Studies on the enhancement of 5-hydroxytryptamine-mediated behaviour by chlormethiazole and phenytoin

Pre-treatment of rats with chlormethiazole (35 mg/kg) or diphenylhydantoin (phenytoin: 40 mg/kg) markedly enhanced the behavioural syndrome which is induced by injection of tranylcypromine (10 mg/kg) followed by L-tryptophan (50 mg/kg). Phenobarbitone (35 mg/kg) pre-treatment was without effect on the syndrome. This enhancement apparently involved a pre-synaptic mechanism since pre-treatment with chlormethiazole or phenytoin did not result in enhancement of the behavioural syndrome when it was induced by injection of the 5-HT(1A) agonist 8-OH-DPAT (0.75 mg/kg). Pre-treatment of rats with chlormethiazole did not alter the rate of 5-HT synthesis as measured by the accumulation of 5-HT following tranylcypromine. The K(+)-evoked release of endogenous 5-HT from brain slices was unaltered by addition of chlormethiazole (100 μM) to the medium while addition of phenytoin (100 μM) caused a small decrease. Administration of chlormethiazole or phenytoin failed to alter either the 5-HT(2) receptor-mediated head twitch behaviour in mice induced by 5-hydroxytryptophan or the hypothermic response induced in mice by injection of 8-OH-DPAT (0.5 mg/kg s.c.). These data extend the original observation of enhancement of the 5-HT(1A) receptor-mediated behavioural syndrome by phenytoin, using a lower dose of the drug, and show that chlormethiazole has a similar effect, apparently through a pre synaptic mechanism. Some similarities to the effect of administration of Ca(2+) antagonists and lithium are noted but no clear mechanism involving changes in ion flux have been identified to explain the mechanisms involved.