Effects of the two antidepressant drugs mianserin and indalpine on the serotonergic system: Single-cell studies in the rat

Abstract

Several antidepressant treatments enhance serotonergic neurotransmission. The present electrophysiological studies were undertaken to assess the effect of mianserin and indalpine, two antidepressant drugs with different pharmacological profiles, on serotonergic neurotransmission. In a first series of experiments, the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE) and γ-aminobutyric acid (GABA) was assessed following mianserin, imipramine (5 mg/kg/day IP) or saline administration for 14 days. At 48 h after the last dose of mianserin, responsiveness to 5-HT was increased whereas that to NE and GABA was not modified. The degree of sensitization to 5-HT was the same as that produced by imipramine. Acute IV administration of mianserin (up to 10 mg/kg) did not decrease the firing rate of dorsal raphe 5-HT neurons. In a second series of experiments, long-term administration of indalpine (5 mg/kg/day IP for 14 days) did not modify the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT, NE and GABA whereas imipramine treatment (5 mg/kg/day IP) increased selectively their sensitivity to 5-HT when compared to indalpine-treated rats. In keeping with its potent reuptake-blocking property, acute IV indalpine produced a marked decrease in the firing rate of dorsal raphe 5-HT neurons (ED₅₀ 0.33 mg/kg). The firing rate of dorsal raphe 5-HT neurons was assessed following 2-, 7- and 14-day treatments with indalpine (5 mg/day IP). After 2 days, the firing rate of 5-HT neurons was greatly reduced, after 7 days it had recovered partially and after 14 days it had returned to normal. At this point, the responsiveness of 5-HT neurons to IV LSD, an agonist of the 5-HT autoreceptor, and to microiontophoretically-applied 5-HT was decreased twofold, indicating desensitization of the autoreceptor. In conclusion, it is proposed that long-term treatment with mianserin, as with tricyclic antidepressant drugs and electroconvulsive shocks, increases 5-HT neurotransmission via sensitization of postsynaptic neurons to 5-HT whereas long-term treatment with indalpine, as with zimelidine, results in the same final effect via its presynaptic effect on 5-HT neurons presumably by blocking 5-HT reuptake. These data further support the notion that enhancing 5-HT neurotransmission might have an antidepressant effect.