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 tyrosine hydroxylase messenger RNA (mRNA) levels and tyrosine hydroxylase enzyme activity in the adrenal medulla of senescent compared with younger animals. In addition, tyrosine hydroxylase gene expression in the senescent rat is resistant to further stimulation by cold exposure as compared with younger animals. Collectively, these observations suggest either that tyrosine hydroxylase expression is already maximally stimulated in senescent rats or that tyrosine hydroxylase gene induction pathways 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 increased tyrosine hydroxylase mRNA levels 2.5-fold in adrenal medulla from young rats but did not increase either tyrosine hydroxylase immunoreactivity or tyrosine hydroxylase enzyme activity 5 h after administration. Prolonged treatment with forskolin (3 doses, 12 h apart) increased tyrosine hydroxylase mRNA levels and tyrosine hydroxylase immunoreactivity and tyrosine hydroxylase enzyme activity. In senescent rats, the baseline level of tyrosine hydroxylase mRNA was more than 2-fold higher compared with young rats. A single injection of the lower dose of forskolin increased tyrosine hydroxylase mRNA levels by the same increment in senescent as compared with young rats. These data indicate that the tyrosine hydroxylase gene in the adrenal medulla from senescent rats is still capable of further stimulation.