title: Olanzapine augments the effect of selective serotonin reuptake inhibitors by suppressing GABAergic inhibition via antagonism of 5-HT₆ receptors in the dorsal raphe nucleus.
abstract: The combination of the selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotic drugs shows better therapeutic efficacy than SSRI monotherapy in the treatment of depression. However, the underlying mechanisms responsible for the augmenting effects of olanzapine are not fully understood. Here, we report that olanzapine enhances the SSRI-induced increase in extracellular serotonin (5-HT) levels and antidepressant-like effects by inhibiting GABAergic neurons through 5-HT6 receptor antagonism in the dorsal raphe nucleus (DRN). In organotypic raphe slice cultures, treatment with olanzapine (1-100 μM) enhanced the increase in extracellular 5-HT levels in the presence of fluoxetine (10 μM) or citalopram (1 μM). The enhancing effect of olanzapine was not further augmented by the GABAA receptor antagonist bicuculline. Electrophysiological analysis revealed that olanzapine (50 μM) decreased the firing frequency of GABAergic neurons in acute DRN slices. Among many serotonergic agents, the 5-HT6 receptor antagonist SB399885 (1-100 μM) mimicked the effects of olanzapine by enhancing the SSRI-induced increase in extracellular 5-HT levels, which was not further augmented by bicuculline or olanzapine. SB399885 (50 μM) also decreased the firing frequency of GABAergic neurons in the DRN. In addition, an intraperitoneal administration of SB399885 (10 mg/kg) to mice significantly enhanced the antidepressant-like effect of a subeffective dose of citalopram (3 mg/kg) in the tail-suspension test. These results suggest that olanzapine decreases local inhibitory GABAergic tone in the DRN through antagonism of 5-HT6 receptors, thereby increasing the activity of at least part of serotonergic neurons, which may contribute to the augmentation of the efficacy of SSRIs.
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Nozomi
authors: N
authors: Asaoka
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors: Kazuki
authors: K
authors: Nagayasu
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Naoya
authors: N
authors: Nishitani
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Mayumi
authors: M
authors: Yamashiro
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Hisashi
authors: H
authors: Shirakawa
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan. Electronic address: tknakaga@kuhp.kyoto-u.ac.jp.
authors: Takayuki
authors: T
authors: Nakagawa
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Shuji
authors: S
authors: Kaneko
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: D000928:Antidepressive Agents; D001569:Benzodiazepines; D001640:Bicuculline; D015283:Citalopram; D005473:Fluoxetine; D058787:GABA-A Receptor Antagonists; D000077152:Olanzapine; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; C503990:SB 399885; C097216:serotonin 6 receptor
keywords: 5-HT(6) receptor; Depression; GABAergic neurons; Olanzapine; Selective serotonin reuptake inhibitor; Serotonergic neurons