不安障害における扁桃体セロトニンの役割(シンポジウム:脳科学による心身症の解明,2008年,第49回日本心身医学会総会(札幌))  [in Japanese] The Role of Amygdalar Serotonin in Anxiety Disorder(Symposium/Psychosomatic Disorders as Revealed by Brain Science)  [in Japanese]

選択的セロトニン再取り込み阻害薬(SSRI)はほとんどすべての不安障害亜型に対して有効であるが,その作用機序は十分に解明されていない.われわれは恐怖条件づけストレス(conditioned fear stress;CFS:以前に逃避不可能な電撃ショックを四肢に受けたことのある環境への再曝露)を不安・恐怖の動物モデルとして用い,不安・恐怖とセロトニンの関連について検討してきた.すくみ行動を不安の指標として用いると,ベンゾジアゼピン系抗不安薬と同様に,SSRIはラットのCFSで抗不安作用を示す.SSRIの両側扁桃体基底外側核への局所投与はCFSで抗不安作用を示した.さらに,CFSによって扁桃体基底外側核のc-Fos蛋白発現は亢進し,SSRI全身投与はCFSで抗不安作用を示すと同時に,CFSによるc-Fos蛋白発現を抑制した.以上のことから,SSRIの不安障害への効果は扁桃体に対する抑制効果を介していることが示唆された.

Selective serotonin reuptake inhibitors (SSRIs) have wide indications for the treatment of anxiety disorders, including panic disorder, generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder and social anxiety disorder in addition to depression. Until recently, no animal model has been available for screening the anxiolytic effect of SSRIs and studying its mechanism of action. We have investigated the relationship between serotonin neurotransmission and anxiety using conditioned fear stress (CFS), an animal model of anxiety. CFS increased serotonin neurotransmission in the medial prefrontal cortex and amygdala. In behavioral pharmacological studies, SSRIs, serotonin_<1A> agonists and monoamine oxidase inhibitors, which are assumed to facilitate serotonin neurotransmission, decreased conditioned freezing, an index of anxiety or fear, in CFS. In vivo microdialysis studies showed that serotonin neurotransmission in the medial prefrontal cortex increased after recovered from the freezing behavior. Microinjection of SSRI to the basolateral nucleus of the amygdala reduced conditioned freezing, indicating that the amygdala is one of target brain sites of anxiolytic action of SSRIs. Furthermore, CFS-induced c-Fos expression in the basolateral nucleus of the amygdala was reduced by SSRI pretreatment. Taken together, our animal studies suggest that facilitation of brain serotonin neurotransmission decreases anxiety in agreement with the clinical evidence, and that SSRI-induced inhibition of the neuronal activity of the basolateral nucleus of the amygdala is the mechanism of action of the anxiolytic efficacy of SSRIs.