ACTION OF ZOLPIDEM ON RESPONSES TO GABA IN RELATION TO MESSENGER-RNASFOR GABA(A) RECEPTOR-ALPHA SUBUNITS WITHIN SINGLE CELLS - EVIDENCE FOR MULTIPLE FUNCTIONAL GABA(A) ISORECEPTORS ON INDIVIDUAL NEURONS
He. Criswell et al., ACTION OF ZOLPIDEM ON RESPONSES TO GABA IN RELATION TO MESSENGER-RNASFOR GABA(A) RECEPTOR-ALPHA SUBUNITS WITHIN SINGLE CELLS - EVIDENCE FOR MULTIPLE FUNCTIONAL GABA(A) ISORECEPTORS ON INDIVIDUAL NEURONS, Neuropharmacology, 36(11-12), 1997, pp. 1641-1652
The relationship between zolpidem sensitivity and GABA(A) receptor alp
ha subunits was studied in individual dissociated neurons from rat bra
in. Using whole-cell recording, similar EC50 values were demonstrated
for the effect of gamma-aminobutyric acid (GABA) on gated-chloride cur
rents from substantia nigra reticulata (SNR) and lateral septal neuron
s. Subsequently, many neurons from both the SNR or lateral septum were
found to exhibit enhanced GABA-gated chloride currents across concent
rations of zolpidem ranging from 10 to 300 nM. Some neurons exhibited
a greater than 20 % increase in responsiveness to GABA at 30 nM of zol
pidem without further increase at higher concentrations of zolpidem. C
onversely, zolpidem enhancement of GABA from another group of neurons
was not observed at 30 nM zolpidem, but between 100 and 300 nM the res
ponse to GABA increased greater than 20 %. Finally, a third group of n
eurons reached both of these criteria for zolpidem enhancement of GABA
. This latter spectrum of responses to GABA after varying concentratio
ns of zolpidem was consistent with the presence of either two GABA(A)
receptors or a single receptor with differing affinities for zolpidem
on an individual neuron. Following determination of the sensitivity of
neurons from SNR or lateral septum to zolpidem, cytoplasm was extract
ed from some individual cells to allow identification of cellular mRNA
s for the alpha 1, alpha 2 and alpha 3 GABA(A) receptor subunits with
RT-PCR. Those neurons that responded to the 30 nM zolpidem concentrati
on invariably expressed the alpha 1-GABA(A) receptor subunit. This res
ult is consistent with the GABA(A) alpha 1-receptor subunit being an i
ntegral part of a functional high-affinity zolpidem type 1-BZD recepto
r complex on neurons in brain. Those neurons which showed enhancement
of GABA from 100 to 300 nM zolpidem contained mRNAs for the alpha 2 an
d/or the alpha 3 receptor subunits, a finding consistent with these al
pha subunits forming type 2-BZD receptors. Some individual dissociated
SNR neurons were sensitive to both low and high concentrations of zol
pidem and contained mRNAs for all three alpha-receptor subunits. These
latter individual neurons are proposed to have at least two functiona
l GABA(A) receptor subtypes. Thus, the present investigation emphasize
s the importance of characterizing the relationship between endogenous
GABA(A) receptor function and the presence of specific structural com
ponents forming GABA(A) receptor subtypes on neurons. (C) 1998 Elsevie
r Science Ltd. All rights reserved.