PMID- 9353389
OWN - NLM
STAT- MEDLINE
DCOM- 19971208
LR  - 20131121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 283
IP  - 2
DP  - 1997 Nov
TI  - Desensitization of a gamma-aminobutyric acid type A receptor in rat is increased 
      by chronic treatment with chlordiazepoxide: a molecular mechanism of dependence.
PG  - 704-11
AB  - When rats were made tolerant to the benzodiazepine tranquilizer chlordiazepoxide 
      (CDPX) by its steady administration, a particular gamma-aminobutyric acid type A 
      (GABAA) receptor in cerebral cortex was modified. Its rate of desensitization in 
      the absence of CDPX was enhanced (3-fold with 10 microM GABA) below saturation 
      with GABA, and the dependence of this rate on GABA concentration was changed from 
      sigmoid to hyperbolic. This mimicked the effect of the presence of CDPX on 
      desensitization of the naive receptor. This receptor has been characterized by 
      its rapid desensitization (t1/2 = 30 msec at saturation). In contrast, a 
      different, slower desensitizing GABAA receptor, on the same membrane, was 
      unaffected, and the initial transmembrane halide exchange rate of the faster 
      desensitizing receptor was unaltered. In the presence of CDPX, the initial halide 
      exchange rate of the modified receptor was enhanced, but the already enhanced 
      desensitization rate was not altered. During chronic presence of CDPX and the 
      development of tolerance, the total signal due to this receptor remained constant 
      at the value before exposure. After discontinuation, the total signal decreased 
      but could be restored to the original value by the presence of CDPX. It was 
      postulated that dependence and withdrawal syndromes result from a decreased ratio 
      of initial chloride flux rate to desensitization rate, caused by an increase in 
      desensitization. The contribution of this effect in vivo would depend on 
      desensitization making a contribution to signal termination [or the fraction of 
      receptors that are inactive (desensitized)]. In the quench flow experiments, the 
      total signal due to this receptor from naive rat did not depend much on GABA 
      concentration or the presence of CDPX because the result of increased channel 
      opening was counterbalanced by increased desensitization. In contrast, the total 
      signal of this receptor from tolerant rat was significantly increased by CDPX or 
      increased GABA concentration. Differences between these experiments and 
      measurements reported with other drugs could be explained if, in those 
      experiments, the halide exchange rate, as well as its desensitization rate, 
      retained an enhanced value in the absence of the drug.
FAU - Cash, D J
AU  - Cash DJ
AD  - Department of Biochemistry, School of Medicine, University of Missouri, Columbia, 
      Missouri 65211, USA.
FAU - Serfozo, P
AU  - Serfozo P
FAU - Allan, A M
AU  - Allan AM
LA  - eng
GR  - AA08219/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anti-Anxiety Agents)
RN  - 0 (Receptors, GABA-A)
RN  - 6RZ6XEZ3CR (Chlordiazepoxide)
SB  - IM
MH  - Animals
MH  - Anti-Anxiety Agents/*pharmacology
MH  - Chlordiazepoxide/*pharmacology
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, GABA-A/*drug effects
MH  - Substance-Related Disorders/*etiology
EDAT- 1997/11/14 00:00
MHDA- 1997/11/14 00:01
CRDT- 1997/11/14 00:00
PHST- 1997/11/14 00:00 [pubmed]
PHST- 1997/11/14 00:01 [medline]
PHST- 1997/11/14 00:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 1997 Nov;283(2):704-11.