Trazodone inhibits T-type calcium channels

Trazodone is one of the most commonly prescribed medicines for treating depression and insomnia. However, the pharmacological mechanism of action underlying trazodone's unique effects is unclear. Despite its nanomolar affinity for 5HT2A receptors, histamine1 receptors and α1 adrenoceptors the drug is given at high doses to achieve clinical efficacy suggesting that other target activities may also contribute to its effects. Here we report that trazodone inhibits recombinant T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3) in whole-cell patch-clamp studies at therapeutically relevant concentrations (IC50 = 43 μM, 45 μM, 23 μM, respectively). Inhibition was not use-dependent and showed only moderate voltage-dependence. Tonic block of Cav3.1 channels held at negative membrane potentials suggested drug interaction with channels in the resting state. The major metabolite of trazodone, m-chlorophenylpiperazine, showed comparable potency on Cav3.3 channels (IC50 = 35 μM) and was less active on Cav3.1 channels (IC50 = 317 μM). We also demonstrate trazodone's inhibitory effects on native T-type calcium currents recorded from subthalamic neurons in a patch-clamp rat brain slice assay (∼30% inhibition at 100 μM). Our data suggest that T-type calcium channel antagonism may contribute to the pharmacology of trazodone and its reported neurological effects.