Neonatal ACTH administration elicits long-term changes in forebrain monoamine innervation. Subsequent disruptions in hypothalamic-pituitary-adrenal and gonadal function

Abstract

The findings from this study demonstrated that the manipulation of the HPA system resulting from ACTH administration during neonatal development produces long-term, differential effects, not only on adrenocortical activity, but also on the activity and integrity of the forebrain monoamine systems. Increased concentrations of the monoamines within the forebrain regions studied at days 7 and 15, suggest a hastened maturation of these neural systems in animals neonatally treated with ACTH. The observed neurochemical alterations in these animals at one year are suggestive of an accelerated aging in the monoamine systems. A further consequence of these disturbances during development is an altered functioning of the HPG axis, as demonstrated by a delayed onset of puberty as previously reported, as well as significantly decreased proestrus plasma estradiol. Although deficits in sexual behavior also existed, it seems probable that these behavioral changes are a manifestation of altered neural systems regulating the ability to cope with a novel stimulus or situation, rather than a disruption of the "feminization" of the brain during sexual differentiation. This is in contrast to the male rat which exhibits permanent deficits in male typical sexual behavior following developmental ACTH treatment. The clinical relevance of these findings may be extensive. Perinatal exposure to events or agents that markedly increase ACTH and the corticosteroids may cause significant immediate and long-term changes in central monoamine functioning. These changes may constitute some of the most deleterious effects of stress exposure in infants and children. The alterations may be especially devastating in individuals with predispositions to stress-sensitive disorders such as anxiety, depression, and Tourette's syndrome. Finally, the use of ACTH in the treatment of infantile spasms may need to be reassessed in light of the possible long-term effects of ACTH on central monoamine functioning.