Vol. 286, Issue 3, 1412-1419, September 1998

Modulation of Epileptiform Activity by Adenosine A1 Receptor-Mediated Mechanisms in the Juvenile Rat Hippocampus¹

Virginia Tancredi, Margherita D'Antuono, Astrid Nehlig and Massimo Avoli

Dipartimento di Neuroscienze, Università degli Studi di Roma "Tor Vergata," 00173 Rome, Italy (V.T., M.D.); INSERM U398, 67091 Strasbourg Cedex, France (A.N.) and Research Group on Cell Biology of Excitable Tissue, Montreal Neurological Institute and Departments of Neurology and Neurosurgery, and Physiology, McGill University, Montreal, Quebec, H3A 2B4 Canada (M.A.)

The modulatory role played by purinergic mechanisms on the epileptiform discharges induced by 4-aminopyridine (4AP, 50 µM) in juvenile (10 to 25-day-old) rat hippocampal slices was studied with field potential recordings in the CA3 stratum radiatum. 4AP-induced activity consisted of interictal and ictal discharges along with isolated -aminobutyric acid-mediated potentials. The adenosine analogues 2-Cl-adenosine (10-200 µM) and N-ethylcarboxamido-adenosine (5-10 µM), the A1 receptor agonist N⁶-(L2-phenylisopropyl)-adenosine (2-10 µM), and the adenosine uptake inhibitor dipyridamole (1-40 µM) reduced and eventually abolished interictal and ictal discharges with IC₅₀ values that were larger for ictal discharges as compared to interictal activity. These purinergic agents did not modify the rate of occurrence of the -aminobutyric acidmediated potentials recorded during application of excitatory amino acid receptor antagonists. The changes induced by 2-Cl-adenosine, N⁶-(L2-phenylisopropyl)-adenosine, or dypiridamole were reversed by caffeine (500 µM) or 8-cyclopentyl-1,3-dipropylxantine (100 µM). However, these adenosine receptor antagonists did not alter the epileptiform discharges induced by 4AP. The depressant effects induced by N⁶-(L2-phenylisopropyl)-adenosine on the epileptiform activity were maintained in the presence of barium (2 mM), which blocks adenosine postsynaptic actions. These results demonstrate that activation of adenosine A1 receptors in the juvenile rat hippocampus leads to an anticonvulsant action that can be ascribed to a decreased release of glutamate from CA3 pyramidal cell terminals. We also propose that during the first weeks of postnatal life endogenous adenosine does not activate A1 receptors to a degree to control the ability of hippocampal neurons to generate epileptiform activity in the 4AP model.