Chronic ethanol administration alters the modulatory effect of 5alpha-pregnan-3alpha-ol-20-one on the binding characteristics of various radioligands of GABAA receptors.
In this study, we investigated the modulatory effect of 5alpha-pregnan-3alpha-ol-20-one, a neurosteroid, on the binding characteristics of [3H]flunitrazepam (2 nM), [3H]muscimol (5 nM), and 4 nM [35S]t-butylbicyclophosphorothionate (TBPS) in cerebral cortex, cerebellum, and hippocampus of control, ethanol-dependent, and ethanol-withdrawn rats. 5alpha-Pregnan-3alpha-ol-20-one potentiated the binding of [3H]flunitrazepam and [3H]muscimol in all the rat brain regions investigated in this study. There was a significant increase in the maximal potentiation of [3H]flunitrazepam as well as [3H]muscimol binding (Emax) in the ethanol-dependent rat cerebellum as compared to control group (p<0. 025). Furthermore, 5alpha-pregnan-3alpha-ol-20-one elicited a biphasic response, i.e., it potentiated the binding of [35S]TBPS at lower concentrations (<=100 nM) and inhibited the binding at higher concentrations (>100 nM). There was a significant higher inhibition of [35S]TBPS binding (-Emax) by 5alpha-pregnan-3alpha-ol-20-one in the hippocampus of ethanol-dependent as well as ethanol-withdrawn rats (p<0.025). These observations suggest that the neurosteroid binding site associated with the gamma-aminobutyric acidA (GABAA) receptors in cerebellum and hippocampus plays an important role during ethanol-dependence and ethanol-withdrawal, and some of the changes following ethanol dependence and its withdrawal may be mediated through the neurosteroid binding site.
Mehta
A K
AK
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7764, USA.
Ticku
M K
MK
D000818:Animals; D001921:Brain / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D009118:Muscimol / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018755:GABA Agonists; D018757:GABA Modulators; D009118:Muscimol; D000431:Ethanol; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone