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Adenosine A_2A receptors mediate GABAergic inhibition of respiration in immature rats

¹Department of Pediatrics, Rainbow Babies and Children's Hospital, and Case Western Reserve University, Cleveland, Ohio; and ²Department of Physiology and Biophysics, Howard University, Washington, District of Columbia

Submitted 22 April 2005 ; accepted in final form 29 August 2005

Adenosine is a known inhibitor of respiratory output during early life. In this study we investigated the developmental changes in adenosine A_2A-receptor activation on respiratory timing, as well as the relationship between adenosine and GABA. The specific adenosine A_2A-receptor agonist CGS-21680 (CGS) or vehicle control was injected into the fourth ventricle of 14-day (n = 9), 21-day (n = 9), and adult (n = 5) urethane-anesthetized rats while diaphragm electromyogram was monitored as an index of respiratory neural output. CGS injection resulted in a decrease in frequency and/or apnea in all 14-day-old rats and in 66% of 21-day-old rats. There was no effect of CGS injection on respiratory timing in adult rats. Prior injection of the GABA_A-receptor blocker bicuculline at 14 and 21 days eliminated the CGS-induced decrease in frequency and apnea. We conclude from these studies that the inhibitory effect of A_2A-receptor activation on respiratory drive is age dependent and is mediated via GABAergic inputs to the inspiratory timing neural circuitry. These findings demonstrate an important mechanism by which xanthine therapy alleviates apnea of prematurity.

neural modulation; -aminobutyric acid; development; respiratory rhythm

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