Adenosinergic modulation of respiratory activity: Developmental plasticity induced by perinatal caffeine administration

https://doi.org/10.1016/j.resp.2008.07.013Get rights and content

Abstract

Caffeine is an adenosine receptor antagonist that is commonly used in the clinic as a respiratory stimulant to treat apnea of prematurity. A recent clinical study showed that newborns treated with caffeine present no neuro-developmental disabilities at 2 years of age in comparison to placebo-treated children [Schmidt, B., Roberts, R.S., Davis, P., Doyle, L.W., Barrington, K.J., Ohlsson, A., Solimano, A., Tin, W., 2007. Long-term effects of caffeine therapy for apnea of prematurity. N. Engl. J. Med. 357, 1893–1902]. Although neonatal caffeine administration in this population is associated with clear short- and long-term health improvements, the consequences of this treatment on basic homeostatic functions such as respiratory regulation are unknown. This article reviews evidence indicating that neonatal caffeine treatment modifies respiratory control development and that these changes persist until adulthood. The mechanisms contributing to this form of developmental plasticity are unknown but current data indicate that caffeine treatment, especially during the perinatal period, alters adenosinergic neuromodulation of the respiratory control system. While human data show that neonatal caffeine treatment is relatively safe for some aspects of neural development, the results obtained in animal studies raise important questions pertaining to the potential long-term effects of this treatment on the respiratory control system.

Introduction

Caffeine is a methylxanthine which has been effectively used for several decades as a respiratory stimulant to treat apnea of prematurity (Marchal et al., 1987, Bhatt-Mehta and Schumacher, 2003). Apnea of prematurity, a cessation of breathing frequently associated with bradycardia and desaturation (Martin et al., 2004), is alleviated by caffeine administration, an effect attributed to its action on the central nervous system (CNS) where it stimulates minute ventilation and improves sensitivity and/or responsiveness to changes in arterial O2 and CO2 levels. Moreover, caffeine attenuates respiratory depression during hypoxia, reduces periodic breathing, and enhances diaphragmatic activity (Marchal et al., 1987, Bhatt-Mehta and Schumacher, 2003). Caffeine exerts its effect by inactivating brainstem adenosine A1 and A2A receptors located on groups of neurons involved in the generation of respiratory rhythm (Bhatt-Mehta and Schumacher, 2003). To date, human data show that such caffeine treatment has no major side effects on neuro-developmental outcome in children up to 2 years after the treatment (Schmidt et al., 2007). In rats, however, limited exposure to therapeutic doses of caffeine during early life (postnatal days 3–6) changes the distribution, density, and sensitivity of adenosine receptor in several CNS regions, which persists until adulthood (Guillet and Kellogg, 1991). We recently investigated the effects of a neonatal caffeine treatment that mimicked the approach commonly used by neonatologists, on respiratory control development. This review summarizes results from this and other laboratories proposing that neonatal caffeine treatment induces changes in respiratory activity, and that this effect persists well beyond the time of treatment. Based on neuroanatomical and pharmacological evidence, we propose that these changes are due, at least in part, to functional changes of adenosine receptors involved in the control of breathing. These data are important because premature infants (who commonly receive caffeine treatment) are at higher risk of sudden infant death syndrome (Thach, 2005) or to develop sleep-disordered breathing during infancy (Rosen et al., 2003). This review also highlights the importance of understanding the mechanisms involved in caffeine-induced developmental plasticity. This knowledge could ultimately help clinical decisions and develop new and better therapies to treat apnea of prematurity and sleep-disordered breathing later in life (Finer et al., 2006).

Section snippets

Adenosinergic neuromodulation of the respiratory control system

Adenosine is a ubiquitous cellular constituent and its level is regulated by the breakdown of adenosine triphosphate (ATP) which depends upon energy utilization of the cell. For example, mild hypoxia increases ATP consumption and raises brain adenosine levels by about 3-fold (Zetterstrom et al., 1982). At physiological levels (30–300 nM), adenosine activates adenosine A1 and A2A receptors (Dunwiddie and Masino, 2001) with the highest affinity for the A1 receptor subtype; A2B and A3 receptors

Adult mammals exposed to chronic caffeine

Caffeine is a non-selective antagonist which inactivates all adenosine receptor subtypes. At micromolar concentrations, however, caffeine preferentially acts on A1 and A2A receptors and has the highest affinity for the A1 receptor subtype (Fredholm et al., 1999). Following acute injection, caffeine elicits transient, temporary inactivation of adenosine receptors. With time, however, chronic administration (defined as a sustained and repeated administration of caffeine during several days)

Caffeine-induced developmental plasticity of the respiratory control system

The literature reviewed in the previous sections clearly indicates that, regardless of the developmental stage at which it occurs, chronic caffeine exposure has long-lasting effects on adenosinergic modulation of neural circuits and their performance. To assess the long-term impact of neonatal caffeine exposure on respiratory control development, we administered neonatal caffeine treatment (15 mg/kg/day) daily from postnatal day 3 to 12 (Fig. 2). This treatment yields plasma caffeine levels of

Clinical relevance and future directions

Caffeine has been used in the clinic for several years to treat apneas in premature newborns (Comer et al., 2001). Results of a recent clinical study show that neonatal caffeine administration is not associated with neurological deficits at 2 years of age (Schmidt et al., 2007). However, neither cardio-respiratory functions nor the response to stress were assessed in this population. This is an important issue because hypoxemia and repeated hypoxia have been associated with neurodevelopmental

Acknowledgments

This work was supported by the Canadian Institutes of Health Research (operating grant MOP-81101 to A.B.) and the Foundation for the Research into Children’ Disease. R.K. holds a Canada Research Chair in Respiratory Neurobiology. G.M. was supported by PhD awards from the Foundation for the Research into Children’ Disease and the J.-and-J.-L.-Levesque Perinatalogy Chair. The authors thank Richard L. Horner for his careful reading of the manuscript.

References (74)

  • E.B. Gauda et al.

    Differential expression of a(2a), A(1)-adenosine and D(2)-dopamine receptor genes in rat peripheral arterial chemoreceptors during postnatal development

    Brain Res.

    (2000)
  • E.B. Gauda et al.

    Peripheral arterial chemoreceptors and sudden infant death syndrome

    Respir. Physiol. Neurobiol.

    (2007)
  • S.P. Gaytan et al.

    Effect of postnatal exposure to caffeine on the pattern of adenosine A(1) receptor distribution in respiration-related nuclei of the rat brainstem

    Auton. Neurosci.

    (2006)
  • R. Guillet et al.

    Neonatal exposure to therapeutic caffeine alters the ontogeny of adenosine A1 receptors in brain of rats

    Neuropharmacology

    (1991)
  • M. Hawkins et al.

    Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain

    Brain Res. Bull.

    (1988)
  • P.J. Marangos et al.

    Effects of chronic caffeine on brain adenosine receptors: regional and ontogenetic studies

    Life Sci.

    (1984)
  • R.J. Martin et al.

    Apnoea of prematurity

    Paediatr. Respir. Rev.

    (2004)
  • D. Monti et al.

    Adenosine analogues modulate the incidence of sleep apneas in rats

    Pharmacol. Biochem. Behav.

    (1995)
  • R.Y. Moon et al.

    Sudden infant death syndrome

    Lancet

    (2007)
  • F.L. Powell et al.

    Time domains of the hypoxic ventilatory response

    Respir. Physiol.

    (1998)
  • C.L. Rosen et al.

    Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity

    J. Pediatr.

    (2003)
  • M. Runold et al.

    Effect of adenosine on chemosensory activity of the cat aortic body

    Respir. Physiol.

    (1990)
  • J.L. Seagard et al.

    Discharge patterns of baroreceptor-modulated neurons in the nucleus tractus solitarius

    Neurosci. Lett.

    (1995)
  • B.T. Thach

    The role of respiratory control disorders in SIDS

    Respir. Physiol. Neurobiol.

    (2005)
  • P. Wessberg et al.

    Adenosine mechanisms in the regulation of breathing in the rat

    Eur. J. Pharmacol.

    (1984)
  • C.G. Wilson et al.

    Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets

    Respir. Physiol. Neurobiol.

    (2004)
  • S.I. Zaidi et al.

    Adenosine A2A receptors are expressed by GABAergic neurons of medulla oblongata in developing rat

    Brain Res.

    (2006)
  • T. Zetterstrom et al.

    Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre

    Neurosci. Lett.

    (1982)
  • U. Aden et al.

    Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain

    Pediatr. Res.

    (2000)
  • A. Bairam et al.

    Effects of caffeine on carotid sinus nerve chemosensory discharge in kittens and cats

    J. Appl. Physiol.

    (1997)
  • A. Bairam et al.

    Neonatal environment and neuroendocrine programming of the peripheral respiratory control system

    Curr. Pediatr. Rev.

    (2006)
  • V. Bhatt-Mehta et al.

    Treatment of apnea of prematurity

    Paediatr. Drugs

    (2003)
  • D.C. Carrettiero et al.

    Adenosine A1 receptor distribution in the nucleus tractus solitarii of normotensive and spontaneously hypertensive rats

    J. Neural. Transm.

    (2004)
  • R.J. Cerniway et al.

    Targeted deletion of A(3) adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium

    Am. J. Physiol. Heart Circ. Physiol.

    (2001)
  • E.L. Coates et al.

    Widespread sites of brain stem ventilatory chemoreceptors

    J. Appl. Physiol.

    (1993)
  • A.M. Comer et al.

    Caffeine citrate: a review of its use in apnoea of prematurity

    Paediatr. Drugs

    (2001)
  • S.V. Conde et al.

    Hypoxia induces adenosine release from the rat carotid body

    J. Neurochem.

    (2004)
  • Cited by (0)

    1

    These senior authors have equally contributed to this work.

    View full text