Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal studies have shown that chronic ethanol consumption produces physical dependence upon ethanol and alters gamma-aminobutyric acid-A (GABA(A)) receptor subunit gene expression in brain. Although extensive investigation has been conducted in animal models, relatively little work has been performed directly on human alcoholic brain tissue to determine if there are alterations in GABA(A) receptor gene expression. In this study, GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and peptide expression in postmortem frontal cortex from human alcoholics (n = 15) and age- and sex-matched controls (n = 13) were measured by quantitative, competitive reverse transcription polymerase chain reaction and Western blot analysis. GABA(A) receptor beta3 subunit mRNA expression was 35% greater (p < 0.05) in alcoholics, compared with nonalcoholic controls. We found no significant difference in alpha1 and alpha4 subunit mRNA levels between groups. However, there was a trend toward greater (21%) alpha1 subunit mRNA expression. There was no difference in alpha1, alpha4, or beta2/3 subunit peptide levels in frontal cortex between controls and alcoholics. Neither the age of the subjects nor the postmortem interval correlated with mRNA or peptide levels. Blood ethanol content also did not correlate with mRNA or peptide expression in alcoholic samples. These data suggest that GABA(A) receptor adaptations, resulting from prolonged alcohol consumption in human alcoholics, may differ from animal models of alcohol dependence. These differences may be related to the longevity of alcohol exposure in human alcoholics, as well as variability in the dependence/withdrawal state of the human subjects. Therefore, further studies in human postmortem brain tissue are warranted.
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PMID:GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and protein expression in the frontal cortex of human alcoholics. 966 Mar 6

Inhalable solvents possess significant abuse liability and produce many of the neurobehavioral effects typically associated with central nervous system-depressant agents, including motor incoordination, anxiolysis, and the elicitation of signs of physical dependence on withdrawal. We tested the hypothesis that the commonly abused solvents toluene, 1,1,1-trichloroethane (TCE), and trichloroethylene (TCY) affect ligand-gated ion channel activity, as do other classes of central nervous system-depressive agents. TCE and toluene, like ethanol, reversibly enhanced gamma-aminobutyric acid (GABA)(A) receptor-mediated synaptic currents in rat hippocampal slices. All three inhalants significantly and reversibly enhanced neurotransmitter-activated currents at alpha1beta1 GABA(A) and alpha1 glycine receptors expressed in Xenopus oocytes. We previously identified specific amino acids of glycine and GABA(A) receptor subunits mediating alcohol and volatile anesthetic enhancement of receptor function. Toluene, TCE, and TCY were tested on several glycine receptor mutants, some of which were insensitive to ethanol and/or enflurane. Toluene and TCY enhancement of glycine receptor function was seen in all these mutants. However, the potentiating effects of TCE were abolished in three mutants and enhanced in two, a pattern more akin to that seen with enflurane than ethanol. These data suggest that inhaled drugs of abuse affect ligand-gated ion channels, and that the molecular sites of action of these compounds may overlap with those of ethanol and the volatile anesthetics.
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PMID:Glycine and gamma-aminobutyric acid(A) receptor function is enhanced by inhaled drugs of abuse. 1082 91

The mechanisms by which nitrous oxide (N(2)O) produces physical dependence and withdrawal seizures are not well understood, but both N(2)O and ethanol exert some of their effects via the GABA(A) receptor and several lines of evidence indicate that withdrawal from N(2)O and ethanol may be produced through similar mechanisms. Expression levels of mRNA transcripts encoding several GABA(A) receptor subunits change with chronic ethanol exposure and, therefore, we hypothesized that N(2)O exposure would produce changes in mRNA expression for the alpha(1) subunit. Male, Swiss--Webster mice, 10--12 weeks of age, were exposed for 48 h to either room air or a 75%:25% N(2)O:O(2) environment. Brains were sectioned and mRNA for the alpha(1) subunit was detected by in situ hybridization using an 35S-labelled cRNA probe. N(2)O exposure produced a significant increase in expression levels of the alpha(1) subunit mRNA in the cingulate cortex, the CA1/2 region of the hippocampus, the dentate gyrus, the subiculum, the medial septum, and the ventral tegmental area. These results lend support to the hypothesis that N(2)O effects are produced, at least in part, through the GABA(A) receptor and that N(2)O produces these effects through actions in the cingulate cortex, hippocampus, ventral tegmental area and medial septum. These results are also further evidence that ethanol and N(2)O produce dependence and withdrawal through common mechanisms.
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PMID:Increased mRNA expression for the alpha(1) subunit of the GABA(A) receptor following nitrous oxide exposure in mice. 1131 74

SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one] is a novel pyridoindole derivative that displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha2 (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these data (K(i), alpha1beta2gamma2 = 17, alpha2beta2gamma2 = 73, alpha5beta3gamma2 = 215 nM) and indicate intermediate affinity for the alpha3beta2gamma2 subtype (K(i) = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha2 and alpha3 subunits and as a partial agonist at recombinant GABA(A) receptors expressing alpha1 and alpha5 subunits. SL651498 elicited anxiolytic-like activity similar to that of diazepam [minimal effective dose (MED): 1-10 mg/kg, i.p.] in three conflict models, in the elevated plus-maze, the light/dark test, and the defense test battery in rats and mice. Results from activity tests and electroencephalogram analysis indicated that SL651498 induced muscle weakness, ataxia, or sedation at doses much higher than those producing anxiolytic-like activity (MED > or = 30 mg/kg, i.p.). Repeated treatment for 10 days with SL651498 (30 mg/kg, i.p., b.i.d.) in mice was not associated with the development of tolerance to its anticonvulsant effects or physical dependence. Furthermore, SL651498 was much less active than diazepam in potentiating the depressant effects of ethanol in mice. The "anxioselective" profile of SL651498 points to a major role for GABA(A) alpha2 subtype in regulating anxiety and suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity.
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PMID:SL651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors. 1145 40

The effects of long-term treatment with and subsequent withdrawal of the two hypnotic drugs zaleplon and zolpidem on the abundance of gamma-aminobutyric acid type A (GABA(A)) receptor subunit mRNAs in cultured rat cerebellar granule cells were investigated. Incubation of neurons with either drug at a concentration of 10 microM for 5 days did not significantly affect the amounts of mRNAs encoding the alpha(1), alpha(4), beta(1), beta(2), beta(3), gamma(2)L, or gamma(2)S subunits. As expected, similar treatment with the nonselective benzodiazepine diazepam resulted in a decrease in the abundance of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. Withdrawal of zaleplon or zolpidem, like that of diazepam, induced a marked increase in the amount of the alpha(4) subunit mRNA. In addition, discontinuation of treatment with either hypnotic drug resulted in a decrease in the amounts of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. These effects of zaleplon and zolpidem on GABA(A) receptor gene expression are consistent with the reduced tolerance liability of these drugs, compared with that of diazepam, as well as with their ability to induce both physical dependence and withdrawal syndrome.
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PMID:Changes in GABA(A) receptor gene expression induced by withdrawal of, but not by long-term exposure to, zaleplon or zolpidem. 1180 15

SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABA(A) receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha(2) (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these findings and indicate intermediate affinity for the alpha(3)beta(2)gamma(2) subtype. SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha(2) and alpha(3) subunits, and as a partial agonist at recombinant GABA(A) receptors expressing alpha(1) and alpha(5) subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg/kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential profile of SL651498 as compared to BZs may be related to its selective efficacy at the alpha(2)- and alpha(3)-containing GABA(A) receptors. This suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity. SL651498 represents a promising alternative to agents currently used for the treatment of anxiety disorders and muscle spasms without the major side effects seen with classical BZs.
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PMID:SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. 1259 9

With the exception of obsessive compulsive disorder, benzodiazepines (BZs) remain a major first line treatment for anxiety disorders. However, as well as being anxiolytic, BZs also cause sedation acutely, related to the fact that BZs are also used as hypnotics, and chronically may have abuse potential as well as cause physical dependence which manifests itself as the demonstration of a number of adverse events upon discontinuation. The molecular mechanisms of BZs are now well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to a specific recognition site on GABA(A) receptors containing alpha1, alpha2, alpha3 and alpha5 subunits. Compounds that bind at this modulatory site and enhance the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds which bind but have no effect on GABA inhibition are termed antagonists. The clinically used BZs are full agonists and between the opposite ends of the spectrum, i.e. full agonist and full inverse agonist, are a range of compounds with differing degrees of efficacy, such as partial agonists and partial inverse agonists. Attempts have been made to develop compounds which are anxioselective in that they retain the anxiolytic properties of the full agonist BZs but have reduced sedation and dependence (withdrawal) liabilities. Such compounds may interact with all four (i.e. alpha1-, alpha2-, alpha3- and alpha5-containing) GABA(A) receptor subtypes and have partial rather than full agonist efficacies. Examples of nonselective partial agonists include bretazenil, imidazenil, FG 8205, abecarnil, NS 2710, pagoclone, RWJ-51204 and (S)-desmethylzopiclone. Alternatively, a compound might have comparable binding affinity but different efficacies at the various subtypes, thereby preferentially exerting its effects at subtypes thought to be associated with anxiety (alpha2- and/or alpha3-containing receptors) rather than the subtype associated with sedation (alpha1-containing receptors). Examples of efficacy selective compounds include L-838417, NGD 91-3 and SL651498. For each compound, preclinical and where available clinical data will be reviewed. Emerging themes include the lack of definitive intrinsic efficacy data for certain compounds (e.g. abecarnil, ocinaplon, pagoclone) and the difficulty in translating robust anxiolysis and a separation between anxiolytic and sedative doses of non-selective partial agonists in preclinical species into consistent clinical benefit in man (e.g. bretazenil, abecarnil, pagoclone). With respect to efficacy selective compounds, NGD 91-3 was not anxiolytic in man but in the absence of efficacy data, these results are difficult to interpret. Nevertheless, efficacy selective compounds represent a novel approach to targeting specific subtypes of the GABA(A) receptor, the ultimate test of which will be evaluation in the clinic.
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PMID:Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. 1287 Oct 32

Non-selective benzodiazepine (BZ) binding-site full agonists, exemplified by diazepam, act by enhancing the inhibitory effects of GABA at GABA(A) receptors containing either an alpha1, -2, -3 or -5 subunit. However, despite their proven clinical anxiolytic efficacy, such compounds possess a relatively narrow window between doses that produce anxiolysis and those that cause sedation, and are also associated with physical dependence and a potential for abuse. In the late 1980s and early 1990s a number of non-selective partial agonists, exemplified by bretazenil, pazinaclone and abecarnil, were described. Their reduced intrinsic efficacy relative to full agonists such as diazepam resulted in an improved preclinical pharmacological profile in that there was a large window between anxiolytic and sedative doses and their dependence and abuse liabilities were much lower. Unfortunately, these compounds failed, for a variety of reasons, to translate into clinical benefit, and as the public perception of BZs deteriorated interest in the area waned. However, the advent of molecular genetic and pharmacological approaches has begun to delineate which GABA(A) receptor subtypes are associated with the various pharmacological effects of the non-selective BZs. More specifically, the alpha2- and/or alpha3-containing GABA(A) receptors play a role in anxiety whereas the alpha1 subtype is involved in sedation, raising the possibility of a compound that selectively modulates alpha2- and/or alpha3-containing receptors but does not affect alpha1-containing receptors would be a non-sedating anxiolytic. In order to achieve selectivity for the alpha2/alpha3 subtypes relative to alpha1, two approaches may be used; selective affinity or selective efficacy. Selective affinity relies on a compound binding with higher affinity to the alpha2/alpha3 compared with alpha1 subtypes, but to date no such compounds have been described. On the other hand, subtype-selective efficacy relies on a compound binding to all subtypes but having different efficacies at various subtypes (relative selective efficacy, for example SL654198 or pagoclone) or having efficacy at some subtypes but none at others (absolute selective efficacy; for example, L-838417). The status of these and other BZ site compounds with claimed, but often not explicitly stated, GABA(A) subtype selectivity (such as ELB-139 and ocinaplon) will be reviewed in relation to their development as non-sedating anxiolytics for the treatment of generalised anxiety disorder.
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PMID:The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. 1592 67

Chronic insomnia affects a significant proportion of young adult and elderly populations. Treatment strategies should alleviate nighttime symptoms, the feeling of nonrestorative sleep, and impaired daytime function. Current pharmacological approaches focus primarily on GABA, the major inhibitory neurotransmitter in the central nervous system. Benzodiazepine receptor agonists (BzRA) have been a mainstay of pharmacotherapy; the classical benzodiazepines and non-benzodiazepines share a similar mode of action and allosterically enhance inhibitory chloride currents through the GABA(A) receptor, a ligand-gated protein comprising 5 subunits pseudosymmetrically arranged around a core anion channel. Variations in GABA(A) receptor subunit composition confer unique pharmacological, biophysical, and electrophysiological properties on each receptor subtype. Classical benzodiazepines bind non-selectively to GABA(A) receptors containing a gamma2 subunit, whereas non-benzodiazepine hypnotics bind with higher relative affinity to alpha1-containing receptors. The non-benzodiazepine compounds generally represent an improvement over benzodiazepines as a result of improved binding selectivity and pharmacokinetic profiles. However, the enduring potential for amnestic effects, next day residual sedation, and abuse and physical dependence, particularly at higher doses, underscores the need for new treatment strategies. Novel pharmacotherapies in development act on systems believed to be specifically involved in the regulation of the sleep-wake cycle. The recently approved melatonin receptor agonist, ramelteon, targets circadian mechanisms. Gaboxadol, an investigational treatment and a selective extrasynaptic GABA(A) receptor agonist (SEGA), targets GABA(A) receptors containing a delta subunit, which are located outside the synaptic junctions of thalamic and cortical neurons thought to play an important regulatory role in the onset, maintenance, and depth of the sleep process.
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PMID:Treating insomnia: Current and investigational pharmacological approaches. 1687 55