The involvement of the BDNF signal transduction to the pathogenesis of ssstress-related psychiatric disorders

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To elucidate the involvement of the dysfunction of the BDNF signal transduction to the pathogenesis of stress-related psychiatric illnesses including depression, at first, the influence of various chronic stress paradigms on the expression of BDNF and trkB mRNA, and the activity of mitogen activated protein (MAP) kinase was examined in rat frontal cortex and hippocampus. In second, the effect of co-administration of a phosphodiesterase IV (PDE4) inhibitor on the induction of the BDNF signal transduction by antidepressant treatments, and NKH477 (water-soluble forskolin derivative) administration on the BDNF signal transduction were determined. Various acute and chronic stress paradigms significantly decreased the expression of BDNF and trkB mRNA in rat brain. While both acute and chronic restraint stress significantly increased the activity of MAP kinase in rat brain mediately after stress, both stress paradigms did not change the activity of MAP kinase i or 3 h after stress. The co-administration of a PDE4 inhibitor with an antidepressant as well as NKH477 administration significantly induced the expression of BDNF and trkB mRNA, and the increase in MAP kinase activity in rat brain. This co-administration (7 days) and NKH477 administration (1 h) shortened the time required for the significant induction of BDNF and trkB mRNA by antidepressant treatments (21 days). The results of this study may indicate that the decrease in BDNF mRNA expression by stress dose not affect the postsynaptic BDNF signa transductiorn However, it is possible that the enhancement of MAP kinase activity by stress may mask the decrease in MAP kinase activity due to the reduction of BDNF and trkB expression. The present results indicating the activation of the BDNF signal transduction by this co-administration and NKH477, raise the possibility that the stimulation of the cAMP signal transduction may have potential as a novel pharmacotherapy for depression.