|Budget Amount *help
¥6,600,000 (Direct Cost : ¥6,600,000)
Fiscal Year 1992 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1991 : ¥5,300,000 (Direct Cost : ¥5,300,000)
In the present study, it was clearly demonstrated that subchronic ACTH treatment increased the density of 5-HT-2 receptor binding sites in rat frontal cortex, which was prevented by adrenalectomy, suggesting there may be a tight corelation between both hyperfunction of hypothalamopituitary-adrenal axis and 5-HT-2 receptors in affective disorders. Subcronic treatment with dexamethasone(DEX) also reduced the density of 5-HT-2 receptors in rat cerebral cortex, suggesting that type 2 glucocorticoid receptors are involved in the up-regulation of 5-HT-2 receptors induced by subchronic treatment with ACTH and corticosterone. In addition, DEX treatment for 6 - 48 hrs potentiated 5-HT-2 receptor-stimulated inositol-1,4,5 trisphosphate formation and Ca mobilization in C6 glioma cells and GTP binding protein activator, NaF-induced Ca mobilization as well, although 5-HT-2 receptor mRNA expression was reduced by this DEX treatment, suggesting that the enhanced GTP binding protein function is one of
the mechanisms which are responsible for the enhancement of 5-Ht-stimulated Ca mobilization induced by DEX treatment. To clarify a pharmacological profile of the GTP binding protein coupled to 5-HT-2 receptors, we investigated the effect of Pertussis toxin on 5-Ht-2 receptor-stimulated Ca mobilization in C6 cells, and found Pertussis toxin did not affect 5-HT response, suggesting that the 5-Ht-2 receptor-coupled GTP binding protein may belong to Gq family of GTP binding proteins.
In order to know the precise mechanisms of the apparent lack of gluco-corticoid receptor sensitivity observed in depression, it is necessary to make a animal model which have increased activity of the HPA axis, indicated by failure to DEX suppression, and increased density of 5-HT-2 receptors in cerebral cortex. Preliminary results suggest that prenatal crowding stress significantly increased the density of 5-Ht-2 receptors in cerebral cortex of postnatal 12 weeks offspring, as well as resistance to suppress immobilizatoin-induced corticosterone secretion by DEX. Less