Abstracts

RATIONALE: The concentration of endogenous adenosine increases during epileptic seizures and/or in conditions of hypoxia/ischemia, a potentially beneficial effect as activation of A[sub]1 [/sub]adenosine receptors inhibits neuronal activity. However, the recently described A[sub]3 [/sub] receptor subtype, although with a lower affinity for adenosine than the A[sub]1 [/sub] receptor, generates excitatory effects. We therefore studied the effects of A[sub]3 [/sub] receptor activation on the excitatory (disinhibited) field potentials in immature hippocampus.
METHODS: Excitatory CA3 field potentials were recorded during perfusion with the GABA[sub]A[/sub] receptor antagonist, bicuculline (BMI 10[mu]M), from immature (postnatal days 10-20) hippocampal slices. The effects of the selective A[sub]3 [/sub] agonist 2-Cl-IB-MECA (1[mu]M), the adenosine uptake blocker NBTI (50[mu]M), the A[sub]3 [/sub] antagonist MRS 1220 (1[mu]M), the A[sub]1 [/sub] receptor antagonist DPCPX (1[mu]M) and the A[sub]2A [/sub] receptor antagonist ZM241385 (0.1[mu]M) were tested on these responses.
RESULTS: In BMI, 2-Cl-IB-MECA (n=20 slices) increased reversibly the fEPSP amplitude as well as the amplitude and number of population spikes of the evoked responses by 15-30%, and enhanced the frequency of spontaneous discharges. The adenosine uptake blocker NBTI 50[mu]M, added in BMI, had mixed (excitatory or inhibitory) effects on evoked responses. In BMI and NBTI (n=19 slices), 2-Cl-IB-MECA had comparable excitatory effects to those in BMI alone, thus suggesting that its effects did not depend on the concentration of endogenous adenosine. The A[sub]3[/sub] antagonist MRS 1220 occluded (3/4slices) or reversed (4/4 slices) the excitatory effects of 2-Cl-IB MECA on evoked responses. By contrast, 2-Cl-IB-MECA enhanced excitatory potentials in the presence of the A[sub]1[/sub] receptor antagonist DPCPX (8/12 slices) or the A[sub]2A[/sub] receptor antagonist ZM 241385 (7/12 slices); its effects were subsequently blocked by addition of the A[sub]3[/sub] antagonist MRS 1220. These experiments suggest that the excitatory effects of 2-Cl-IB-MECA in immature CA3 were mediated by activation of A[sub]3[/sub] receptors and did not depend on prior activation of A[sub]1[/sub] or A[sub]2A[/sub] adenosine receptors.
CONCLUSIONS: These experiments demonstrate that activation of A[sub]3[/sub] adenosine receptors can enhance excitatory-epileptiform responses in immature hippocampus, an effect of possible physiological relevance during seizures and/or hypoxia-ischemia when the extracellular levels of adenosine rise considerably.
Support: NSERC, Savoy Found. for Epilepsy, FRSQ (CP:Cherch.-Bours. Jr II).