Pre‐ and postsynaptic effects of zimelidine and norzimelidine on the serotoninergic system: single cell studies in the rat

The pre‐ and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague‐Dawley rats. The potency of the presynaptic effect was estimated from their ability to depress the rate of firing of serotonin (5‐HT)‐containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5‐HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5‐HT, norepinephrine (NE) and γ‐aminobutyric acid (GABA). Consistent with their known 5‐HT reuptake blocking property, acute intravenous administration of zimelidine and norzimelidine depressed the firing rate of 5‐HT‐containing dorsal raphe neurons. ED 50 of zimelidine and norzimelidine were respectively 1.1 mg/kg and 0.8 mg/kg. Chronic administration of zimelidine (5 and 10 mg/kg, q.d. for 14 days) did not modify the responsiveness of hippocampal pyramidal cells to iontophoretic applications of 5‐HT, NE and GABA, whereas chlorimipramine (5 mg/kg, q.d. for 14 days) increased selectively their sensitivity to 5‐HT. Since the antidepressant efficacy of zimelidine is well documented, it is concluded that sensitization of forebrain postsynaptic 5‐HT receptors is not a prerequisite for a drug to exert an antidepressant effect. It is suggested that an enhancement of the 5‐HT‐mediated synaptic transmission might be the final effect of the various types of antidepressant treatment whether their primary effect is pre‐ or postsynaptic.