Anxiolytic activity of the progesterone metabolite 5 alpha-pregnan-3 alpha-o1-20-one.
3 alpha-hydroxylated pregnane steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, metabolites of progesterone and deoxycorticosterone, 5 alpha-pregnan-3 alpha-o1-20-one (3 alpha-OH-DHP) and 5 alpha-pregnan-3 alpha,21-diol-20-one (5 alpha-THDOC), respectively, were tested for anxiolytic effects in N.I.H. Swiss-Webster mice using the light/dark transition, open-field and lick-suppression tests. Similar to the benzodiazepine (BZ) diazepam, 3 alpha-OH-DHP (5-40 mg/kg) and 5 alpha-THDOC (5-40 mg/kg) significantly increased the number of light/dark transitions. 3 alpha-OH-DHP's effects were stereospecific as its diasteriomer, 3 beta-OH-DHP was devoid of activity. The benzodiazepine antagonist CGS-8216 (10 mg/kg) blocked diazepam's (1.0 mg/kg) anxiolytic effects, but did not have any effect against 3 alpha-OH-DHP (20 mg/kg). The data indicate that the pregnane steroids produce their anxiolytic effects through a separate mechanism than the BZs. 3 alpha-OH-DHP (20 mg/kg), 5 alpha-THDOC (20 mg/kg) and diazepam (1.0 mg/kg) increased activity in a open-field test. 3 beta-OH-DHP had no effect in the open-field test. Furthermore, 3 alpha-OH-DHP produced a 235% increase in punished responding in a lick-suppression test. These results demonstrate that the endogenous pregnane steroids possess anxiolytic effects that may be clinically relevant.
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.
S
S
Wieland
N C
NC
Lan
S
S
Mirasedeghi
K W
KW
Gee
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D003624:Darkness; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects*; D008027:Light; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013237:Stereoisomerism
D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011374:Progesterone; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; D011280:Pregnanolone