Caffeine alters sleep and breathing without an increase in brain serotonin in developing rat pups

Abstract

In rat pups a reduction in serotonin (5HT) input to respiratory networks impairs anoxic auto‐resuscitation and impairs arousal during hypoxia. In contrast, blockade of adenosine receptors enhances auto‐resuscitation and attenuates the VE decline during the biphasic hypoxic ventilatory response. Caffeine (Caf), an adenosine receptor antagonist, used to treat apnea of prematurity in human infants, has well known effects on sleep and vigilance in adults and in some reports increases the levels of brain 5HT. We therefore examined the pharmacodynamics and the physiological effects of single IP injections of Caf (base) at 5 to 40 mg/kg in P9–P11 pups. Plasma Caf levels reached 10.9 and 76.3 mg/l for 5 and 40 mg/kg, respectively, at 60 min, and were stable until at least 90 min. Caf increased the % time awake at 10 and 40 mg/kg and at 40 mg/kg decreased the % time in active sleep. Caf did not change baseline heart or respiratory rate but the effect of Caf on VT and VE was dependent on state and dose. At 40 mg/kg, VT was increased during wake and quiet sleep whereas VE was increased only during wake. No increases in brainstem 5HT were found at either 10 or 40 mg/kg. In rat pups, a low dose of Caf alters sleep and at higher doses stimulates respiration. The effects of Caf on auto‐resuscitation and ventilation during hypoxia do not appear to be related to an increase in brainstem 5HT levels. NICHD 5‐PO1 HD036379 15