beta-adrenoceptor signaling in the developing brain: sensitization or desensitization in response to terbutaline

beta (2)-Adrenoceptor agonists are commonly used to arrest preterm labor bu t they also penetrate the placenta to stimulate fetal beta -adrenergic rece ptors (P AR), and have been implicated in subsequent neurobehavioral defici ts. We administered terbutaline to pregnant rats on gestational days (GD) 1 7-20 and during two postnatal (PN) periods, PN2-5 and PN11-14, that corresp ond to third trimester human neurological development. We then examined bet a AR binding sites and adenylyl cyclase (AC) signaling in fetal brain or ne onatal brain regions. Although fetal terbutaline administration evoked beta AR downregulation, the ability of isoproterenol to stimulate AC was enhanc ed instead of desensitized. Sensitization occurred at post-receptor signali ng proteins, as augmented responses were also seen for stimulants that bypa ss the receptors to work on G-proteins (NaF) or that stimulate AC directly (forskolin and Mn2+). When terbutaline was given on PN2-5, beta AR downregu lation was obtained in brainstem, forebrain and cerebellum, but desensitiza tion of the AC response was seen only in the forebrain; the desensitization was heterologous, reflecting decrements in total AC activity rather than s pecific loss of the beta AR response. With treatment on PN11-14, only the c erebellum showed beta AR downregulation and induction at the level of post- receptor signaling proteins maintained the beta AR-mediated AC response. Ou r results indicate that, unlike the adult, beta AR signaling in the fetus a nd neonate is resistant to homologous desensitization by beta -agonists, an d in fact, displays heterologous sensitization that sustains or enhances th e overall response. The inability to desensitize PAR responses may lead to disruption of neural cell development as a consequence of tocolytic therapy . (C) 2001 Elsevier Science B.V All rights reserved.