Prenatal nicotine exposure increases the strength of GABAA receptor-mediated inhibition of respiratory rhythm in neonatal rats

Zili Luo, Seres Costy-Bennett, Ralph F Fregosi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Infants born to mothers that smoke while pregnant have a relatively high incidence of central respiratory control abnormalities. Recent studies have shown that prenatal nicotine exposure increases GABA release and the frequency of GABAergic currents, leading to an up-regulation of GABAA receptors in central neurones. Activation of GABAA receptors inhibits ventilatory activity, with intense activation causing apnoea. These observations lead us to hypothesize that prenatal nicotine exposure alters GABAergic control of respiratory motor pattern in the early neonatal period. Osmotic minipumps were implanted in pregnant Sprague-Dawley rats on the fifth day of gestation, and filled with nicotine (6 mg kg-1 day-1 2.5 μl h-1) or physiological saline (2.5 μl h-1). Brainstem-spinal cord preparations from 1 - to 3-day-old neonates were studied under in vitro conditions. Electrical activity was recorded from the fourth cervical ventral root (C4 VR), which contains the axons of phrenic motoneurones. Bath application of GABAA receptor agonists muscimol (250 μm) or pentobarbital sodium (60 μm) to the brainstem led to consistent, reversible and significant reductions in C4 VR burst frequency. In saline-exposed animals, frequency (bursts min-1) fell from 6.8 ± 0.4 to a nadir of 2.8 ± 0.5 with muscimol, and from 6.5 ± 0.3 to a nadir of 2.9 ± 0.3 for pentobarbital; in nicotine-exposed animals, frequency fell from 6.3 ± 0.4 to 1.0 ± 0.4 with muscimol and from 6.4 ± 0.2 to 1.7 ± 0.4 with pentobarbital (P < 0.05 in all cases). The decrease in C4 VR frequency was significantly greater in nicotine-exposed compared to saline-exposed preparations with both muscimol and pentobarbital (P < 0.001 for both). There were no changes in the amplitude of C4 VR bursts under any condition. The GABAA receptor antagonist bicuculline methiodide (8 μm) did not change C4 VR frequency or amplitude in either group, although it was effective in reversing the effects of muscimol. These experiments demonstrate that prenatal nicotine exposure alters the GABAergic regulation of respiratory rhythm in a reduced preparation. The results may lead to a better understanding of the perturbed breathing pattern observed in neonates that are exposed to nicotine in uttero.

Original languageEnglish (US)
Pages (from-to)387-393
Number of pages7
JournalJournal of Physiology
Volume561
Issue number2
DOIs
StatePublished - Dec 1 2004

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GABA-A Receptors
Nicotine
Muscimol
Pentobarbital
Brain Stem
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Spinal Nerve Roots
Motor Neurons
Apnea
Diaphragm
Inhibition (Psychology)
Baths
Smoke
gamma-Aminobutyric Acid
Sprague Dawley Rats
Axons
Spinal Cord
Respiration
Up-Regulation

ASJC Scopus subject areas

  • Physiology

Cite this

Prenatal nicotine exposure increases the strength of GABAA receptor-mediated inhibition of respiratory rhythm in neonatal rats. / Luo, Zili; Costy-Bennett, Seres; Fregosi, Ralph F.

In: Journal of Physiology, Vol. 561, No. 2, 01.12.2004, p. 387-393.

Research output: Contribution to journalArticle

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