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 held excitatory post-synaptic potential (f.e.p.s.p.) slope (27+/-4%) recorded from hippocampal slices and the evoked [H-3]-acetylcholine ([H-3]-ACh) release from the motor nerve terminals (25+/-2%). 3 alpha,beta-Methylene adenosine diphosphate (AOPCP) in concentrations (100-200 mu 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 [H-3]-ACh release from motor nerve terminals by 27+/-3%. 4 Addition of erogenous 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 mu 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 mu 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.