The effects of neurosteroids on rat behavior and 3H-muscimol binding in the brain.
The effects of ICV administration of metabolites of progesterone and deoxycorticosterone [i.e., neurosteroids: AP (3alpha-hydroxy-5alpha-pregnan-20-one, allopregnanolone), 5alpha(-THDOC (3alphat-21-dihydroxy-5alpha-pregnan-20-one, 5alpha-tetrahydrodeoxycorticosterone), 5beta-THDOC (3alpha-21-dihydroxy-5beta-pregnan-20-one, 5beta-tetrahydrodeoxycorticosterone), and PS (3beta-hydroxy-5-pregnen-20-one sulfate, pregnenolone sulfate] were studied in the open-field test of neophobia and Vogel's test of conflict behavior in rats. The influence of in vivo administered 5beta-THDOC, a positive allosteric modulator of the GABA(A) receptor complex, on 3H-muscimol binding in different brain structures, was also studied with the help of quantitative autoradiography. The presented data did not reveal any anxioselective effects for a range of centrally active neurosteroids, in the ethologically orientated and conflict models of anxiety, after intracerebral drug administration. Their central effects appeared secondary to changes in rat gross behavior. It is possible that high local concentration of neurosteroids after ICV injection and production of a narrower range of behavioral effects than that of benzodiazepines, precluded manifestation of the antianxiety effects of AP, 5alpha-THDOC and 5beta-THDOC. Autoradiography did not reveal any significant changes in the specific binding of 3H-muscimol in brain structures after in vivo ICV administration of 5beta-THDOC at the behaviorally active dose. Thus, the possibility that neuroactive neurosteroids may provide a novel potential site for therapeutic interventions in anxiety disorders is not supported. The part of the experiment with 5beta-THDOC is interpreted as contributing to other results, suggesting the existence of a new category of neurosteroids acting as partial agonists of the GABA(A) receptor.
Członkowska
A I
AI
Department of Experimental and Clinical Pharmacology, Medical Academy, Warsaw, Poland.
Sienkiewicz-Jarosz
H
H
Siemiatkowski
M
M
Bidziński
A
A
Płaźnik
A
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D003220:Conflict, Psychological; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000523:psychology; D018755:GABA Agonists / Q000378:metabolism*; D018757:GABA Modulators / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009118:Muscimol / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D018757:GABA Modulators; D018377:Neurotransmitter Agents; D013256:Steroids; C018370:pregnenolone sulfate; D009118:Muscimol; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011284:Pregnenolone; D011280:Pregnanolone; D008874:Midazolam