Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia

In neonatal rodents, serotonin (5-HT) neurons are critical for successful autoresuscitation. We hypothesized that caffeine, a respiratory stimulant, would hasten the onset of gasping and improve autoresuscitation in 5-HT-deficient, Pet-1(-/-) mice.

Using a head-out system and electrocardiogram, we measured respiratory and heart rate (HR) responses of Pet-1(-/-) rodents and their littermates during episodic asphyxia at postnatal days 8-9 (P8-9). After a baseline recording, we injected either vehicle or caffeine (i.p.) at doses of 1, 5, or 10 mg/kg. We then induced 10 brief (~30 s) episodes of asphyxia, each interspersed with 5 min of room air to allow autoresuscitation. In addition to measuring survival, we measured the duration of hypoxic apnea (time to initiate gasping) and time to recover eupnea and HR.

Caffeine had a dose-dependent effect of hastening the onset of gasping, recovery of breathing, and restoration of HR in Pet-1(-/-) (but not in wild-type) rodents, thereby improving survival across asphyxic episodes. Increased survival was strongly correlated with hastened onset of gasping.

Our data suggest that caffeine reduces mortality relating to asphyxia and 5-HT deficiency. These findings may be relevant for efforts to reduce the incidence of sudden infant death syndrome (SIDS), given that SIDS is associated with failed autoresuscitation and reduced brainstem 5-HT.