Elsevier

Life Sciences

Volume 50, Issue 26, 1992, Pages 2125-2138
Life Sciences

Fluoxetine-induced inhibition of synaptosomal [3H] 5-HT release: Possible CA2+-channel inhibition

https://doi.org/10.1016/0024-3205(92)90579-EGet rights and content

Abstract

Fluoxetine, a selective 5-HT uptake inhibitor, inhibited 15 mM K+-induced [3H] 5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K+ used to depolarize the synaptosomes and the concentration of external Ca2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [3H] 5-HT release induced by the Ca2+-ionophore A 23187 or Ca2+-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K+-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca2+ channels and Ca2+ entry. Whereas fluoxetine and paroxetine inhibited binding of [3H] nitrendipine to the dihydropyridine-sensitive L-type Ca2+ channel, the less selective uptake inhibitors did not alter binding. The dihydropyridine antagonist nimodipine partially blocked fluoxetine-induced inhibition of release. Moreover enhanced K+-stimulated release due to the dihydropyridine agonist Bay K 8644 was reversed by fluoxetine. Fluoxetine also inhibited the K+-induced increase in intracellular free Ca2+ in fura-2 loaded synaptosomes. These data are consistent with the suggestion that fluoxetine inhibits K+-induced [3H] 5-HT release by antagonizing voltage-dependent Ca2+ entry into nerve terminals.

References (39)

  • D.T. Wong et al.

    Life Sci.

    (1974)
  • K.A. Stauderman et al.

    Brain Res

    (1985)
  • D.T. Wong et al.

    Biochem. Pharmacol.

    (1983)
  • P.J. Silver et al.

    Eur. J. Pharmacol.

    (1986)
  • L.L. Martin et al.

    Neuropharmacology

    (1982)
  • R.S. Aronstam et al.

    Biochem. Pharmacol.

    (1985)
  • V.C. Gandhi et al.

    Eur. J. Pharmacol.

    (1990)
  • P.R. Dunkley et al.

    J.A.P. Rostas

    Brain Res.

    (1986)
  • P.J. Robinson et al.

    Neurochem. Int.

    (1986)
  • G. Grynkiewicz et al.

    J. Biol. Chem.

    (1985)
  • K.A. Stauderman et al.

    Eur. J. Pharmacol.

    (1986)
  • R.A. Janis et al.

    Eur. J. Pharmacol.

    (1982)
  • P.J. Marangos et al.

    Life Sci.

    (1982)
  • M. Geoffroy et al.

    Eur. J. Pharmacol.

    (1988)
  • D.R. Thomas et al.

    Psychopharmacol.

    (1987)
  • J.M. Ellison et al.

    J. Clin. Psychiatry

    (1990)
  • P.A. Lavoie et al.

    Can. J. Physiol. Pharmacol.

    (1990)
  • P.Garcia De Jalon et al.

    Br. J. Pharmacol.

    (1978)
  • S. Rodriguez et al.

    Br. J. Pharmacol.

    (1980)
  • Cited by (0)

    View full text