Influence of ACTH on tyrosine hydroxylase activity in the locus coeruleus of mouse brain

Tyrosine hydroxylase activity in noradrenergic neurons of the locus coeruleus was found to rise in bilaterally adrenalectomized adult mice, with maximum increase of the enzyme activity (52% above control) occurring 7 days after the surgery. No such increase of tyrosine hydroxylase activity was found in dopaminergic neurons of the substantia nigra. The increase of enzyme activity in the locus coeruleus following adrenalectomy was totally prevented by corticosterone replacement. Moreover, the adrenalectomy effect was abolished by hypophysectomy, indicating the involvement of the pituitary rather than the adrenocortical function. Chronic administration of ACTH (20 IU/kg, i.p., daily) resulted in an increase of tyrosine hydroxylase activity in the locus coeruleus, with a time course and magnitude similar to those found after adrenalectomy. Additionally, the effects of four ACTH analogs were determined. ACTH 1-24 and ACTH 4-10 were as effective as the whole ACTH molecule, whereas ACTH 4-10,7-D-Phe and ACTH 11-24 were ineffective. The effect of ACTH 4-10, a peptide fragment with no adrenocorticotrophic activity, further indicates that glucocorticoids are not involved. From these data, it appears that tyrosine hydroxylase in the locus coeruleus neurons is under the regulatory influence of pituitary ACTH. It remains to be determined whether the hormone can be transported from its pituitary origin to the locus coeruleus and exerts a direct action on the noradrenergic neurons. Regardless of the mechanism, the response of the noradrenergic neurons to pituitary activity may be an important component in physiological adaptation of the central nervous system to chronic stress.