Abstract
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 γ-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 γ-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.
Footnotes
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Send reprint requests to: M. Avoli, 3801 University Street, Montreal, Quebec, H3A 2B4 Canada.
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↵1 This work was supported by a grant from the Consiglio Nazionale della Ricerca (CNR) of Italy to VT, and grants from the Medical Research Council (MRC) of Canada, the Hospital for Sick Children Foundation and the Savoy Foundation to MA. V.T. and M.A. were also supported in part by CNR-MRC travel grants.
- Abbreviations:
- ACSF
- artificial cerebrospinal fluid
- 4AP
- 4-aminopyridine
- CNQX
- 6-cyano-7-nitro-quinoxaline-2,3 dione
- CPP
- 3-3,(2-carboxypiperazine-4-yl)propyl-1-phosphonate
- DPCPX
- 8-cyclopentyl-1,3-dipropylxantine
- L-PIA
- N6-(L2-phenylisopropyl)-adenosine
- NECA
- N-ethylcarboxamido-adenosine
- NMDA
- N-methyl-d-aspartate
- DMSO
- dimethyl sulfoxide
- GABA
- γ-aminobutyric acid
- Received December 19, 1997.
- Accepted May 1, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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