Postsynaptic serotonergic blockade following chronic antidepressive treatment with trazodone in an animal model of depression

Acute pretreatment with clinically equivalent doses of antidepressive drugs has been observed to block D,L-5-hydroxytryptophan (5-HTP) induced behavioral depression in rats working on a food-reinforced operant schedule. Data from studies designed to distinguish presynaptic from postsynaptic events, indicated that the antidepressants were acting in part as blockers of postsynaptic serotonergic receptors. Using the same 5-HTP model of depression, we studied both the chronic and acute effects of a recently introduced antidepressant, triazolopyridine compound. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 50 mg/kg 5-HTP were pretreated (one hr before 5-HTP) with 1, 2, or 4 mg/kg trazodone with resulting blockade of 5-HTP induced depression of 35, 62 and 70% respectively. Chronic administration of trazodone (2 mg/kg trazodone/day) also resulted in a significant blockade of the 5-HTP effect (75%). Neither 2 mg/kg or 4 mg/kg trazodone was found to potentiate the shorter period of depression following 25 mg/kg 5-HTP. Chronic treatment with the antidepressant drugs, amitriptyline or mianserin also blocked 5-HTP depression. Thus, as in our earlier studies, these data suggest an important postsynaptic mechanism associated with chronic administration of trazodone, amitriptyline and mianserin which could be implicated in the therapeutic effectiveness of these drugs. The potency of trazodone in relation to other antidepressant drugs in our behavioral model of depression paralleled their potency in displacing radioligand binding to 5-HT receptors, and gives additional support for the new hypersensitive postsynaptic serotonin receptor theory of depression.