title: Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats.
abstract: The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity.
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Tokyo Medical University, Tokyo 160-0023, Japan. Electronic address: tinoue@tokyo-med.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kitaichi
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Ce
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kusumi
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000187:drug effects* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078785:Mirtazapine; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000929:Antidepressive Agents, Tricyclic; D010879:Piperazines; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D008803:Mianserin; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000078785:Mirtazapine; D004298:Dopamine
keywords: 5-HT(1A) receptor; Contextual fear conditioning; Hippocampus; Median raphe nucleus; Serotonin