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Bursts of action potentials are crucial for most neurotransmitter release from dense core granules.This has been most definitively shown for neuropeptide release from the Hypothalamic Neurohypophysial System.We have shown that exogenous ATP induces inward currents and causes release of only vasopressin (AVP) from neurohypophysial terminals;both effects are inhibited by suramin and PPADS, selective P2X2 and P2X3 purinergic receptor antagonists.Recently, we determined, in the rat neurohypophysis, that endogenous ATP levels were sufficient to facilitate depolarization induced AVP release.Therefore, we have used specific P2X receptor knockout (rKO) mice and selective P2X receptor antagonists to determine the P2X receptor subtype responsible for endogenous ATP induced potentiation of electrically stimulated neuropeptide release by bursts.Intact neurohypophyses (NH) from wild type (WT), P2X3, P2X2/3 and P2X7 rKO mice were electrically stimulated with four AVP-like bursts separated by 20 second interburst intervals with or without selective P2X2-3 (suramin) or P2X7 (brilliant blue-G;BBG) receptor antagonists.Treatment of WT mouse NH with suramin significantly reduced electrically stimulated AVP release.A similar inhibition by suramin was observed in electrically stimulated NH from P2X3 and P2X7 rKO mice, but not P2X2/3 rKO mice.Surprisingly, electrically stimulated OT release from WT, P2X3, P2X2/3 and P2X7 rKO mice was potentiated by suramin.Furthermore, BBG treatment of WT mouse NH reduced electrically stimulated OT release with no effect on AVP release.These results show that sufficient endogenous ATP is released during bursting stimulation to act at P2X2 and/or P2X7 receptors in a positive-feedback-mechanism to differentially potentiate AVP and OT release, respectively.We proposed a model to explain how purinergic feedback is important for burst-induced neuropeptide release from nerve terminals.(Supported by NIH grant NS29470 to JRL).