title: Study of antidepressant drugs in GPR39 (zinc receptor⁻/⁻) knockout mice, showing no effect of conventional antidepressants, but effectiveness of NMDA antagonists.
abstract: The monoamine-based antidepressants that are currently used generate many side effects, and more than 30% of depressed patients do not respond to this therapy. Glutamate-based antidepressants seem to play an important role in therapy for depression, but there is still an extensive search for safe drugs. An antagonist of the glutamatergic NMDA receptor - namely, zinc - plays a part in maintaining homeostasis between glutamate and GABA via the GPR39 receptor, which has been found to be involved in the pathophysiology of depression. In this study we investigated the behavioral response resulting from chronic or acute treatment with monoamine-based antidepressants, such as imipramine, escitalopram or reboxetine, and from glutamate-based MK-801 or ketamine, as measured by the forced swim test (FST) in GPR39 knockout (GPR39 KO, -/-) mice versus wild-type (WT, +/+) controls. All the tested agents reduced the immobility time in the FST in the wild-type animals. However, only chronic or acute administration of MK-801 and ketamine (but not monoamine-based antidepressants) were active in the FST in GPR39 KO mice. Our results show for the first time that GPR39 is required for the antidepressant effect of monoamine-based antidepressants.
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: katarzyna.mlyniec@uj.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Młyniec
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gaweł
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015283:Citalopram / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D011581:Psychological Tests; D000077593:Reboxetine; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; C512928:GPR39 protein, mouse; D009025:Morpholines; D043562:Receptors, G-Protein-Coupled; D016194:Receptors, N-Methyl-D-Aspartate; D015283:Citalopram; D007649:Ketamine; D016291:Dizocilpine Maleate; D000077593:Reboxetine; D007099:Imipramine
keywords: Antidepressants; GPR39; Ketamine; MK-801; NMDA; Zinc