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)

Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia. Current developments in benzodiazepine receptor pharmacology, i.e. the advent of partial agonists and receptor subtype specific agonists (Fig. 1), however, might eventually overcome these limitations, thus greatly improving therapeutic prospects. The present study demonstrates that subchronic administration of alprazolam (a high-efficacy agonist) results in strong withdrawal reactions upon injection of a benzodiazepine receptor antagonist in mice and monkeys. The partial agonist bretazenil, as well as the benzodiazepine receptor type 1-preferring agonist zolpidem, however, are much less prone to producing such reactions. Neurochemical studies showed that subchronic infusion of lorazepam (a high-efficacy agonist), in contrast to betrazenil, led to benzodiazepine receptor downregulation in vivo and reduced potentiation of gamma-aminobutyric acid (GABA)-stimulated chloride flux by diazepam ex vivo. These findings indicate that partial and receptor subtype 1-selective agonists differ from full, non-selective agonists in their liability to induce drug dependence and tolerance upon chronic administration. It is hypothesized that the neurochemical basis of these adaptive phenomena may be receptor downregulation and/or reduced coupling between GABAA receptor/chloride channel gating and benzodiazepine receptor binding.
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PMID:Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence. 791 Jul 39

A critical mass of evidence now supports the existence of a novel class of neuroactive steroids. These steroids are devoid of any known steroid hormone activity and have high specificity for the gamma-aminobutyric acidA receptor complex (GRC), which is a ligand-gated chloride channel that mediates the inhibitory action of the neurotransmitter gamma-aminobutyric acid (GABA). The action of these steroids at the GRC is to allosterically potentiate the effect of GABA on chloride channel conductance through a unique site on the GRC. These neuroactive steroids have been termed the epalons, a shortened form of epiallopregnanolone, an endogenous metabolite of progesterone with potent actions at the GRC. Putative epalon receptors may be unique sites on the GRC that mediate the effects of epalons on GABA-gated channel function. The pharmacological profile of the epalons is consistent with those of other positive modulators of GABA action (e.g., the clinically useful benzodiazepines (BZs) and barbiturates). These neuroactive steroids have anxiolytic, anticonvulsant, and sedative-hypnotic properties. Based upon some of the unique characteristics of the epalons relative to barbiturates and the BZs, it is plausible that the epalons can be developed into a novel class of therapeutic agents for the treatment of anxiety, epilepsy, and insomnia.
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PMID:A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons. 858 84

Steroids are usually identified as genomic regulators, yet recently a body of evidence has accumulated demonstrating specific plasma membrane effects, as well as coordinative effects, of some steroids on both membrane and intracellular receptors. The resulting rapid (<1 min) modulation of cellular activity has strongly suggested a non-genomic, and possibly modulatory, role for certain steroid compounds, and dramatic effects on membranes of excitable as well as other tissues have been demonstrated. Steroid synthesis and metabolism have been shown to exist in the CNS, and the effects have been seen in both the central and peripheral nervous systems. The major groups of neuroactive steroids, and their metabolites, have been progesterone, deoxycorticosterone, and some androgens, notably dihydroxyepiandrosterone (DHEA). These compounds show increased concentrations both in blood and in the brain following stress and they have also been associated with anxiolytic effects and antiepileptic activity. In the periphery, some of these compounds show remarkable inhibitory effects on the secretion of catecholamines and other neurotransmitters. The mechanism for the majority of the effects of these steroids is via their effect on receptor-mediated binding to ligand-gated ion channels. Activation of the GABAA receptor complex, resulting in the opening of its central chloride channel, is the major target of the neuroactive steroids, resulting in re-polarization of the plasma membrane and inhibition of further neuronal firing. The anxiolytic, anti-convulsant and sedative-hypnotic actions of these neuroactive steroids have resulted in their being used as therapeutic agents for the treatment of anxiety, epilepsy, insomnia, and possibly for the alteration of pain thresholds.
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PMID:Neuroactive steroids: their mechanism of action and their function in the stress response. 1060 19

Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class that is used to treat insomnia in humans. Zolpidem binds selectively to the benzodiazepine omega-1 receptor and increases the frequency of chloride channel opening, which results in inhibition of neuronal excitation. A retrospective study was conducted of zolpidem ingestion in dogs that were reported to the ASPCA Animal Poison Control Center (APCC) between January 1998 and July 2000. Data analysis included amount ingested, clinical effects, and time of onset of signs. Thirty-three reports of zolpidem ingestion in dogs (ranging in age from 5 months to 16 years) were evaluated. Approximate ingested dosages ranged from 0.24 to 21 mg/kg. Clinical signs reported included ataxia (18 dogs; 54.5%), hyperactivity (10 dogs; 30.3%), vomiting (7 dogs; 21.2%), and lethargy (5 dogs; 15.2%), as well as panting, disorientation, nonspecific behavior disorder, and hypersalivation (4 dogs each sign; 12.1%). Other signs reported include tachycardia, tremors, apprehension, vocalization, hypersalivation, weakness, and hyperesthesia. In 85% percent of reports, clinical signs developed within 1 hour and usually resolved within 12 hours. Although central nervous system (CNS) depression is reported as a primary effect of zolpidem in humans and would also be expected in dogs, information obtained from this study indicates that some dogs may exhibit a paradoxical excitation reaction. This effect appears to vary among individual dogs.
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PMID:Clinical syndrome associated with zolpidem ingestion in dogs: 33 cases (January 1998-July 2000). 1189 40