title: Essentiality of central GABAergic neuroactive steroid allopregnanolone for anticonvulsant action of fluoxetine against pentylenetetrazole-induced seizures in mice.
abstract: Fluoxetine, a selective serotonin reuptake inhibitor, is known to increase the cortical content of allopregnanolone (ALLO) without altering the level of other neurosteroids. In contrast to the proconvulsant effect of many antidepressants, fluoxetine exhibits anticonvulsant effects. The present study was undertaken to examine the role of ALLO in the anticonvulsant action of fluoxetine against pentylenetetrazole (PTZ)-induced seizures in mice. Prior administration of GABA(A) receptor agonist muscimol or neurosteroid ALLO or progesterone, a precursor of ALLO or neurosteroidogenic drugs like FGIN 1-27, an agonist at the mitochondrial diazepam binding inhibitor receptor (MDR) or metyrapone, an 11beta-hydroxylase inhibitor, significantly potentiated the anticonvulsant effect of fluoxetine. In contrast, the effect of fluoxetine was counteracted by inhibition of the neurosteroid biosynthesis using drugs like 5alpha-reductase inhibitor, finasteride; 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane; 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin; MDR antagonist, PK 11195; or the GABA(A) receptor antagonist, bicuculline. Further, bilateral adrenalectomy had no significant effect on the anticonvulsant action of fluoxetine, suggesting negligible contribution from peripheral steroidogenesis. The anticonvulsant effect of fluoxetine was partially abolished in 5,7-DHT treated mice, indicating that the effect may also, in part, be dependent on serotonergic transmission. Thus, our data indicate that increased synthesis of ALLO in CNS is a major factor that ultimately leads to anticonvulsant effects of fluoxetine against PTZ-induced seizures.
authors.affiliation: University Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 033, Maharashtra, India.
authors.forename: Rajesh Ramesh
authors.initials: RR
authors.lastname: Ugale
authors.forename: Nutan
authors.initials: N
authors.lastname: Mittal
authors.forename: Khemraj
authors.initials: K
authors.lastname: Hirani
authors.forename: Chandrabhan Tukaram
authors.initials: CT
authors.lastname: Chopde
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D011280:Pregnanolone / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D005473:Fluoxetine; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D010433:Pentylenetetrazole