Effects of repeated trazodone administrations on serotonergic neurotransmission: biochemical studies

1. Repeated administrations of trazodone as well as imipramine or mianserin (10 mg/kg i.p. twice daily for 3 weeks) attenuated the norepinephrine (NE) stimulation of adenylate cyclase studied in brain minces. Therefore trazodone shares with "tricyclic" (imipramine) and "atypic" (mianserin) antidepressants the capability to modulate the beta-adrenergic function. 2. Daily treatments with imipramine or trazodone enhanced the Vmax of neural uptake of serotonin (5HT) in minces prepared from rat frontal cortex; in contrast mianserin failed to modify the [3H]-5HT uptake. 3. Repeated administrations of imipramine but not of trazodone or mianserin reduced the maximum number of [3H]-imipramine recognition sites which are located on serotonergic axon terminals. 4. Differently, only repeated administration of trazodone decreased Bmax values of [3H]-mianserin binding sites which are located on membranes innervated by serotonergic neurons. Moreover trazodone did not change the number or affinity of 5HT2 receptors either after single or repeated administrations; in contrast even a single administration with mianserin or repeated administrations with imipramine down-regulated [3H]-ketanserin specific binding in membranes prepared from the frontal cortex. 5. Our observations therefore suggest that trazodone, imipramine or mianserin exerts similar effects on the adenylate cyclase system, by acting on a interneuronal loop which links serotonergic and noradrenergic transmission function. However, its exact mechanism of action, in part resembling both tricyclic and atypic depressants, requires further examination.