title: Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus.
abstract: Adenosine and gamma-aminobutyric acid (GABA) are both major inhibitory neuromodulators/neurotransmitters in the CNS. We now investigated if endogenous GABA modulates adenosine A(1)-mediated action on synaptic transmission in the hippocampus. Field excitatory postsynaptic potentials (fEPSP) were recorded from the CA(1) area of rat hippocampal slices. The adenosine analogue 2-chloroadenosine (0.15-1 microM) inhibited synaptic transmission with an EC(50) of 398 nM. Blocking GABA(A) receptors with the specific antagonists, bicuculline (10 microM) or picrotoxin (10 microM) potentiated the inhibitory effect of 2-chloroadenosine. The concentration-response curve for 2-chloroadenosine was displaced to the left by a factor of 2 (EC(50)=210 nM) in the presence of bicuculline (10 microM). GABA(A) receptor blockade also potentiated the action of N(6)-cyclopentyladenosine (CPA, 10 nM), a specific adenosine A(1) 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 A(1)-mediated response by bicuculline was abolished when nitric oxide (NO) synthase was inhibited with nitroarginine (100 microM), and when guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 20 microM). The NO donors, (+/-)-S-nitroso-N-acetylpencillamine (SNAP, 300 microM) and diethylamine NONate diethylammonium salt (DEA/NO, 100 microM), significantly enhanced the inhibitory action of 2-chloroadenosine (150 nM). It is concluded that the blockade of GABA(A) receptors induces a potentiation of adenosine A(1) receptor-mediated inhibitory action, an effect that involves NO acting through guanylyl cyclase. Therefore, endogenous GABA might exert an inhibitory effect over adenosine A(1)-mediated responses in the hippocampus, which may represent a physiologic regulatory mechanism between the two inhibitory mediators.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Instituto de Medicina Molecular, Universidade de Lisboa, Portugal.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Fragata
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D043682:Receptor, Adenosine A1; D011963:Receptors, GABA-A; C110881:S-nitro-N-acetylpenicillamine; D015762:2-Chloroadenosine; D019335:Nitroarginine; D009569:Nitric Oxide; C048599:N(6)-cyclopentyladenosine; D005680:gamma-Aminobutyric Acid; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D010396:Penicillamine; D000241:Adenosine; D001640:Bicuculline