Effects of chronic administration of antidepressant drugs on central serotonergic receptor mechanisms

Chronic treatment with three antidepressants—desipramine, imipramine, and zimelidine—altered behavioral responses to serotonin (5-HT) agonists in rats, with effects depending on agonist dose and the behavior measured. At a high dose of the 5-HT agonist 5-MeO-DMT (4 mg/kg), all three drugs reduced head twitches, while at a low dose (1 mg/kg) or with a low dose of the 5-HT precursor 5-HTP (12.5 mg/kg), head twitches increased. Zimelidine and imipramine enhanced hyperlocomotion at the high agonist dose but reduced it at the low dose. Long-term zimelidine treatment produced subsensitivity in avoidance learning but enhanced responses in the tail-flick test, though overall it shortened response latency, suggesting decreased 5-HT activity.

Study at a glance

Abstract

The present studies have shown that chronic antidepressant treatment with desipramine (DMI), imipramine (IMI) and zimelidine produced behavioral evidence for sub- and supersensitivity depending on 5-HT agonist dose and types of behavior examined. Thus, chronic treatment with all three drugs reduced head twitches induced by a high dose of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, 4 mg/kg) while an enhanced response was observed at a low 5-MeO-DMT dose (1 mg/kg) or a low dose of the 5-HT precursor 1-5-hydroxytryptophan (12.5 mg/kg). Chronic ZIM and IMI treatment tended to enhance 5-HT receptor activity as assessed by the induction of hyperlocomotion by a high 5-MeO-DMT dose (4 mg/kg) while they reduced the effect of a low dose (1 mg/kg). Long-term ZIM treatment gave evidence of behavioral subsensitivity to the 5-HT agonist 5-MeO-DMT in avoidance learning, while an enhanced response to 5-MeO-DMT was observed in the tail-flick model. However, chronic ZIM treatment shortened response latency in the tail-flick model suggesting that the net result is a decrease in 5-HT activity.