Adenosine acting on A1 receptors protects NO-triggered rebound potentiation and LTP in rat hippocampal slices.

Abstract

Exposure of hippocampal slices to nitric oxide (NO) results in a depression of CA1 synaptic transmission. Under 0.2-Hz stimulation, washout of NO leads to a persistent potentiation that depends on N-methyl-D-aspartate (NMDA) receptors and endogenous NO formation and that occludes tetanus-induced long-term potentiation (LTP). The experiments were initially aimed at determining the relationship between the NO-induced synaptic depression and rebound potentiation. The adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) partially inhibited the depression produced by the NO donor diethylamine NONOate (300 microM). It also led to a complete block of both the rebound potentiation and the subsequent tetanus-induced LTP. LTP was preserved in the presence of DPCPX if the stimulation frequency was reduced to 0.033 Hz or if the NO application was omitted. The NO-triggered rebound potentiation was restored if the experiment (DPCPX followed by exogenous NO) was conducted in the presence of an NMDA antagonist. The restored potentiation was completely blocked by the NO synthase inhibitor, L-nitroarginine. It is concluded that the NO-induced depression is partially mediated by increased release of endogenous adenosine acting on A1 receptors. Moreover, tonic A1 receptor activation by adenosine protects LTP and the rebound potentiation from being disabled by untimely NMDA receptor activity. Hence, the NO-induced depression and rebound potentiation are linked in the sense that the depression helps to preserve the capacity of the synapses to undergo potentiation. Finally, the results give the first example of exogenous NO eliciting an enduring potentiation of hippocampal synaptic transmission that is dependent on endogenous NO formation, but not on NMDA receptors.