ALTERATIONS OF CAMP RESPONSE ELEMENT-BINDING ACTIVITY IN THE AGED RAT-BRAIN IN RESPONSE TO ADMINISTRATION OF ROLIPRAM, A CAMP-SPECIFIC PHOSPHODIESTERASE INHIBITOR

Transcription factor, cAMP response element-binding protein (CREB), wh ich is phosphorylated by cAMP-dependent kinase via an increase in cAMP , and regulates gene transcription by binding to the cAMP response ele ment (CRE) on target genes. We examined age-dependent alterations in t he DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown i n all brain regions examined, especially in the basal forebrain, the s triatum and the hippocampus. Furthermore, CRE-binding activities in th e basal forebrain of both young-adult and aged rats significantly incr eased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolip ram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram r eversed the decrease in the maximum CRE-bindings in the basal forebrai n with aging. Since the 5' upstream region of the rat choline acetyltr ansferase (ChAT) gene contains CRE, and ChAT-positive neurons in the b asal forebrain project to the frontal cortex and the hippocampus, roli pram may exert its previously reported ameliorating effect on the age- related reductions of ChAT activities in the frontal cortex and the hi ppocampus by phosphorylating CREB in the basal forebrain with activati on of cAMP-dependent protein kinase via inhibition of PDE.