Adenosine A2 receptor mediation of pre- and postsynaptic excitatory effects of adenosine in rat hippocampus in vitro

Excitatory effects of adenosine in the rat hippocampus were studied by intracellular recording from CA1 pyramidal cells in vitro. Application of 100 microM adenosine induced a rapid hyperpolarization and a decrease in input resistance, and depressed the excitatory postsynaptic potentials (EPSPs) evoked by stimulation of Schaffer collaterals in all neurons tested. In 55% of the neurons this was followed by an excitation. This excitation consisted of a slow depolarization lasting 9 +/- 4.7 min, an increase in input resistance and an increase in the amplitude of the evoked EPSPs. This excitation could also be observed when synaptic transmission was prevented by 1 microM tetrodotoxin (tetrodotoxin). In the presence of 5 microM 8-(p-sulphophenyl)theophylline (8-SPT) adenosine (10 microM) enhanced the amplitude of evoked EPSPs by 20% +/- 3.6 (n = 5) in all neurons tested. Chloroadenosine (chloroadenosine; a stable analog of adenosine; 20 microM) induced a similar hyperpolarization associated with decrease in input resistance; this was followed by a similar excitation as seen with adenosine in 22 of the 27 neurons tested. L-baclofen (20 microM) induced a hyperpolarization associated with decrease in input resistance in all six neurons tested but an ensuing excitation was not observed. CGS 21680 (30 nM), a selective adenosine A2 receptor agonist, induced a slow depolarization associated with an increase in input resistance and, in 11 of 36 neurons, enhanced the amplitude of evoked EPSPs. These excitatory effects of CGS 21680 were blocked by the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM). In the presence of 1 microM tetrodotoxin 30 nM CGS 21680 still produced a slow depolarization and an increase in input resistance. In addition, high doses of CGS 21680 (10 and 20 microM) depressed the amplitude of EPSPs evoked by stimulation of Schaffer collateral afferents, yet there was little effect on the resting membrane potential or input resistance despite the fact that 20 microM chloroadenosine caused a pronounced hyperpolarization associated with a decrease in input resistance in the same cell. These results indicate that the excitatory effects of adenosine may be mediated via activation of adenosine A2 receptors at both presynaptic and postsynaptic sites in the hippocampal CA1 region.