Influence of the combined treatment of LY 300164 (an AMPA/kainate receptor antagonist) with adenosine receptor agonists on the electroconvulsive threshold in mice

Abstract

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7 H-1,3-dioxolo-4,5 H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N 6-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A 1/A 3 receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5′- N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A 1/A 2 receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.