Opposite modulation of 4-aminopyridine and hypoxic hyperexcitability by A1 and A2 adenosine receptor ligands in rat hippocampal slices

Abstract

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-phenylisopropyl)adenosine (R-PIA), and 2-[p-(carboxyethyl)phenylethylamino]-5′- N-ethylcarbox-amidoadenosine (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 μM) 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 μM) or with the selective A2 adenosine receptor agonist CGS 21680 significantly ( P < 0.05) increased the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period but did not affect the duration of the hypoxia-induced epileptiform bursting. Neither drug significantly affected the number of slices showing functional recovery after hypoxia. Slice perfusion with DPCPX (0.2 μM) also significantly increased ( P < 0.05) the number of slices showing persistent 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 μM) or R-PIA (5 μM) significantly ( P < 0.05) decreased the duration of the CA1 epileptiform bursting induced by 100 μM 4-aminopyridine. CGS 21680 (5 μM) perfused together with CPA (2 μM) 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. The 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.