Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat

Abstract

Zimelidine, a selective serotonergic (5HT) reuptake blocker, is a clinically effective antidepressant.However, its rapid action on reuptake is in apparent discrepancy with its delayed clinical efficacy, and data on the effect of its chronic administration on 5-HT neurotransmission have never been provided.In the first series of experiments, the response of CA3 hippocampus pyramidal neurons to the electrical stimulation of the ventromedial ascending 5-HT pathway was assessed from peristimulus time histograms, and the responsiveness of the same cells to iontophoretic applications of 5-HT and y-aminobutyric acid (GABA) was measured using the I.TbO method.The suppression of firing of pyramidal neurons induced by the stimulation was significantly greater in zimelidine-treated rats (5 mg/kg, i.p., q.d. for 14 days) than in controls, but the I. T50 for 5-HT and GABA was not modified by the zimelidine treatment.In a second series of experiments, unitary recordings of 5-HT neurons were obtained from the mesencephalic dorsal raphe nucleus.After 2 days of zimelidine treatment (5 mg/kg, i.p., q.d.), the number of 5-HT units discharging spontaneously was greatly reduced.After 7 days of treatment, the number of active 5-HT neurons had returned to normal values, but their firing rate was slower than in control animals.After a treatment of 14 days, both the number of active 5-HT units and their mean firing rate were within normal range.At this time, the responsiveness of 5-HT neurons to intravenous lysergic acid diethylamide (LSD) was assessed: the EDbO of LSD was 2-to 3-fold greater than in control rats, indicating that their autoreceptors had desensitized.It is concluded that long-term zimelidine treatment enhances the efficacy of 5-HT neurotransmission in the hippocampus.However, the reuptake blockade by zimelidine cannot result in an enhanced 5-HT neurotransmission until 5-HT neurons resume a normal electrical activity.This sequence of events may well account for the delayed antidepressant effect of zimelidine in major depression.