Aj. Thomas et al., Alterations in respiratory behavior, brain neurochemistry and receptor density induced by pharmacologic suppression of sleep in the neonatal period, DEV BRAIN R, 120(2), 2000, pp. 181-189
The present study examined if drug suppression of active sleep (AS) in the
neonate affected the development and expression of respiratory behavior. Se
condly, we assessed brain neurochemistry acid receptor density in specific
supra-medullary brain regions to identify coincident biochemical alteration
s. Sprague-Dawley newborn rat pups were randomized and divided among six ra
t mothers (n = 10/mother/group), each mother housed separately. Two untreat
ed control (UC) groups received either no interventions or were fed milk ve
hicle twice daily and were handled similarly to the drug intervention anima
ls. Pharmacological disruption of sleep was achieved by administration (2 g
roups of each) of either clonidine (CLO) 100 mu m/kg, or scopolamine (SCO)
800 mu m/kg, given orally twice daily for the first 7 days of life. On post
natal (P) days P10 and P19 of life, pups were assessed for metabolism, minu
te ventilation (V-E), tidal volume (V-t) and frequency (f). On P21 (14 days
after the end of drug exposure), pups from each condition were sacrificed
and punch biopsies of the frontal cortex, hypothalamus, and hippocampus wer
e examined for hydroxytryptophan (5-HT), and norepinepherine (NE) by HPLC.
An equal number of pups were sacrificed and brains examined for muscarinic
acetylcholine (mAch), alpha(2)-adrenergic and I-1-imidazoline receptor dens
ity. Results: Both CLO and SCO exposed animals had a lower V-t and respirat
ory quotient than UC animals (p < 0.01). CLO animals exhibited a higher f (
p < 0.01) and both CLO and SCO exhibited a lower V-t (p < 0.05) than the UC
groups; V-E was reduced in the SCO groups, compared with CLO and UC groups
(p < 0.01). Pattern of breathing in response to brief hypoxia exposure was
altered for CLO and SCO, The normal decline in V-E during sleep was not ob
served in CLO rats. Both drug exposures resulted in a comparable reduction
in hypothalamic NE and 5-HT levels (p < 0.05), while in the frontal cortex,
and the hippocampus variable changes in NE and 5-HT, occurred. In CLO and
SCO rats mAch receptors were increased in cortex, and reduced in hypothalam
us; I-1-imidazoline receptors were increased in hypothalamus and decreased
in hippocampus (p < 0.05 for each). in contrast, alpha(2)-adrenergic recept
ors were increased in cortex for both CLO and SCO, decreased in hypothalamu
s for CLO, and decreased in hippocampus for SCO (p < 0.05 for each). Conclu
sions: these data show that drug-induced neonatal sleep suppression will al
ter ventilatory pattern, metabolism, and site-specific concentrations of ad
renergic neurotransmitters and in receptor density, perhaps as a result of
suppression of neonatal AS. (C) 2000 Elsevier Science B.V. All rights reser
ved.