不安障害 Anxiety Disorders

P3-2-216 恐怖記憶の想起による神経内分泌反応には内側扁桃体ー延髄PrRP産生ニューロン経路が関与する Importance of the medial amygdala-medullary PrRP synthesizing neurons pathway in neuroendocrine responses to conditioned fear stimuli ○吉田匡秀1, 高柳友紀1, 尾仲達史1 ○Masahide Yoshida1, Yuki Takayanagi1, Tatsushi Onaka1 自治医科大学医学部　生理学講座　神経脳生理学部門1 Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University1 Fear learning is an evolutionarily advantageous neural mechanism. However, excessive fear memory induces posttraumatic stress disorder (PTSD). To understand neural bases that underlie PTSD, it is important to clarify neural circuit of fear memory. Fear conditioning is one of the suitable models for studying neural and molecular mechanisms of fear memory. Conditioned fear stimuli (CFS) induce freezing behavior and neuroendocrine responses. The central amygdala has been shown to be necessary for expression of freezing behavior following CFS. On the other hand, the mechanisms of neuroendocrine responses remain to be determined. The medial amygdala (MeA) was lesioned by infusion of NMDA after fear conditioning training. Plasma ACTH, oxytocin and prolactin concentrations were significantly increased after CFS in sham-lesioned rats. In the MeA-lesioned rats, neuroendocrine responses were significantly impaired as compared with those in sham-lesioned rats. On the other hand, facilitative neuroendocrine responses were induced after exposure to novel environmental stimuli in MeA-lesioned rats, and the magnitude of the responses was not significantly different in between MeA-lesioned and sham-lesioned rats. These results indicate that the MeA plays essential roles for neuroendocrine responses to CFS. We previously demonstrated that some of medullary prolactin releasing peptide (PrRP)-synthesizing neurons directly project to the supraoptic nucleus and paraventricular nucleus in the hypothalamus where neurosecretory cells exist. CFS activated 65 % of PrRP-expressing neurons in the medulla oblongata. In the MeA-lesioned rats, the percentage of PrRP-expressing neurons activated after CFS was significantly decreased to 20 %. Furthermore, neuroendocrine responses following conditioned fear stimuli disappeared in PrRP-deficient mice. These findings suggest that the MeA-medullary PrRP synthesizing neurons pathway plays an important role in neuroendocrine responses to CFS.

P3-2-217 恐怖条件付けにおけるmirtazapineの抗不安効果とそのリチウム増強効果は正中縫線核への効果を介している Anxiolytic effect of mirtazapine and its lithium augmentation on conditioned fear mediates its effect in the median raphe nucleus ○安燕1, 井上猛1, 北市雄士1, 中川伸1, 泉剛1, 宋寧1, 陳沖1, 小山司1, 久住一郎1 ○Yan An1, Takeshi Inoue1, Yuji Kitaichi1, Shin Nakagawa1, Takeshi Izumi1, Ning Song1, Chong Chen1, Tsukasa Koyama1, Ichiro Kusumi1 北海道大学大学院医学研究科神経病態学講座精神医学1 Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine1 Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), blocks the noradrenergic α2 auto- and hetero-receptors, which are responsible for controlling noradrenaline and serotonin release. Although preclinical and clinical studies have shown that mirtazapine exerts anxiolytic action, its precise brain target sites remain unclear. Furthermore, animal and clinical studies have shown that lithium enhances the antidepressant action of tricyclic antidepressants, SSRIs and SNRIs through monoamine systems. Previous studies have shown that both lithium and mirtazapine have serotonergic anxiolytic action, which suggests the possibility that combination of lithium and mirtazapine have better effects for anxiety disorders. In this study using freezing behavior as an animal model of anxiety, we investigated the effect of mirtazapine microinjection into the median raphe nucleus (MRN), hippocampus and amygdala on the expression of contextual fear conditioning in rats and the effect of subchronic lithium (0.2% Li2CO3 in food for 1 week) in combination with local microinjection of mirtazapine into the MRN on it. The results showed that intra-MRN microinjection of mirtazapine reduced freezing behavior significantly, while microinjections into the hippocampus or the amygdala did not. In addition, subchronic lithium treatment enhanced the inhibitory effect of local microinjection of mirtazapine into the MRN. These results suggest that the anxiolytic effect of mirtazapine is mediated by its action on the MRN, and the combination of subchronic lithium treatment enhances the anxiolytic-like effect of mirtazapine in the MRN.

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