-tolyl)guanidine (DTG). Unlike (+)-SKF-10,047 and dextromethorphan, the non-competitive NMDA receptor antagonists, phencyclidine and dizocilpine, attenuated the conditioned fear stress only at high doses that induced marked hypermotility in non-stressed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not phencyclidine and dizocilpine, on the conditioned fear stress were antagonized by the sigma receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol hydrochloride). Interestingly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsant drug, whereas those of (+)- pentazocine, DTG, phencyclidine, and dizocilpine were not. These results suggest that activation of phenytoin-regulated type sigma 1 receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on stress-induced motor suppression.
PMID: 8901003
[Anti-amnesic effects of sigma (sigma)-receptor agonists]
[Article in Japanese]Matsuno K.
Discovery Research Division, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Both traditional and novel sigma (sigma)-receptor agonists have been reported to possess anti-amnesic effects in rodents. In particular, the anti-amnesic effects induced by the novel sigma1-receptor agonists, such as (+)-pentazocine, SA4503 and PRE-084, were shown in beta amyloid-peptide-induced, basal forebrain (BF)-lesioned and carbon monoxide (CO)-induced amnesia models and senescence-accelerated mouse (SAM). In addition, these sigma1-receptor agonists have good profiles for the central acetylcholine and dopamine systems. Moreover, they also have neuroprotective and anti-depressive effects. These evidence suggested that the sigma1-receptor agonists may be promising compounds for the treatment of dementing disorders such as Alzheimer's disease, senile dementia and vascular dementia. However, the sigma-receptor family is still considered to be enigmatic molecular targets. More molecular cloning and biochemical studies on the sigma-receptor family are needed.
PMID: 10562962
Dehydroepiandrosterone alleviates copulatory disorder induced by social stress in male rats.
INTRODUCTION: Social stress induces sexual dysfunction and reduces serum testosterone (T) level in rats. Stressful events exert an influence on a variety of behaviors and physiology through hormonal changes. The mechanism of stress-induced sexual dysfunction is unknown. AIM: To investigate the role of dehydroepiandrosterone (DHEA) in copulatory behavior induced by social stress in rats. METHODS: Stress-induced male rats were subjected to social stress in which the males lived in a wire-mesh siege located in a colony of male and female rats and were exposed daily to a brief defeat by the colony of males for five consecutive days. After the stress period, copulatory behavior and serum concentrations of DHEA and T were measured. MAIN OUTCOME MEASURES: The effects of DHEA, T, and NE-100, a selective sigma 1 receptor antagonist, on copulatory behavior following social stress were examined. RESULTS: The males exhibited a marked suppression of copulatory behavior (elongation of intromission and ejaculation latencies). Serum concentrations of DHEA and T were significantly lower than those in nonstressed control males. Another three groups of social stressed males were injected daily with DHEA, T, or DHEA + NE-100 during the stress period. Injections of DHEA attenuated the stress-induced suppression of copulatory behavior, whereas T had no effect. The combined treatment of NE-100 made DHEA ineffective at restoring copulatory behavior. CONCLUSIONS: These results indicate that DHEA, but not its conversion to T, alleviates the suppressive effect of social stress on copulatory behavior via sigma 1 receptors. We suggest that the decreased endogenous DHEA is involved in copulatory disorders induced by social stress in rats.
PMID: 16839317
i think it is also anticarcinogenic in some way...
cocaine, memantine, and dextromethorphan also are ligands for it...haldol is a strong antagonist.
-d/r
poster:desolationrower
thread:876047
URL: http://www.dr-bob.org/babble/20090104/msgs/876218.html