Preferential activation of excitatory adenosine receptors at rat hippocampal and neuromuscular synapses by adenosine formed from released adenine nucleotides

1 In the present work, we investigated the action of adenosine originating from extracellular catabolism of adenine nucleotides, in two preparations where synaptic transmission is modulated by both inhibitory A 1 and excitatory A 2a ‐adenosine receptors, the rat hippocampal Schaffer fibres/CA1 pyramid synapses and the rat innervated hemidiaphragm. 2 Endogenous adenosine tonically inhibited synaptic transmission, since 0.5‐2 u ml −1 of adenosine deaminase increased both the population spike amplitude (30 ± 4%) and field excitatory post‐synaptic potential (f.e.p.s.p.) slope (27 ± 4%) recorded from hippocampal slices and the evoked [ 3 H]‐acetylcholine ([ 3 H]‐ACh) release from the motor nerve terminals (25 ± 2%). 3 a, b̊‐Methylene adenosine diphosphate (AOPCP) in concentrations (100–200 μ m ) that almost completely inhibited the formation of adenosine from the extracellular catabolism of AMP, decreased population spike amplitude by 39 ± 5% and f.e.p.s.p. slope by 32 ± 3% in hippocampal slices and [ 3 H]‐ACh release from motor nerve terminals by 27 ± 3%. 4 Addition of exogenous 5′‐nucleotidase (5 u Ml −1 ) prevented the inhibitory effect of AOPCP on population spike amplitude and f.e.p.s.p. slope by 43–57%, whereas the P 2 antagonist, suramin (100 μ m ), did not modify the effect of AOPCP. 5 In both preparations, the effect of AOPCP resulted from prevention of adenosine formation since it was no longer evident when accumulation of extracellular adenosine was hindered by adenosine deaminase (0.5‐2 u ml −1 ). The inhibitory effect of AOPCP was still evident when A 1 receptors were blocked by 1,3‐dipropyl‐8‐cyclopentylxanthine (2.5‐5 nM), but was abolished by the A 2 antagonist, 3,7‐dimethyl‐1‐propargylxanthine (10 μ m ). 6 These results suggest that adenosine originating from catabolism of released adenine nucleotides preferentially activates excitatory A 2 receptors in hippocampal CA1 pyramid synapses and in phrenic motor nerve endings.