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)

The functional state of GABAA receptors during physical dependence on ethanol was evaluated in two ways. First, the ability of ethanol dependence to change the convulsant potency of GABAA antagonists microinjected into the inferior colliculus was examined. A second approach evaluated the effects of ethanol dependence on the ability of muscimol or pentobarbital to stimulate chloride uptake in rat brain vesicles. In the studies examining changes in convulsant potency, bilateral microinfusions of GABAA antagonists, bicuculline methiodide and picrotoxinin, as well as the excitatory amino acid agonist, kainic acid (used as a positive control) induced similar dose-related increases in the frequency of wild-running seizures. Ethanol dependence did not significantly change susceptibility to wild-running seizure induction by an of the convulsants, although susceptibility to the more severe, clonic seizures was significantly increased for each convulsant. This suggested that the receptor-blocking effects of GABAA antagonists responsible for inducing wild-running seizures were not selectively increased by ethanol dependence, but that spread of seizure activity responsible for clonic seizures following the initiation of wild running was generally increased. Finally, in studies examining changes in GABAA receptor-mediated chloride uptake, both muscimol and pentobarbital were found to induce concentration-dependent increases in chloride uptake in rat brain vesicles. However, responses to these drugs were not reduced by ethanol dependence suggesting that a generalized adaptive decrease in GABAA receptor function was unlikely. Together these results do not provide support for the hypothesis that the GABAA receptor-chloride channel complex is down-regulated during the development of physical dependence on ethanol.
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PMID:Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake. 178 22

A model for the development of pentobarbital tolerance and dependence was characterized and correlated with changes in radioligand binding to the GABAA-benzodiazepine receptor chloride channel complex. While one day of pentobarbital exposure decreased the duration of loss of righting reflex, tolerance to the hypothermic effects of thiopental and barbital took 7 days to develop, indicating that pharmacokinetic and pharmacodynamic tolerance are separable. Increased sensitivity to pentylenetetrazol-induced seizures was first observed after 3 days of pentobarbital exposure, suggesting brain areas involved in seizure control develop tolerance to, and dependence on pentobarbital faster than those involved in temperature regulation. Acute exposure to pentobarbital in vivo did not affect cortical binding of [3H]muscimol in vitro, while tolerance caused a decrease in binding due to an increase in the low-affinity site KD. Pentobarbital tolerance also caused a decrease in the cortical binding of the benzodiazepine, [3H]flunitrazepam. These observations suggest that the acute effects of barbiturates on the GABAA receptor complex are reversible, while tolerance causes receptor modifications which may be related to the development of physical dependence.
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PMID:Pentobarbital tolerance and withdrawal: correlation with effects on the GABAA receptor. 196 22

Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesthetics and anticonvulsants. However, prolonged use of the drugs produces physical dependence, and the drugs have a high abuse liability. The gamma-aminobutyric acidA (GABAA) receptor is one of barbiturates' main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates. Recent advances in the study of the GABAA receptor/chloride channel complex allow us to examine possible mechanisms that underlie barbiturate tolerance/dependence in a new light. In this minireview, we mainly focus on molecular and cellular aspects of the action of barbiturates and the possible mechanisms that contribute to development of tolerance to and dependence on barbiturates.
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PMID:Pharmacology of barbiturate tolerance/dependence: GABAA receptors and molecular aspects. 869 29