Adenosine receptor antagonists induce persistent bursting in the rat hippocampal CA3 region via an NMDA receptor-dependent mechanism

Adenosine receptor antagonists initiate repetitive bursting activity in the CA3 region of hippocampal slices. Although some studies have suggested tha t this effect is irreversible, this has been difficult to establish because many adenosine antagonists wash out of brain slices extremely slowly. Furt hermore the cellular mechanism that underlies persistent bursting is unknow n. To resolve these issues, we studied the effects of nonselective (8-p-sul fophenyl-theophylline, 8SPT, 50-100 mu M), A(1)-selective (8-cyclopentyl-1, 3-dipropylxanthine, 100 nM; xanthine carboxylic acid congener, 200 nM), and A(2A)-selective (chlorostyryl-caffeine; 200 nM) adenosine antagonists in t he CA3 region of rat hippocampal slices using extracellular recording. Supe rfusion with all of the: adenosine antagonists except chlorostyryl-caffeine induced bursting, and the burst frequency after 30 min drug superfusion di d not differ for the different antagonists. Most slices showed a period of rapid initial bursting, followed either by stable bursting at a lower frequ ency or a pattern of oscillating burst frequency. In either case, the burst ing continued after drug washout. Virtually identical patterns of long-term bursting activity were observed when 8SPT was washed out or applied contin uously. Control experiments using exogenous adenosine to characterize the p ersistence of 8SPT in tissue demonstrated >95% washout at 60 min, a time wh en nearly all slices still showed regular bursting activity. When the N-met hyl-D-aspartate (NMDA) antagonists DL-2-amino-5-phosphonovaleric acid (AP5; 50 mu M) or dizocilpine (10 mu M) were applied before and during 8SPT supe rfusion, bursting occurred in the presence of the NMDA antagonists but did not persist once the 8SPT was washed out. AP5 had no effect on persistent b ursting when applied after the initiation of spiking. The selective calcium /calmodulin-dependent protein kinase inhibitor 1-[N, O-bis-(5-isoquino-line sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62; 3 mu M), which has been shown to block NMDA receptor-dependent synaptic plasticity in the CA1 region, also significantly decreased the long-term effect of 8SPT. Thus ad enosine antagonists initiate persistent spiking in the CA3 region; this act ivity does not depend on continued occupation of adenosine receptors by ant agonists, and can be blocked by treatments that prevent NMDA receptor-depen dent plasticity.