Action of chronically administered antidepressants on the serotonergic postsynapse in a model of depression

A theory of excessive transmission of serotonin (5-HT) in depression has been previously proposed. The purpose of the present study was to test this theory further by using the model of depression in rats induced by L-5-hydroxytryptophan (5-HTP), the precursor of 5-HT. The drug effects on 5-HTP (25 mg/kg) induced behavioral depression were tested by chronic administration using methysergide which is a postsynaptic blocker of 5-HT, or by comparable clinical doses of antidepressant drugs. Methysergide (2 mg/kg) blocked 5-HTP induced depression on days 8 and 22 after initiation of medication by 70% and 83%, respectively. Among antidepressants, mianserin (2 mg/kg) was the first to produce an effect, displaying a 38% effect as early as 1 day after the start of medication and having blocking effects of 52% and 72% on days 8 and 22. Desipramine (5 mg/kg), doxepine (5 mg/kg), imipramine (5 mg/kg) and trazodone (10 mg/kg) showed no significant effect on days 1 and 8, and on day 22, 64, 36, 33 and 32% blocking, respectively. Amitriptyline had an initial effect of 41% at a dose of 10 mg/kg. Clomipramine (5 mg/kg), zimelidine (6 mg/kg) and chlorpromazine (2.5 mg/kg), which is a neuroleptic, showed no effect. Considering these results in light of recent data reported on the 5-HT synapse, it was suggested that 5-HTP induced depression may be induced by excessive transmission of 5-HT and that some antidepressant drugs may produce their effect by blocking this postsynaptic transmission. Based on these results, the mechanisms of human depression were discussed.