INDUCTION OF TYROSINE-HYDROXYLASE BY FORSKOLIN - MODULATION WITH AGE

With aging, circulating catecholamines are elevated in both humans and animals. This may be related to the increased basal levels of tyrosin e hydroxylase messenger RNA (mRNA) levels and tyrosine hydroxylase enz yme activity in the adrenal medulla of senescent compared with younger animals. In addition, tyrosine hydroxylase gene expression in the sen escent rat is resistant to further stimulation by cold exposure as com pared with younger animals. Collectively, these observations suggest e ither that tyrosine hydroxylase expression is already maximally stimul ated in senescent rats or that tyrosine hydroxylase gene induction pat hways are impaired with senescence. To help distinguish between these possibilities, we examined the induction of tyrosine hydroxylase mRNA, tyrosine hydroxylase immunoreactivity and tyrosine hydroxylase enzyme activity in the adrenal medulla following forskolin administration to young and old F-344 rats. Forskolin at doses of 1.8 and 3.5 mg/kg inc reased tyrosine hydroxylase mRNA levels 2.5-fold in adrenal medulla fr om young rats but did not increase either tyrosine hydroxylase immunor eactivity or tyrosine hydroxylase enzyme activity 5 h after administra tion. Prolonged treatment with forskolin (3 doses, 12 h apart) increas ed tyrosine hydroxylase mRNA levels and tyrosine hydroxylase immunorea ctivity and tyrosine hydroxylase enzyme activity. In senescent rats, t he baseline level of tyrosine hydroxylase mRNA was more than 2-fold hi gher compared with young rats. A single injection of the lower dose of forskolin increased tyrosine hydroxylase mRNA levels by the same incr ement in senescent as compared with young rats. These data indicate th at the tyrosine hydroxylase gene in the adrenal medulla from senescent rats is still capable of further stimulation. (C) 1997 Elsevier Scien ce B.V.