title: Trazodone inhibits T-type calcium channels.
abstract: 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 5HT(2A) receptors, histamine(1) receptors and alpha(1) 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 (Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3) in whole-cell patch-clamp studies at therapeutically relevant concentrations (IC(50)=43 microM, 45 microM, 23 microM, respectively). Inhibition was not use-dependent and showed only moderate voltage-dependence. Tonic block of Ca(v)3.1 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 Ca(v)3.3 channels (IC(50)=35 microM) and was less active on Ca(v)3.1 channels (IC(50)=317 microM). 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 (approximately 30% inhibition at 100 microM). Our data suggest that T-type calcium channel antagonism may contribute to the pharmacology of trazodone and its reported neurological effects.
authors.affiliation: Sleep Research Department, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. richard_kraus@merck.com
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Aneta
authors.initials: A
authors.lastname: Jovanovska
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D014196:Trazodone / Q000494:pharmacology*
chemical_list: D020747:Calcium Channels, T-Type; D010879:Piperazines; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; C015068:1-(3-chlorophenyl)piperazine