Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gaboxadol, a selective extra synaptic GABA(A) receptor agonist, has been in clinical development for the treatment of insomnia. Development of tolerance to therapeutic effects (e.g. hypnotic and anticonvulsant and sedative) and withdrawal symptoms (e.g. REM sleep rebound and reduced seizure threshold) upon treatment discontinuation is reported for GABA(A) receptor allosteric modulators acting via the benzodiazepine binding site, e.g. zolpidem and indiplon. We conducted a head to head comparison in rats of the hypnotic (sleep EEG after 21 daily doses and 24 and 48 h after the last dose) and seizure threshold modifying (bicuculline assay 24 h after 28 daily doses) effects of gaboxadol and benzodiazepine ligands. Furthermore, we investigated in further details a previously reported apparent rapid development of tolerance to gaboxadol's effects in a rat rotarod motor coordination assay and related this effect to CNS exposure levels and in vitro potency at extra synaptic GABA(A) receptors. Sleep EEG studies demonstrated lack of tolerance and withdrawal effects after 28 daily doses with gaboxadol, whereas zolpidem produced both tolerance and withdrawal effects under a similar dosing regimen. Daily dosing with gaboxadol, zolpidem or indiplon for 28 days and acute discontinuation of treatment left the threshold to bicuculline-induced seizures unchanged. The rapidly attenuated effect of repeated gaboxadol dosing was confirmed in the rotarod model. However, re-challenge of gaboxadol insensitive animals with gaboxadol produced a maximum response, ruling out that receptor desensitisation accounts for these effects. By comparing CNS exposure at rotarod responses and concentration response relation at cloned GABA(A) receptors expressed in Xenopus oocytes it appears that the decline in response in the rotarod model coincides with the steep part of the concentration response curve for gaboxadol at extra synaptic GABA(A) receptors. In conclusion, rat sleep EEG repeated dose studies of gaboxadol confirm a hypnotic-like profile and no withdrawal effects, whereas tolerance and withdrawal effects were shown with zolpidem. Withdrawal from gaboxadol, zolpidem and indiplon did not affect the seizure threshold to bicuculline. Gaboxadol's apparent rapid development of tolerance in the rotarod assay appears to be kinetically determined.
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PMID:Gaboxadol -- a different hypnotic profile with no tolerance to sleep EEG and sedative effects after repeated daily dosing. 1830 23

Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the delta-subunit containing extrasynaptic GABA(A) receptors that will soon enter the U.S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I (2007) The EEG effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893-1899]. Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats [Lancel M, Langebartels A (2000) Gamma-aminobutyric acid(A) (GABA(A)) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293:1084-1090; Walsh JK, Deacon S, Dijk DJ, Lundahl J (2007) The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30:593-602]. However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal [McCarley RW (2007) Neurobiology of rapid eye movement (REM) and NREM sleep. Sleep Med 8:302-330], we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep-wakefulness during the light period in freely behaving rats. Microdialysis perfusion of THIP (100 microM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected. This is the first study implicating the delta-subunit containing extrasynaptic GABA(A) receptors in PFH in control of sleep-wakefulness in freely behaving rats.
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PMID:Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep-wakefulness: role of delta-subunit containing extrasynaptic GABAA receptors. 1840 65

Drinking alcohol is associated with the disturbance of normal sleep rhythms, and insomnia is a major factor in alcoholic relapse. The thalamus is a brain structure that plays a pivotal role in sleep regulation and rhythmicity. A number of studies have implicated GABA(A) receptors (GABA(A)-Rs) in the anxiolytic, amnestic, sedative, and anesthetic effects of ethanol. In the present study, we examined the effects of ethanol on both synaptic and extrasynaptic GABA(A)-Rs of relay neurons in the thalamus. We found that ethanol (> or =50 mM) elicits a sustained current in thalamocortical relay neurons from the mouse ventrobasal thalamus, and this current is associated with a decrease in neuronal excitability and firing rate in response to depolarization. The steady current induced by ethanol was totally abolished by gabazine and was absent in relay neurons from GABA(A)-R alpha(4) subunit knockout mice, indicating that the effect of ethanol is to enhance tonic GABA-mediated inhibition. Ethanol (50 mM) enhanced the amplitude of tonic inhibition by nearly 50%. On the other hand, ethanol had no effect on spontaneous or evoked inhibitory postsynaptic currents (IPSCs) at 50 mM but did prolong IPSCs at 100 mM. Ethanol had no effect on the paired-pulse depression ratio, suggesting that the release of GABA from presynaptic terminals is insensitive to ethanol. We conclude that ethanol, at moderate (50 mM) but not low (10 mM) concentrations, can inhibit thalamocortical relay neurons and that this occurs mainly via the actions of ethanol at extrasynaptic GABA(A)-Rs containing GABA(A)-R alpha(4) subunits.
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PMID:Ethanol modulates synaptic and extrasynaptic GABAA receptors in the thalamus. 1847 66

Clustering of inhibitory gamma-aminobutyric acid(A) (GABA(A)) and glycine receptors at synapses is thought to involve key interactions between the receptors, a "scaffolding" protein known as gephyrin and the RhoGEF collybistin. We report the identification of a balanced chromosomal translocation in a female patient presenting with a disturbed sleep-wake cycle, late-onset epileptic seizures, increased anxiety, aggressive behavior, and mental retardation, but not hyperekplexia. Fine mapping of the breakpoint indicates disruption of the collybistin gene (ARHGEF9) on chromosome Xq11, while the other breakpoint lies in a region of 18q11 that lacks any known or predicted genes. We show that defective collybistin transcripts are synthesized and exons 7-10 are replaced by cryptic exons from chromosomes X and 18. These mRNAs no longer encode the pleckstrin homology (PH) domain of collybistin, which we now show binds phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P), a phosphoinositide with an emerging role in membrane trafficking and signal transduction, rather than phosphatidylinositol 3,4,5-trisphosphate (PIP3/PtdIns-3,4,5-P) as previously suggested in the "membrane activation model" of gephyrin clustering. Consistent with this finding, expression of truncated collybistin proteins in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABA(A) receptors. These results suggest that collybistin has a key role in membrane trafficking of gephyrin and selected GABA(A) receptor subtypes involved in epilepsy, anxiety, aggression, insomnia, and learning and memory.
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PMID:A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. 1861 34

Nearly one half of the adult population in the U.S. experience some symptoms of insomnia (difficulties with getting to sleep, maintaining sleep, and/or sleep quality) on a weekly basis. Although most people with insomnia complain primarily of issues related to sleep maintenance and quality, current therapeutic approaches, including GABA(A) agonists, off label antidepressant use, H(1) antagonists and melatonin agonists, primarily address sleep onset latency. The overall sleep architecture, especially that of the deeper stages of NREM sleep known as slow wave sleep (SWS), plays a crucial role in restorative, restful sleep. Through the 5-HT(2A) receptor, serotonin plays an active role in the regulation of sleep architecture. Antagonists / inverse-agonists of 5-HT(2A), such as APD125, volinanserin, eplivanserin, pruvanserin and pimavanserin, are currently being investigated as therapeutics that could improve the treatment of sleep maintenance and quality in people with insomnia.
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PMID:5-HT(2A) inverse-agonists for the treatment of insomnia. 1867 66

An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society. However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA(A)) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia. Ramelteon (Rozerem; Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT(1)/MT(2) receptor agonist. Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT(1) and MT(2) receptors, which are primarily located in the suprachiasmatic nucleus, the body's "master clock." As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades. Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia.
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PMID:Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. 1922 78

Indiplon is a novel sedative-hypnotic recently approved for the treatment of insomnia. Like other non-benzodiazepine hypnotics, its mechanism of action is to modulate subunits, especially the alpha-1 subunit, of the GABA receptor complex in order to induce sedation. Indiplon was developed in two different formulations to address two different types of insomnia complaint: indiplon-IR (immediate release) was designed for sleep onset difficulties, while indiplon-MR (modified release) was developed for sleep maintenance insomnia. While there are currently few peer reviewed articles about indiplon clinical trial results, the early information that is available seems to indicate that both formulations have been well tolerated and have proven effective at improving both patient reported and objectively measured sleep parameters in both adult and elderly insomnia patients. In May 2006, the FDA indicated that indiplon-IR was approvable and plans are to resubmit the application in 2007. Indiplon-MR was unapprovable and may require further evaluation.
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PMID:Indiplon in the treatment of sleep disorders. 1930 Jun 12

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT(1) and MT(2) melatonin receptors. Ramelteon's half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT(1) and MT(2) of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.
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PMID:Ramelteon: a review of its therapeutic potential in sleep disorders. 1956 3

Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABA(B) receptor agonists such as baclofen or gamma-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.
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PMID:GABA(B) receptors, schizophrenia and sleep dysfunction: a review of the relationship and its potential clinical and therapeutic implications. 1959 97

Circadin is a prolonged-release 2 mg melatonin formulation which, when taken before bedtime, mimics the physiological pattern of the endogenous hormone excreted during the night. It was approved by the EU-EMEA in June 2007 for the short-term treatment of primary insomnia characterized by poor quality of sleep in patients aged 55 or over. Placebo controlled clinical trials demonstrated, beyond the shortening of sleep Latency seen with traditional hypnotics, concomitant improvements in sleep quality and next day alertness and subsequently, quality of life. In contrast to traditional sedative hypnotics, Circadin has shown no evidence of impairing cognitive and psychomotor skills, of rebound, dependence or abuse potential and no significant adverse events compared to placebo. It can be used concomitantly with most medications but may potentiate the effects of GABA-A receptor modulators. Analyses presented here show that Circadin has comparable efficacy and safety in patients with and without history of hypnotic drug use.
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PMID:[Controlled release melatonin (Circadin) in the treatment of insomnia in older patients: efficacy and safety in patients with history of use and non-use of hypnotic drugs]. 1963 Mar 67


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