Ta. Slotkin et al., beta-adrenoceptor signaling in the developing brain: sensitization or desensitization in response to terbutaline, DEV BRAIN R, 131(1-2), 2001, pp. 113-125
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.