DISTRIBUTION OF [H-3] ZOLPIDEM BINDING-SITES IN RELATION TO MESSENGER-RNA ENCODING THE ALPHA-1, BETA-2 AND GAMMA-2 SUBUNITS OF GABA(A) RECEPTORS IN RAT-BRAIN

Localization of the messenger RNAs that encode the alpha 1, beta 2 and gamma 2 subunits of GABA(A) showed a distinct topographic pattern in rat brain which corresponded with [H-3]zolpidem binding in most brain regions. The close topographic correspondence between the specific rec eptor subunits examined and the distribution of [H-3]zolpidem binding sires provides support for the hypothesis that this benzodiazepine typ e 1 selective ligand binds to a GABA(A) receptor that consists of alph a 1, beta 2 and gamma 2 subunits in the rat brain. Brain regions with relatively high densities of alpha 1, beta 2 and gamma 2 subunits of G ABA(A) and [H-3]zolpidem binding included olfactory bulb, medial septu m, ventral pallidum, diagonal band, inferior colliculus, substantia ni gra pars reticulata and specific layers of the cortex. Two areas with low [H-3]zolpidem binding and a virtual absence of these GABA(A) recep tor subunit messenger RNAs were the lateral septum and the striatum. I n contrast to the discrete pattern observed for alpha 1 and beta 2 sub unit messenger RNAs, the gamma 2 subunit messenger RNA was distributed more diffusely in brain. Only the hippocampus, layer 2 of the pirifor m cortex and the cerebellum showed a strong concentration of the gamma 2 subunit messenger RNA. It was determined with a polymerase chain re action assay that both long and short variants of the gamma 2 subunit messenger RNAs were present within several of the brain sites selected for examination. Sites with high densities of [H-3]zolpidem binding s ites had a greater relative abundance of the gamma 2 long splice varia nt, compared to the gamma 2 short variant. There were some regions tha t expressed high levels of alpha 1, beta 2 and gamma 2S subunit messen ger RNAs but low [H-3]zolpidem binding, suggesting that gamma 2 splice variant expression may modulate high-affinity [H-3]zolpidem binding. To determine relationships between in vitro [H-3]zolpidem binding and functional sensitivity in vivo, interactions between zolpidem and GABA were assessed in brain regions that contained high and low densities of [H-3]zolpidem binding sites. In the medial septum, a brain region w ith a high concentration of [H-3]zolpidem binding sites, iontophoretic application of zolpidem enhanced the inhibitory effect of GABA respon ses on 70% of the neurons examined. In the lateral septum, which conta ins very low densities of [H-3]zolpidem binding sites, neurons were no t sensitive to zolpidem enhancement of GABA-induced inhibition. These electrophysiological results demonstrate a correspondence between the regional distribution of [H-3]zolpidem binding in vitro and functional sensitivity to the drug in vivo.