Changes in GABAA receptor function and cross-tolerance to ethanol in diazepam-dependent rats.
Changes in gamma-aminobutyric acidA (GABAA) 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 The 38Cl- influx into cerebral cortical synaptoneurosomes induced by 10 microM GABA in DZP-withdrawn rats was significantly increased, compared with control and DZP-tolerant rats. Although enhancement of GABA-dependent 38Cl- 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 On the other hand, GABA-dependent 38Cl- influx was enhanced by FZ in the withdrawn group. The addition of picrotoxin and bicuculline inhibited GABA-dependent 38Cl- influx in each group. The stimulatory effect of FZ on GABA-dependent 38Cl- 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 However, such an inhibitory effect was not observed in the withdrawn group.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of Ro 15-4513 on EtOH stimulation of GABA-dependent 38Cl- influx observed in the control was not recognized in the withdrawn group. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors, Bmax values were significantly increased in DZP-withdrawn animals, but decreased in the DZP-tolerant group, compared with the control. When [3H]muscimol binding was examined, the Kd of high-affinity sites of the GABAA receptor in withdrawn rats was significantly lower than in the control. In low-affinity binding sites, the values of Kd and Bmax 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 GABAA/BZ/chloride channel complex function may be related to the cross-tolerance between BZ and EtOH.
Toki
S
S
Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, Japan.
Saito
T
T
Nabeshima
A
A
Hatta
S
S
Watanabe
M
M
Takahata
N
N
D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology; D018118:Chloride Channels / Q000502:physiology; D046508:Culture Techniques; D003975:Diazepam / Q000633:toxicity; D004361:Drug Tolerance; D000431:Ethanol / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000503:physiopathology*; D013570:Synaptic Membranes / Q000502:physiology
D018118:Chloride Channels; D011963:Receptors, GABA-A; D000431:Ethanol; D003975:Diazepam