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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since benzodiazepines have been used widely in the treatment of anxiety, sleeplessness, and epilepsy, the receptor sites for the benzodiazepine are of prime importance. Quantitative structure-activity relationship (QSAR) studies and receptor modeling via Flexible Atom Receptor Model (FLARM) for the binding affinities of a series of imidazobenzodiazepines at five recombinant receptor subtypes were carried out successfully. The 3D-QSAR models for all five receptor subtypes were examined by a set of test set and demonstrated their high predictability for affinities of imidazobenzodiazepines at five receptor subtypes. The pseudoreceptors yielded by FLARM were compared to the united pharmacophore/receptor model. The result shows that two hydrogen bonds and other regions in the united pharmacophore/receptor model are presented in the pseudoreceptors, which demonstrates the receptor modeling capability of FLARM. The models and pseudoreceptors can help design high affinity ligands on the GABA(A)/BZ receptor and understand the GABA(A) receptor.
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PMID:Pseudoreceptor models and 3D-QSAR for imidazobenzodiazepines at GABA A/BzR subtypes alphaxbeta3gamma2 [x = 1-3, 5, and 6] via flexible atom receptor model. 1515 82

Clinically used benzodiazepine and nonbenzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter GABA at the GABA(A) receptor. Indiplon is a novel pyrazolopyrimidine sedative-hypnotic agent, currently in development for insomnia. Using radioligand binding studies, indiplon inhibited the binding of [(3)H]Ro 15-1788 (flumazenil) to rat cerebellar and cerebral cortex membranes with high affinity (K(i) values of 0.55 and 0.45 nM, respectively). [(3)H]Indiplon binding to rat cerebellar and cerebral cortex membranes was reversible and of high affinity, with K(D) values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABA(A) receptors containing alpha1 subunits. In "GABA shift" experiments and in measurements of GABA-induced chloride conductance in rat cortical neurons in culture, indiplon behaved as an efficacious potentiator of GABA(A) receptor function. In both the radioligand binding and electrophysiological experiments, indiplon had a higher affinity than zolpidem or zaleplon. These in vitro properties are consistent with the in vivo properties of indiplon as an effective sedative-hypnotic acting through allosteric potentiation of the GABA(A) receptor.
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PMID:Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor. 1525 40

The gamma-aminobutyric acid-A (GABA(A)) receptors is the target for the most widely prescribed sleep medicines. It is a ligand-gated ion channel, activated by the amino acid neurotransmitter GABA, which normally results in hyperpolarization of neurons leading to reduced action potential firing, and thereby a reduction in neuronal activity. It has a rich pharmacology with a number of separate modulator binding sites. The best studied of these is the benzodiazepine site. Modulation of GABA(A) receptor activity by benzodiazepines produces sedative, hypnotic, anxiolytic and anticonvulsant activities. Short half-life benzodiazepines such as triazolam have been particularly useful in treating insomnia, but concerns have been raised regarding tolerance potential and dependence liability of classical benzodiazepines, which has led to reduced prescribing of these agents. In recent years, the treatment of sleep disorders has moved towards the use of non-benzodiazepine sedative hypnotics. These agents act at the same site on the GABA(A) receptor, but feature less of the problems associated with classical benzodiazepines. Recent progress in our understanding of the diversity and pharmacology of GABA(A) receptor subtypes has provided a rational explanation for the efficacy of these compounds. Findings from preclinical studies reveal promising avenues for the design of better therapeutics in the near future.
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PMID:The benzodiazepine site of the GABAA receptor: an old target with new potential? 1530 92

Antipsychotic-induced akathisia is characterized by subjective and objective motor restlessness, which is observed as a common extrapyramidal side-effect of antipsychotic agents. A patient is described who had antipsychotic-induced akathisia unresponsive to conventional therapy, and who began gabapentin therapy for insomnia. Significant improvement in his akathisia occurred when the gabapentin dose was increased, and his other treatment for akathisia was decreased and discontinued. Gabapentin may be effective by mechanisms similar to its action in restless legs syndrome and Parkinsonism, and/or via the GABA neurotransmitter system.
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PMID:Gabapentin in the treatment of antipsychotic-induced akathisia in schizophrenia. 1581 71

Insomnia is a common sleep complaint even in young adults and has important daytime consequences. Several subjective and objective tools are recommended to assess the magnitude of the problem and to try to find a cause. Chronic insomnia is often caused by precipitating factors, such as acute stress, work conditions, illness, and travel, and perpetuating factors, such as poor sleep hygiene, anxiety, and medications. Insomnia may have implications in athletic performance resulting from physical and cognitive effects. Several pharmacologic and nonpharmacologic approaches are employed in the management of insomnia that have proven effective for short-term treatment. The pharmacologic approaches include the use of zolpidem and specific GABA agonists, benzodiazepines for specific indications, antidepressants, and melatonin. The nonpharmacologic approaches include stimulus control, sleep restriction, relaxation strategies, and cognitive behavioral therapy.
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PMID:Insomnia and sleep disruption: relevance for athletic performance. 1589 23

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor.
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PMID:Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro. 1592 20

The study of alcohol dependence mechanisms has been aided by work in rodents, where regimens of intermittent chronic administration with repeated episodes of intoxication and withdrawal can be coupled with controlled timing of in vitro studies and the possibility of relating them to behavior. The chronic intermittent ethanol (CIE) model in the rat has been found to be a good model of human alcohol dependence, showing persistent signs of withdrawal and self-administration. Studies in CIE rats suggest that plastic changes in GABA-mediated inhibition involving the GABAA receptor system may be responsible for the behavioral alterations. Here we summarize a combination of evidence that the alcoholic rat CIE model demonstrates changes in GABAA receptor subunit levels, in receptor localization, and in physiology and pharmacology, leading to alterations in behavior that contribute to the hyperexcitable alcohol withdrawal state (anxiety, insomnia, seizure susceptibility) and alcohol dependence.
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PMID:Plasticity of GABAA receptors in brains of rats treated with chronic intermittent ethanol. 1636 77

Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABA(A) receptors from rat brain and acts as a positive allosteric modulator of GABA(A) receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABA(A) receptor alpha subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABA(A) receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABA(A) receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for alpha1 subunit-containing receptors over GABA(A) receptors containing alpha2, alpha3, or alpha5 subunits. The EC(50) values were 2.6, 24, 60, and 77 nM for alpha1beta2gamma2, alpha2beta2gamma2, alpha3beta3gamma2, and alpha5beta2gamma2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and >100 times more potent than zaleplon. Moreover, indiplon, up to 1 microM, did not potentiate GABA(A) receptors composed of alpha4beta2gamma2 and alpha6beta2gamma2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.
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PMID:Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. 1639 82

Zolpidem is a GABA (A) agonist, which is indicated for the short-term management of insomnia. Recent research provide evidence suggesting that zolpidem produces spatial working memory (WM) deficits and dependence; however, the underlying mechanisms of these effects are unknown. Since the auditory N400 component of event-related potentials (ERPS) is considered as an index of memory use of context processing, the present study focused on N400 waveform of ERPs elicited during a WM task in a case suffering from zolpidem dependence. The patterns of N400 waveform of this case were compared to the patterns obtained from healthy controls. This comparison revealed that zolpidem dependence is accompanied by reduced amplitudes located at posterior brain areas and diffuse prolongation of N400. These findings may indicate that zolpidem dependence manifests alterations with regard to the memory use of context processing, involving or affecting a wide-ranging network of the brain's structures.
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PMID:Abnormal auditory N400 in a case of zolpidem dependence, during a working memory test. 1651 11

This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing the physiology and topography of normal sleep, the disturbances revealed in studies of sleep in depression using polysomnographic recordings and neuroimaging assessments are discussed. Next, treatment implications of the disturbances are reviewed at both clinical and neurobiologic levels. Most antidepressant medications suppress rapid eye movement (REM) sleep, although this effect is neither necessary nor sufficient for clinical efficacy. Effects on patients' difficulties initiating and maintaining sleep are more specific to particular types of antidepressants. Ideally, an effective antidepressant will result in normalization of disturbed sleep in concert with resolution of the depressive syndrome, although few interventions actually restore decreased slow-wave sleep. Antidepressants that block central histamine 1 and serotonin 2 tend to have stronger effects on sleep maintenance, but are also prone to elicit complaints of daytime sedation. Adjunctive treatment with sedative hypnotic medications--primarily potent, shorter-acting benzodiazepine and gamma-aminobutyric acid (GABA A)-selective compounds such as zolpidem--are often used to treat associated insomnia more rapidly. Cognitive behavioral therapy and other nonpharmacologic strategies are also helpful.
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PMID:Depression and sleep: pathophysiology and treatment. 1688 7


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