Antagonizing central GABAA and adenosine receptors reverses the autoresuscitation defects caused by reduced brainstem serotonin.

Sudden Infant Death Syndrome (SIDS) remains a leading cause of infant death, and its incidence is increasing. SIDS infants harbor numerous defects within the brainstem serotonin (5-hydroxytryptamine, 5-HT) system. There is also evidence that in hypoxic conditions SIDS infants do not successfully autoresuscitate, the integrated response to severe hypoxia necessary to reperfuse the brain, restore eupnea, and promote arousal from hypoxic coma. In animals, a loss of 5-HT or 5-HT2A receptor activity compromises autoresuscitation. Caffeine, via undefined mechanisms, rescues the autoresuscitation of 5-HT-deficient Pet-1-/- mice. Our primary hypothesis here was that reducing GABAergic or adenosinergic activity improves the autoresuscitation of Pet-1-/- mice. We assessed the autoresuscitation of Pet-1-/- mice after blockade of central GABAA receptors as well as adenosine 1 (A1), adenosine 2 A (A2A) receptors. The autoresuscitation of Pet-1-/- mice was significantly improved following the blockade of GABAA receptors; recovery of heart rate and eupnea were expedited, improving their survival. Pilot experiments blocking adenosine receptors had a similar, positive impact on Pet-1-/- autoresuscitation. These data suggest that during severe O2 deprivation, reducing inhibitory GABAergic drive may restore the disruption in excitatory-inhibitory balance due to a loss of excitatory serotonergic drive within circuits required for autoresuscitation. We speculate that, without 5-HT, there is net inhibition within these circuits due to GABA release, delaying the reperfusion of the brain, impeding the restoration of eupnea and arousal, and increasing the risk of sudden death in infancy.