Pharmacological profile of benzodiazepine site ligands with recombinant GABA A receptor subtypes

Abstract

Using [ 3H]flumazenil as a probe we investigated how benzodiazepine site pharmacology of αβγ ternary combinations of GABA A receptors can be influenced upon expression of different isoforms of α, β and γ subunits. The nature of the β subunit did not alter the pharmacology of this site in that the affinities of α 5-containing GABA A receptors for various benzodiazepine modulatory ligands were essentially unchanged upon a comparison of different β-variant forms (α 5β 1γ 2, α 5β 2γ 2 and α 5β 3γ 2). In contrast, both α and γ variants contributed to notable differences in benzodiazepine site pharmacology. Thus α 1β 2γ 2, α 3β 2γ 2 and α 5β 2γ 2 receptors showed high, intermediate and low affinities for zolpidem, respectively. Exchanging γ 2 for γ 3 reduced the affinities of α 1β 2γ and α 3β 2γ receptors for zolpidem by factors of >150 and >5.8, respectively. The α 1β 2γ 3, α 3β 2γ 3 and α 5β 2γ 3 receptors exhibited, in contrast, higher affinity for CL218872 than their corresponding γ 2 receptors. The information on these different recombinant GABA A receptor pharmacological profiles should help in the elucidation of native GABA A receptor subtype diversity.