OPPOSITE MODULATION OF 4-AMINOPYRIDINE AND HYPOXIC HYPEREXCITABILITY BY A1 AND A2 ADENOSINE RECEPTOR LIGANDS IN RAT HIPPOCAMPAL SLICES

The effects of the adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), and of the adenosine agonists N-6-cyclopentyladenosine (CPA), N-6-(2-phyenylisopropyl)adenosine (R-PIA), and 2-[p-(carboxyethyl)phenylethylamino]5'-N-ethylcarboxamidoadenosine (CGS 21680 were investigated on the hyperexcitability induced in the CA1 area of rat hippocampal slices by hypoxia or the epileptogenic agent 4-aminopiridine. Slice perfusion with the mixed adenosine receptor agonist R-PIA (0.2 mu M) significantly (P < 0.05) decreased: (i) the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period; (ii) the duration of the hypoxia-induced epileptiform bursting. Conversely, slice perfusion with the selective A1 adenosine receptor antagonists DPCPX (0.2 mu M) or with the selective A2 adenosine receptor agonist CGS 21580 significantly (P < 0.05) increased the number of slices showing a transient CA1 epileptiform bursting during the reoxygenation period, while the other drugs failed to affect it. Slice perfusion with the selective A1 adenosine receptor agonist CPA (2 mu M or R-PIA (5 mu M) significantly (P < 0.05) decreased the duration of the CA1 epileptiform bursting induced by the 100 mu M 4-aminopyridine. CGS 21680 (5 mu M) perfused together with CPA (2 mu M) significantly (P < 0.05) counteracted the inhibitory effects of the A1 adenosine receptor agonist on 4-aminopyridine epileptiform bursting, while it failed by itself to directly affect the 4-aminopyridine epileptiform bursting duration. Ther results produce evidence for a selective opposite modulation by A1 and A2 adenosine agonists in the control of hippocampal hyperexcitability induced by hypoxia or 4-aminopyridine but not in the post-hypoxic functional recovery.