NEURAL INPUT AND THE DEVELOPMENT OF ADRENERGIC INTRACELLULAR SIGNALING - NEONATAL DENERVATION EVOKES NEITHER RECEPTOR UP-REGULATION NOR PERSISTENT SUPERSENSITIVITY OF ADENYLATE-CYCLASE

In the adult, denervation of adrenergic target tissues leads to compen satory upregulation of receptor sites and to supersensitive responses. When 6-hydroxydopamine (6-OHDA) was given to neonatal rats, cardiac b eta-receptors failed to show significant upregulation throughout the f irst five postnatal weeks and alpha(1)-receptors were unchanged except at 35 days of age, despite 70-95% depletion of norepinephrine. The fa ilure to upregulate could not be attributed to the high background lev el of receptor expression commensurate with ontogenetic increases in r eceptor numbers, since the same deficiency was seen in the fiver, a ti ssue in which beta-receptors decline with development; liver a(1)-rece ptors also failed to upregulate after neonatal denervation. Examinatio n of the linkage of beta-receptors to adenylate cyclase indicated majo r differences from mature regulatory mechanisms, as denervation supers ensitivity was completely absent (liver) or emerged only transiently s everal weeks after 6-OHDA treatment (heart). In the heart, there was e vidence for a defect in the G-protein-dependent component of the recep tor/cyclase linkage that could contribute to the delayed appearance of supersensitivity. Because the fundamental patterns of receptor ontoge ny and of adenylate cyclase responsiveness are still present after neo natal denervation, it is unlikely that neural input provides the major impetus for basal development. However, adult-type regulation of rece ptors and responses did not emerge even after a prolonged period; thus , neural input during a critical developmental stage may be required f or the cell to learn how to adjust receptor expression and the recepto r/cyclase link in response to stimulation.