Stimulation of nerve growth factor biosynthesis in developing rat brain by reserpine: steroids as potential mediators

The stimulation of beta-adrenergic receptors by isoproterenol increases nerve growth factor (NGF) biosynthesis in C6 rat glioma cells, suggesting that norepinephrine may regulate NGF biosynthesis in vivo. We have tested this hypothesis in 21-day-old rats by depleting catecholamine stores with reserpine. Northern blot analysis of NGF mRNA, in combination with a two-site enzyme immunoassay for NGF, showed that depletion of catecholamines was associated with a 3-fold increase in NGF mRNA, which was followed by a significant increase in the NGF content of cerebral cortex. The increase in NGF mRNA was most marked 9 hr after reserpine administration (2 mg/kg, subcutaneously) and was no longer apparent 24 hr after drug administration, when brain monoamine stores were still depleted. Moreover, the lowest dose of reserpine that significantly increased NGF mRNA levels induced only a small change in the content of cortical catecholamines. These results suggest that reserpine mediates the increase in NGF production by a mechanism other than monoamine depletion. Because reserpine increases plasma glucocorticoid concentrations through the pituitary-adrenal axis, we investigated whether adrenal steroids could be responsible for the induction of NGF biosynthesis. The effect of reserpine on NGF biosynthesis was abolished in adrenalectomized rats. Moreover, dexamethasone, a synthetic glucocorticoid, given at a dose of 0.5 mg/kg, subcutaneously, increased the amount of NGF mRNA and NGF in cerebral cortex. NGF biosynthesis in the central nervous system may, thus, be regulated by adrenocortical hormonal secretion.