ANTICONVULSANT DOSES OF 2-CHLORO-N-6-CYCLOPENTYLADENOSINE, AN ADENOSINE-A(1) RECEPTOR AGONIST, REDUCE GABAERGIC TRANSMISSION IN DIFFERENT AREAS OF THE MOUSE-BRAIN

The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABA(A)) receptor complex was evaluated in the mouse brain. We studied the effect of in vitro addition and in vivo administration of 2-chloro-N6-cyclopentyladenosine (CCPA), the most selective ligand for A1 receptors, on the biochemical parameters used currently to evaluate GABAergic function. In vitro, CCPA (0.01-100 muM) failed to modify [H-3] GABA binding, [H-2]flunitrazepam binding, t-[S-35]butylbicyclophosphorothionate ([ S-35]TBPS) binding and muscimol-stimulated Cl-36- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [S-35]TBPS binding in membranes from the cerebral cortex, hippocampus, striatum and substantia nigra, but not from the cerebellum, thalamus, hypothalamus and olfactory tubercle. The specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxantine (9.8 mumol/kg i.p.) abolished the effect of CCPA on [S-35]TBPS binding, indicating that the action of this compound is mediated by its interaction with A1 receptors. Diazepam (1.7 mumol/kg i.p.), a positive modulator of GABAergic transmission, antagonized the increase of [S-35]TBPS binding induced by CCPA. CCPA (2.8-8.3 mumol/kg i.p.) antagonized convulsions induced by isoniazid, an inhibitor of GABA synthesis, but neither antagonized nor potentiated isoniazid-induced increase of [S-35] TBPS binding. CCPA (2.8-8.3 mumol/kg i.p.) antagonized the convulsions induced by pentylenetetrazol (398 mumol/kg i.p.), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (50 mumol/kg i.p.) and bicuculline methiodide (9.8 mumol/kg i.p.). The results show that, in spite of its anticonvulsant activity, CCPA reduces the function of the GABA-coupled chloride channel function. This finding suggests that the anticonvulsant target sites are different from those involved in the action of CCPA on GABA(A) receptors.