As previously reported, we have studied the lasting effects of early infection or malnutrition on the physical development and metabolism of specific pathogen-free mice (1, 2). These stresses have been found to decrease the biosynthesis of protein and ribonucleic acid in various tissues and subcellular fractions of brain. Such metabolic derangements could be corrected by the combined administration of growth hormone and insulin (3). The possibility was considered that early environmental stresses caused abnormality in hormonal systems, thus producing secondary metabolic derangements in protein and ribonucleic acid metabolism. Changes in the intracellular levels of adenosine 3' ,5'-mouophosphate (cyclic AMP) 1 may be a generalized mechanism for the action of hormones in tissues (4, 5). Cyclic AMP has been shown furthermore to mediate the activation of brain protein kinase (6). Among mammalian tissues the brain has the highest activity of adenyl cyclase, the enzyme responsible for the synthesis of cyclic AMP (7), and the highest activity of cyclic 3',5'-nucleotide phosphodiesterase, which inactivates cyclic AMP (8).The present study was undertaken to investigate (a) the effects of neonatal infection or early malnutrition on the metabolic turnover of cyclic A M P in various organs and in synaptosomes in vitro, and (b) the regulatory mechanisms governing the brain level of cyclic AMP. As a measure of metabolic turnover we determined the catabolic activities in terms of production of respiratory 14CO~ from cyclic AMP-8-t4C and its incorporation into various organs and into blood circulation. In addition, we determined the binding activities of synaptosomes for cyclic AMP. We also studied the changes of cyclic A M P caused by neonatal infection or by nutritional deprivation and the enzymatic activities regulating the brain level of nucleotides.
Materials and MethodsExperimental Animals and Enterovlrus.--All experiments were carried out with specific pathogen-free mice of the COBS strain (Charles River Breeding Laboratories, Inc., Wilmington, Mass.). The origin and preparation of the mouse enterovirus have been described in an 1Abbre~'iatlon used in this paper: cyclic AMP, adenosine 3', 5'-monophosphate.