Effects of chlorimipramine and lysergic acid diethylamide on efflux of precursor-formed 3-H-serotonin: correlations with serotonergic impulse flow.

Summary

LSD and the antidepressant chlorimipramine (CIMI) both inhibit the firing of serotonin-producing neurons in the brain, but they affect serotonin release differently. LSD reduces serotonin efflux at doses that also inhibit neuronal firing. A low dose of CIMI inhibits firing without reducing serotonin efflux, suggesting that blocked reuptake compensates for reduced release. A high dose of CIMI actually increases serotonin efflux. The findings indicate that LSD decreases serotonin release by directly inhibiting impulse flow or acting on nerve terminals, while CIMI's net effect on serotonin depends on dose and the balance between reuptake blockade and impulse-dependent release.

Study at a glance

Abstract

The effects of d-lysergic acid diethylamide (LSD) and chlorimipramine (CIMI) on the firing rate of serotonergic (5-HT) neurons and on the in vivo efflux of 5-HT were investigated in parallel. A cerebroventricular perfusing technique was used to measure the efflux of 3-H-5-HT formed in vivo from 3-H-tryptophan. Impulse flow in serotonergic neurons was monitored by single unit recording from raphe (5-HT) neurons. Doses of LSD and CIMI, which caused a similar degree of inhibition of raphe cell firing, were found to affect 5-HT efflux differently. LSD, at both the 75, and 150 mug/kg doses, produced a similar decrease in 3-H-5-HT efflux. In contrast, CIMI at a low dose (5 mg/kg) did not reduce 5-HT efflux, despite an inhibition in impulse flow. At a high dose (20 mg/kg), CIMI produced an increase in 3-H-5-HT efflux. We conclude that 1) LSD decreased 3-H-5-HT efflux by directly inhibiting impulse flow in 5-HT neurons and/or by a local effect on 5-HT terminals and 2) a low dose of CIMI produces no net change in 3-H-5-HT efflux because a reduction in impulse flow-dependent 5-HT release compensates for blockade by CIMI of 5-HT reuptake.