Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P 2 receptor

Abstract

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 μM to 1 mM. A similar depression was obtained with the P 2 receptor agonist, α,β-methylene ATP (α,β-MeATP), and the effect was inhibited by the P 2 receptor antagonists, suramin and PPADS. The inhibitory action of ATP or α,β-MeATP was inhibited by the γ-aminobutyric acid A (GABA A) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P 1) receptors, tetraethylammonium, a broad inhibitor of K + channels, or ecto-protein kinase inhibitors. ATP or α,β-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca 2+ or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or α,β-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P 2 receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.