Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus

Adenosine and γ-aminobutyric acid (GABA) are both major inhibitory neuromodulators/neurotransmitters in the CNS. We now investigated if endogenous GABA modulates adenosine A1-mediated action on synaptic transmission in the hippocampus. Field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 area of rat hippocampal slices. The adenosine analogue 2-chloroadenosine (0.15–1 μM) inhibited synaptic transmission with an EC50 of 398 nM. Blocking GABAA receptors with the specific antagonists, bicuculline (10 μM) or picrotoxin (10 μM) potentiated the inhibitory effect of 2-chloroadenosine. The concentration–response curve for 2-chloroadenosine was displaced to the left by a factor of 2 (EC50 = 210 nM) in the presence of bicuculline (10 μM). GABAA receptor blockade also potentiated the action of N6-cyclopentyladenosine (CPA, 10 nM), a specific adenosine A1 receptor agonist. Prevention of adenosine accumulation with adenosine deaminase (1 U/ml) did not influence bicuculline-induced potentiation of the effect of 2-chloroadenosine. The potentiation of adenosine A1-mediated response by bicuculline was abolished when nitric oxide (NO) synthase was inhibited with nitroarginine (100 μM), and when guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 20 μM). The NO donors, (±)-S-nitroso-N-acetylpencillamine (SNAP, 300 μM) and diethylamine NONate diethylammonium salt (DEA/NO, 100 μM), significantly enhanced the inhibitory action of 2-chloroadenosine (150 nM). It is concluded that the blockade of GABAA receptors induces a potentiation of adenosine A1 receptor-mediated inhibitory action, an effect that involves NO acting through guanylyl cyclase. Therefore, endogenous GABA might exert an inhibitory effect over adenosine A1-mediated responses in the hippocampus, which may represent a physiologic regulatory mechanism between the two inhibitory mediators.