The effects of neurosteroids on rat behavior and H-3-muscimol binding in the brain

The effects of ICV administration of metabolites of progesterone and deoxyc orticosterone [i.e., neurosteroids: AP (3 alpha-hydroxy-5 alpha-pregnan-20- one, allopregnanolone), 5 alpha-THDOC (3 alpha-21-dihydroxy-5 alpha-pregnan -20-one, 5 alpha-tetrahydrodeoxycorticosterone), 5 beta-THDOC (3 alpha-21-d ihydroxy-5 beta-pregnan-20-one, 5 beta-tetrahydrodeoxycorticosterone), and PS (3 beta-hydroxy-5-pregnen-20-one sulfate, pregnenolone sulfate] were stu died in the open-field test of neophobia and Vogel's test of conflict behav ior in rats. The influence of in vivo administered 5 beta-THDOC, a positive allosteric modulator of the GABA(A) receptor complex, on H-3-muscimol bind ing in different brain structures, was also studied with the help of quanti tative autoradiography. The presented data did not reveal any anxioselectiv e effects for a range of centrally active neurosteroids, in the ethological ly orientated and conflict models of anxiety, after intracerebral drug admi nistration. Their central effects appeared secondary to changes in rat gros s behavior. It is possible that high local concentration of neurosteroids a fter ICV injection and production of a narrower range of behavioral effects than that of benzodiazepines, precluded manifestation of the antianxiety e ffects of AP, 5 alpha-THDOC and 5 beta-THDOC. Autoradiography did not revea l any significant changes in the specific binding of H-3-muscimol in brain structures after in vivo ICV administration of 5 beta-THDOC at the behavior ally active dose. Thus, the possibility that neuroactive neurosteroids may provide a novel potential site for therapeutic interventions in anxiety dis orders is not supported. The part of the experiment with 5 beta-THDOC is in terpreted as contributing to other results, suggesting the existence of a n ew category of neurosteroids acting as partial agonists of the GABA(A) rece ptor. (C) 1999 Elsevier Science Inc.