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Eur J Pharmacol ; 543(1-3): 32-9, 2006 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-16831416

RESUMEN

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.


Asunto(s)
Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Receptor de Adenosina A1/metabolismo , Receptores de GABA-A/metabolismo , 2-Cloroadenosina/farmacología , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Animales , Bicuculina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Antagonistas del GABA/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/metabolismo , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Inhibición Neural/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroarginina/farmacología , Oxadiazoles/farmacología , Penicilamina/análogos & derivados , Penicilamina/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptor de Adenosina A1/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo
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