| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
The purpose of this study is to examine the molecular biological and neurochemical mechanism of emotional stress in the amygdala, using freezing behavior induced by conditioned fear stress (CFS) as an index of anxiety.
1) The first study examined CFS-associated genes in the amygdala using DNA microarray (GeneChip Rat Genome 230 2.0 Array including 28000 genes). We detected 18 genes in the amygdala, whose expressions were changed by CFS. Among these genes, only one gene, neurotensin, is an SSRI-CFS associated gene, whose change by CFS is cancelled by SSRI treatment. This result suggests that neurotensin is associated with the mechanism of anxiolytic action of SSRIs.
2) Local infusion of citalopram, a selective serotonin reuptake inhibitor (SSRI), into the amygdala increased extracellular serotonin (5-HT) levels in the amygdala of fear幼onditioned rats and inhibited freezing behavior simultaneously. This result indicates that increased 5-HT induced by SSRI in the amygdala causes an anxiolyt
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ic effect of SSRI.
3) Although one day after fear conditioning, tandospirone, a 5-HT_<1A> agonist, and SSRIs inhibited conditioned freezing significantly in a dose-dependent manner, 14 days after fear conditioning, the anxiolytic effects of these drugs were weakened, suggesting that a 14-days model has validity as an animal model of clinical anxiety disorders. Fourteen days after fear conditioning, co-administration of tandospirone and SSRIs given at subeffective doses enhanced anxiolytic effects. This combination thearapy is a promising strategy for the treatment of anxiety and mood disorders.
4) A selective glycine transporterl inhibitor stimulated NMDA receptor, a subtype of glutamate receptor, via the stimulation of glycine site. Administration of a glycine transporterl inhibitor inhibited both the acquisition and expression of conditioned freezing (in the acquisition experiment, drugs are administered before fear conditioning by footshock, and in the expression experiment, drugs are administered after footshock and before conditioned fear test, re-exposure to shock-chamber). Less
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