DISINHIBITION OF HIPPOCAMPAL CA3 NEURONS INDUCED BY SUPPRESSION OF ANADENOSINE-A(1) RECEPTOR-MEDIATED INHIBITORY TONUS - PRESYNAPTIC AND POSTSYNAPTIC COMPONENTS

Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously pr oduced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylx anthine at concentrations up to 100 nM induced both spontaneous and st imulus-evoked epileptiform burst discharges. Once induced, the 1,3-dip ropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparentl y irreversible even after prolonged superfusion with drug-free solutio n. The blockade of glutamatergic excitatory synaptic transmission by p reincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazo lpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dio ne (10 muM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 muM), prevented the induction o f epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The gen eration of the burst discharges was independent of the membrane potent ial, and the amplitude of the slow component of the paroxysmal depolar ization shift increased with hyperpolarization, indicating that the 1, 3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically medi ated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibitio n. Both 1,3-dipropyl-8-cyclopentylxanthine ard the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depola rization of the membrane potential by about 20 mV. Sometimes, this dep olarization attained the threshold for the generation of putative calc ium spikes, but no potential changes resembling paroxysmal depolarizat ion shift-like events were observed. At the concentrations used in ele ctrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylx anthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochem ical assay in a homogenate of the rat cerebral cortex. Furthermore, ev en high concentrations of the selective phosphodiesterase inhibitor ro lipram (10 muM), which displays no affinity to adenosine receptors, di d not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclope ntylxanthine, thus excluding the possibility that the effects of the A 1 receptor antagonist on neuronal discharge behavior can be ascribed t o an inhibition of phosphodiesterases. The present data demonstrate th at endogenously released adenosine exerts a vigorous control on the ex citability of hippocampal CA3 neurons on both the pre- and postsynapti c sites. The long-lasting disinhibition following a transient suppress ion of adenosinergic inhibition strongly suggests that, besides its we ll-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.