Distribution of [3H]zolpidem binding sites in relation to messenger RNA encoding the alpha 1, beta 2 and gamma 2 subunits of GABAA receptors in rat brain.
Localization of the messenger RNAs that encode the alpha 1, beta 2 and gamma 2 subunits of GABAA showed a distinct topographic pattern in rat brain which corresponded with [3H]zolpidem binding in most brain regions. The close topographic correspondence between the specific receptor subunits examined and the distribution of [3H]zolpidem binding sites provides support for the hypothesis that this benzodiazepine type 1 selective ligand binds to a GABAA receptor that consists of alpha 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 GABAA and [3H]zolpidem binding included olfactory bulb, medial septum, ventral pallidum, diagonal band, inferior colliculus, substantia nigra pars reticulata and specific layers of the cortex. Two areas with low [3H]zolpidem binding and a virtual absence of these GABAA receptor subunit messenger RNAs were the lateral septum and the striatum. In contrast to the discrete pattern observed for alpha 1 and beta 2 subunit messenger RNAs, the gamma 2 subunit messenger RNA was distributed more diffusely in brain. Only the hippocampus, layer 2 of the piriform cortex and the cerebellum showed a strong concentration of the gamma 2 subunit messenger RNA. It was determined with a polymerase chain reaction 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 [3H]zolpidem binding sites had a greater relative abundance of the gamma 2 long splice variant, compared to the gamma 2 short variant. There were some regions that expressed high levels of alpha 1, beta 2 and gamma 2S subunit messenger RNAs but low [3H]zolpidem binding, suggesting that gamma 2 splice variant expression may modulate high-affinity [3H]zolpidem binding. To determine relationships between in vitro [3H]zolpidem binding and functional sensitivity in vivo, interactions between zolpidem and GABA were assessed in brain regions that contained high and low densities of [3H]zolpidem binding sites. In the medial septum, a brain region with a high concentration of [3H]zolpidem binding sites, iontophoretic application of zolpidem enhanced the inhibitory effect of GABA responses on 70% of the neurons examined. In the lateral septum, which contains very low densities of [3H]zolpidem binding sites, neurons were not sensitive to zolpidem enhancement of GABA-induced inhibition. These electrophysiological results demonstrate a correspondence between the regional distribution of [3H]zolpidem binding in vitro and functional sensitivity to the drug in vivo.
Duncan
G E
GE
Department of Psychiatry, University of North Carolina at Chapel Hill 27599, USA.
Breese
G R
GR
Criswell
H E
HE
McCown
T J
TJ
Herbert
J S
JS
Devaud
L L
LL
Morrow
A L
AL
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D004594:Electrophysiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000145:classification / Q000502:physiology*; D000077334:Zolpidem
D006993:Hypnotics and Sedatives; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000077334:Zolpidem