Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding.

Trazodone is an effective antidepressant drug with a broad therapeutic spectrum, including anxiolytic efficacy. Although trazodone is usually referred to as a serotonin (5-HT) reuptake inhibitor, this pharmacological effect appears to be too weak to fully account for its clinical effectiveness. The present study aimed to elucidate the agonist properties of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP), at 5-HT(1A) receptors by means of the guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay. In membranes prepared from Chinese hamster ovary cells expressing human 5-HT(1A) receptors (CHO/h5-HT(1A)), trazodone behaved as an almost full agonist and m-CPP was also a highly efficacious partial agonist at 5-HT(1A) receptors. The intrinsic activities of both compounds were higher than those of tandospirone and buspirone, which are clinically effective anxiolytics with well-known 5-HT(1A) partial agonist properties. These effects were replicated in the 5-HT(1A) receptor-mediated [(35)S]GTPgamma(S) binding assay in native rat brain membranes (at least in hippocampal membranes), although the intrinsic activities of the compounds were low and differently ranked compared to those in CHO/h5-HT(1A) cell membranes. When considering the implications of 5-HT(1A) receptors in anxiety and/or depression, as well as the clinical effectiveness of azapirone anxiolytics with partial 5-HT(1A) receptor agonist properties such as buspirone, it is possible that the agonist effects on 5-HT(1A) receptors of trazodone and its active metabolite m-CPP presented in this study contribute, at least in part, to the clinical efficacy of the atypical antidepressant trazodone.