title: Neonatal caffeine induces sex-specific developmental plasticity of the hypoxic respiratory chemoreflex in adult rats.
abstract: Caffeine is widely used to treat apneas of prematurity during the neonatal period; however, the potential consequences of administering a neonatal caffeine treatment (NCT) during a critical period for respiratory control development are unknown. The present study therefore determined whether NCT in rats alters the hypoxic respiratory chemoreflex measured at adulthood. Newborn rats received either caffeine (15 mg/kg) or water (control) each day from postnatal day 3 to 12. The ventilatory response to a hypoxic challenge (inspired O(2) fraction = 0.12) was first evaluated in awake adult female and male rats using whole body plethysmography. Results showed that NCT increased the initial phase of the breathing frequency response to hypoxia in males only. This result was confirmed in anesthetized and artificially ventilated adult male rats where NCT also increased the phrenic burst frequency response to hypoxia. RT-PCR assessment of mRNA encoding for adenosine A(1A) and A(2A) receptors, dopamine D(2) receptors, and tyrosine hydroxylase in the rat carotid bodies showed that NCT enhanced mRNA expression levels of adenosine A(2A), dopamine D(2) receptors, and tyrosine hydroxylase of males but not females. Subsequent experiments on awake male rats showed that injection of the adenosine A(2A) receptor antagonist ZM2413855 (1 mg/kg ip) before ventilatory measurements abolished, in NCT rats, the enhanced respiratory frequency response observed during the early phase of hypoxia. We propose that NCT elicits a sex-specific increase in the hypoxic respiratory chemoreflex, which is related, at least partially, to an enhancement in adenosine A(2A) receptors in the rat carotid body.
authors.affiliation: Dept. of Physiology, Univ. of Toronto, Medical Sciences Bldg., Rm. 7308, 1, King's College Circle, Toronto, ON, Canada M5S 1A8. gaspard.montandon@utoronto.ca
authors.forename: Gaspard
authors.initials: G
authors.lastname: Montandon
authors.forename: Aida
authors.initials: A
authors.lastname: Bairam
authors.forename: Richard
authors.initials: R
authors.lastname: Kinkead
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000758:Anesthesia; D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine / Q000494:pharmacology*; D002344:Carotid Body / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012018:Reflex / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects; D012727:Sex Characteristics; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: C547770:Adra2a protein, rat; D058669:Adrenergic alpha-2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D002110:Caffeine; D014446:Tyrosine 3-Monooxygenase