Allosteric effects of a GABA receptor-active steroid are altered by stress.
Recently, ring A reduced metabolites of naturally occurring steroids have been shown to act as allosteric modulators of GABA-gated chloride ion conductance. Specifically, 5 alpha-pregnane-3 alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone; 5 alpha-THDOC) was shown to be a positive allosteric effector. For example, 5 alpha-THDOC enhances the specific binding of [3H]flunitrazepam, a benzodiazepine receptor agonist, among other pharmacological actions. Swim stress has been shown to reduce the ability of flurazepam, a prototypic benzodiazepine agonist, to antagonize the electrical precipitation of tonic hindlimb extension in mice. This stress-induced reduction in flurazepam's antiseizure efficacy persists for up to 72 h and is associated with alterations in the specific binding of ligands to the GABAA receptor complex. In the current study, the potentiation of [3H]flunitrazepam binding by 5 alpha-THDOC was greater in cerebral cortical membranes prepared from stressed mice compared with unstressed controls. Moreover, nanomolar concentrations of 5 alpha-THDOC that were ineffective in potentiating the specific binding of [35S]TBPS in cerebral cortical membranes prepared from unstressed control mice were capable of potentiating this binding in membranes prepared from stressed animals. Specifically, 50 nM 5 alpha-THDOC caused a 23% increase in the specific binding of [35S]TBPS in membranes from stressed mice, whereas it was without any significant effect in unstressed controls. This apparent ability of 5 alpha-THDOC to distinguish between the binding of [35S]TBPS to crude membranes prepared from stressed and unstressed control mice was eliminated in the presence of a 5 microM concentration of GABA.(ABSTRACT TRUNCATED AT 250 WORDS)
VA-NIDA Research Unit, Department of Veterans Affairs Medical Center, Washington, DC 20422.
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D000494:Allosteric Regulation; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007700:Kinetics; D008297:Male; D051379:Mice; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018079:Receptors, GABA; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate