The A 3 adenosine receptor agonist 2-Cl-IB-MECA facilitates epileptiform discharges in the CA3 area of immature rat hippocampal slices

Abstract

The effects of the A 3 adenosine receptor agonist 2-Cl-IB-MECA were tested on epileptiform field potentials recorded in the CA3 area of postnatal days 10–20 immature hippocampal slices, during perfusion with the GABA A receptor antagonist bicuculline (10 μM). Evoked potentials: 2-Cl-IB-MECA (1–50 μM, n=17) had consistently excitatory effects, blocked by the A 3 receptor antagonist MRS 1220 (1 μM, n=7), but not occluded in the presence of the A 1 antagonist DPCPX (1 μM, n=12) or the A 2A antagonist ZM-241385 (0.1 μM, n=12). 2-Cl-IB-MECA reversed the inhibitory effects ( n=5) of the adenosine uptake blocker nitrobenzylthioinosine (NBTI, 50 μM), but did not increase its excitatory effects ( n=19). Spontaneous discharges: 2-Cl-IB-MECA (1 μM) induced them or increased their frequency in 14/30 slices, an effect reversed by MRS 1220 ( n=3), and observed also following pre-perfusion with DPCPX ( n=11), ZM-241385 ( n=11) or both ( n=10). In the presence of the A 1 antagonist DPCPX, NBTI increased the frequency of spontaneous discharges, an effect partially reversed by MRS 1220 ( n=8), thus suggesting that a rise in endogenous adenosine during disinhibition may activate A 3 receptors. In conclusion, these findings suggest strongly that activation of A 3 receptors, following a rise in endogenous adenosine (i.e. during seizures, hypoxia), facilitates excitation, thus limiting the known inhibitory and/or neuroprotective effects of adenosine in immature brain.