PT  - JOURNAL ARTICLE
AU  - A Concas
AU  - G Santoro
AU  - M P Mascia
AU  - E Maciocco
AU  - L Dazzi
AU  - E Ongini
AU  - G Biggio
TI  - Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain.
DP  - 1993 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 844--851
VI  - 267
IP  - 2
4099  - http://jpet.aspetjournals.org/content/267/2/844.short
4100  - http://jpet.aspetjournals.org/content/267/2/844.full
SO  - J Pharmacol Exp Ther1993 Nov 01; 267
AB  - The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABAA) 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 microM) failed to modify [3H] GABA binding, [3H]flunitrazepam binding, t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and muscimol-stimulated 36Cl- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [35S]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 [35S]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 [35S]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 [35S]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 GABAA receptors.