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Vol. 283, Issue 1, 384-390, 1997
-Aminobutyric AcidA Receptors
on Clathrin-Coated Vesicles During Chronic Benzodiazepine
Administration In Vivo1
Verna and Marrs McLean Department of Biochemistry, Baylor College
of Medicine, Houston, Texas
Chronic administration of benzodiazepine agonists produces behavioral
tolerance. For induction of tolerance, the use-dependent down-regulation of 
-aminobutyric acidA
(GABAA)/benzodiazepine receptors is a potential cellular
mechanism. We previously identified GABAA receptors on
clathrin-coated vesicles from rat brain, suggesting that surface
receptors can be internalized via endocytosis. To examine a role for coated vesicles in GABAA receptor
down-regulation in vivo, fractions were obtained from
mouse brain microsomes through density centrifugation and treatment
with 0.1% Triton X-100. This coated vesicle preparation was enriched
in clathrin subunits and clathrin light-chain kinase and had twice the
level of [3H]flunitrazepam binding as did vesicles not
exposed to Triton. Adult mice were treated with lorazepam (2 mg/kg/day)
for 7 days via osmotic minipump, achieving a serum level
of 103 ± 8.9 ng/ml. The level of flunitrazepam bound to coated
vesicles was increased by 83 ± 13% in the lorazepam-treated mice
compared with vehicle-treated controls. The
Bmax value for
[3H]flunitrazepam binding to synaptic membranes from
lorazepam-treated animals was 33 ± 4% lower than that of
controls. The amount of GABAA receptor alpha-1
subunits, as quantified by Western blotting, followed a similar
pattern. Relative to controls, immunoreactivity for alpha-1
subunits in coated vesicles from lorazepam-treated mice was increased
by 60.0 ± 10.3%, whereas that in synaptic membranes declined by
12 ± 6%. These results indicate that lorazepam-dependent GABAA receptor sequestration occurs in mouse brain.
Furthermore, it is suggested that this sequestration may play a role in
GABAA receptor down-regulation in vivo.
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