The interaction between zolpidem and β-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem

Abstract

The interaction of β-CMC, an amino β-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like β-CMC binds preferentially to the ω 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, β-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. β-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strenght provoked by zolpidem. In rats trained to discriminate zolpidem, β-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strenght) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the ω 1 (BZ-1) site of the GABA A receptor.