title: In vitro inhibition of mitochondrial respiratory rate by antidepressants.
abstract: Mitochondria represent a possible drug target with unexplored therapeutic and toxicological potential. The possibility was suggested that antidepressants, mood stabilizers and other drugs may show some therapeutic and/or toxic effects through their action on mitochondrial functions. There are no sufficient data about the effect of these drugs on mitochondrial respiration in the brain. We investigated the in vitro effects of amitriptyline, fluoxetine, tianeptine, ketamine, lithium, valproate, olanzapine, chlorpromazine and propranolol on mitochondrial respiration in crude mitochondrial fractions of pig brains. Respiration was energized using substrates of complex I or complex II and dose dependent drug-induced changes in mitochondrial respiratory rate were measured by high-resolution respirometry. Antidepressants, but not mood stabilizers, ketamine and propranolol were found to inhibit mitochondrial respiratory rate. The effective dose of antidepressants reaching half the maximal respiratory rate was in the range of 0.07-0.46 mmol/L. Partial inhibition was found for all inhibitors. Differences between individual drugs with similar physicochemical properties indicate selectivity of drug-induced changes in mitochondrial respiratory rate. Our findings suggest that mood stabilizers do not interfere with brain mitochondrial respiration, whereas direct mitochondrial targeting is involved in mechanisms of action of pharmacologically different antidepressants.
authors: Department of Psychiatry, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague, Czech Republic.
authors: Jana
authors: J
authors: Hroudová
authors: Zdeněk
authors: Z
authors: Fišar
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity*; D019069:Cell Respiration / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004734:Energy Metabolism / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D014149:Tranquilizing Agents / Q000633:toxicity
chemical_list: D000928:Antidepressive Agents; D014149:Tranquilizing Agents