Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice.
The present study demonstrated the antidepressant-like effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT(1B/1C) receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT(2A/1C) receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3alpha, 5alpha THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3alpha, 5alpha THP. Such a potentiating effect of the 5-HT(1A) or the 5-HT(2A/1C) receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s. c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300x3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3alpha, 5alpha THP. The accelerated effect of 3alpha, 5alpha THP in presence of serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3alpha, 5alpha THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.
Khisti
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Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 010, Maharashtra, India. rtkhisti@nagpur.dot.net.in
Chopde
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy*; D004347:Drug Interactions; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000494:pharmacology / Q000627:therapeutic use*; D018490:Serotonin Agents / Q000627:therapeutic use*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D018490:Serotonin Agents; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone