title: Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.
abstract: Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway.
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, 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: Yuji
authors.initials: Y
authors.lastname: Kitaichi
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, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nakagawa
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 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*; D003213:Conditioning, Psychological / Q000187:drug effects; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000523:psychology; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008845:Microinjections; D000078785:Mirtazapine; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D008803:Mianserin; D012701:Serotonin; D008094:Lithium; D000078785:Mirtazapine
keywords: Amygdala; Contextual fear conditioning; Hippocampus; Lithium augmentation; Median raphe nucleus; Mirtazapine