Behavioral action of ethanol in Porsolt's forced swim test: Modulation by 3alpha-hydroxy-5alpha-pregnan-20-one

K. Hirani, R. T. Khisti, C. T. Chopde

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

Ethanol is known to increase cortical and plasma content of GABAergic neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) which is responsible for some of its behavioral and electrophysiological effects. We have previously demonstrated the antidepressant like effect of 3α,5α-THP in mice. This study investigated the role of 3α,5α-THP in acute, chronic and withdrawal effects of ethanol using mouse forced swim test (FST) paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration exhibited an antidepressant like effect, its prolonged consumption produced tolerance to this effect and its withdrawal, on the other hand, elicited enhanced behavioral despair (depression). The antidepressant like effect of ethanol was potentiated by GABAA receptor agonist, muscimol (0.5 mg/kg, i.p.), 3α,5α-THP (0.5, 1 or 2 μg/mouse, i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1 μg/mouse, i.c.v.), or 11β-hydroxylase inhibitor, metyrapone (0.5 or 1 μg/mouse, i.c.v.) which are known to increase endogenous 3α,5α-THP content. Furthermore, inhibition of the endogenous neurosteroid biosynthesis by drugs like 5α-reductase inhibitor, finasteride (50 mg/kg, s.c.), 3β-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg i.p.) or 3α-hydroxysteroid dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABAA receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the antidepressant like effect of ethanol. Withdrawal of ethanol from mice consuming it chronically displayed enhanced behavioral despair and elicited tolerance to antidepressant like action of acute ethanol (2.5, 3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5 μg/mouse, i.c.v.) of 3α,5α-THP and fluoxetine (5 mg/kg, i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression associated with ethanol withdrawal indicating sensitization to their antidepressant action. Thus, 3α,5α-THP plays a pivotal role in the actions of ethanol and in the depression associated with ethanol withdrawal. These findings may be of potential ramification to contribute to the depression associated with alcoholism and its treatment using neurosteroids.

Original languageEnglish (US)
Pages (from-to)1339-1350
Number of pages12
JournalNeuropharmacology
Volume43
Issue number8
DOIs
StatePublished - Dec 2002
Externally publishedYes

Keywords

  • 3α-hydroxy-5α-pregnan-20-one
  • Allopregnanolone
  • Antidepressant
  • Ethanol
  • Forced swim test
  • Neurosteroid
  • Sensitization
  • Tolerance and dependence

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Behavioral action of ethanol in Porsolt's forced swim test: Modulation by 3alpha-hydroxy-5alpha-pregnan-20-one'. Together they form a unique fingerprint.

Cite this