Terbutaline impairs the development of peripheral noradrenergic projections: potential implications for autism spectrum disorders and pharmacotherapy of preterm labor.
Terbutaline, a β2-adrenoceptor agonist, is used off-label for long-term management of preterm labor; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline's effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2-5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic β2-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17-20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both β1- and β2-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline; methoxamine, which stimulates α1-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with β2-adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder.
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