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Changes in GABA A Receptor Function and Cross‐Tolerance to Ethanol in Diazepam‐Dependent Rats
Author(s) -
Toki Sadamu,
Saito Toshikazu,
Nabeshima Akemi,
Hatta Shinichi,
Watanabe Masayuki,
Takahata Naohiko
Publication year - 1996
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1996.tb01726.x
Subject(s) - gabaa receptor , picrotoxin , bicuculline , muscimol , chemistry , diazepam , endocrinology , medicine , receptor , ethanol , benzodiazepine , stimulation , gaba receptor , inhibitory postsynaptic potential , flunitrazepam , gaba receptor antagonist , gamma aminobutyric acid , pharmacology , biochemistry , biology
Changes in γ‐aminobutyric acid A (GABA A ) receptor function and their relation to cross‐tolerance to ethanol (EtOH) were studied in diazepam (DZP)‐dependent rats. Physical dependence on DZP was induced in male Fischer rats by using the drug‐admixed food method. The 36 CI – influx into cerebral cortical synaptoneurosomes induced by 10 μM GABA in DZP‐withdrawn rats was significantly increased, compared with control and DZP‐tolerant rats. Although enhancement of GABA‐dependent 36 CI – influx by the addition of EtOH and flunitrazepam (FZ) was recognized in the control, there was no such effect of EtOH or FZ in the DZP‐tolerant animals. On the other hand, GABA‐dependent 36 CI – influx was enhanced by FZ in the withdrawn group. The addition of picrotoxin and bicuculline inhibited GABA‐dependent 36 CI – influx in each group. The stimulatory effect of FZ on GABA‐dependent 36 CI – influx was inhibited by the addition of Ro 15–1788 in the control group. However, such an inhibitory effect was not observed in the withdrawn group. The antagonistic effect of Ro 15–4513 on EtOH stimulation of GABA‐dependent 36 CI – influx observed in the control was not recognized in the withdrawn group. In a [ 3 H]FZ assay of binding to benzodiazepine (BZ) receptors, B max values were significantly increased in DZP‐withdrawn animals, but decreased in the DZP‐tolerant group, compared with the control. When [ 3 H]muscimol binding was examined, the K d of high‐affinity sites of the GABA A receptor in withdrawn rats was significantly lower than in the control. In low‐affinity binding sites, the values of K d and B max were significantly decreased, compared with those in the control. The present study indicates that GABAergic transmission involving the regulation of GABA‐dependent chloride channels is altered in DZP‐dependent rats. Alterations of the GABA A /BZ/chloride channel complex function may be related to the cross‐tolerance between BZ and EtOH.