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.
ANTICONVULSANT DOSES OF 2-CHLORO-N-6-CYCLOPENTYLADENOSINE, AN ADENOSINE-A(1) RECEPTOR AGONIST, REDUCE GABAERGIC TRANSMISSION IN DIFFERENT AREAS OF THE MOUSE-BRAIN
MASCIA MP;
1993
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
