Cataleptic effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice: modulation by serotonergic agents.
The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3alpha,5alpha-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT(1A) receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT3 agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3alpha,5alpha-THP. Furthermore, FGIN 1-27, an MDR agonist that increases endogenous content of 3alpha,5alpha-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT1A, 5-HT2A/1C or 5-HT3 receptor agonist on 3alpha,5alpha-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 microg/mouse, i.c.v.). However this effect of different 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.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3alpha,5alpha-THP.
Deshpande
L S
LS
Department of Pharmaceutical Sciences, Nagpur University Campus, Amravati Road, 440 010, Maharashtra, Nagpur, India.
Khisti
R T
RT
Chopde
C T
CT
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced* / Q000503:physiopathology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology; D018490:Serotonin Agents / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology
D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D007210:Indoleacetic Acids; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D011280:Pregnanolone; D007213:Indomethacin; D001640:Bicuculline