GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6j mice

被引：69

作者：

Besheer J. ^{[1
]}

Lepoutre V. ^{[1
]}

Hodge C.W. ^{[1
]}

机构：

[1] Bowles Center for Alcohol Studies, Department of Psychiatry, Univ. of NC at Chapel Hill, Chapel Hill

来源：

Psychopharmacology | 2004年 / 174卷 / 3期

关键词：

Alcohol self-administration; Baclofen; GABA[!sub]B[!/sub] agonist; Locomotor activity; Mice; Reinforcement; Sedation; SKF; 97514;

D O I：

10.1007/s00213-003-1769-3

中图分类号：

学科分类号：

摘要：

Rationale: A growing number of studies suggest that γ-aminobutyric acid type-B (GABAB) receptor agonists reduce alcohol use and craving. Objectives: This study was designed to further clarify behavioral mechanism(s) by which GABAB agonists may decrease alcohol reinforcement. Methods: Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABAB agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABAB agonists was examined in ethanol naive and self-administering mice. Results: Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/ kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABAB agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABAB agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABAB agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol. Conclusions: GABAB agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABAB agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABAB positive modulation. These data question the safety of prescribing GABAB agonists to alcoholics since these drugs may potentiate ethanol's sedative/ hypnotic effects during relapse. © Springer-Verlag 2004.

引用

页码：358 / 366

页数：8

共 42 条

[31] Munzar P., Kutkat S.W., Miller C.R., Goldberg S.R., Failure of baclofen to modulate discriminative-stimulus effects of cocaine or methamphetamine in rats, Eur J Pharmacol, 408, pp. 169-174, (2000)
[32] Petry N.M., Benzodiazepine-GABA modulation of concurrent ethanol and sucrose reinforcement in the rat, Exp Clin Psychopharmacol, 5, pp. 183-194, (1997)
[33] Rodgers R.J., Depaulis A., GABAergic influences on defensive fighting in rats, Pharmacol Biochem Behav, 17, pp. 451-456, (1982)
[34] Samson H.H., Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats, Alcohol Clin Exp Res, 10, pp. 436-442, (1986)
[35] Samson H.H., Initiation of ethanol-maintained behavior: A comparison of animal models and their implication to human drinking, Adv Behav Pharmacol, Vol 6. Neurobehavioral Pharmacology, 6, pp. 221-248, (1987)
[36] Shellenberger M.K., Groves L., Shah J., Novack G.D., A controlled pharmacokinetic evaluation of tizanidine and baclofen at steady state, Drug Metab Dispos, 27, pp. 201-204, (1999)
[37] Shelton K.L., Balster R.L., Ethanol drug discrimination in rats: Substitution with GABA agonists and NMDA antagonists, Behav Pharmacol, 5, pp. 441-451, (1994)
[38] Smith B.R., Robidoux J., Amit Z., GABAergic involvement in the acquisition of voluntary ethanol intake in laboratory rats, Alcohol Alcohol, 27, pp. 227-231, (1992)
[39] Smith B.R., Boyle A.E., Amit Z., The effects of the GABA(B) agonist baclofen on the temporal and structural characteristics of ethanol intake, Alcohol, 17, pp. 231-240, (1999)
[40] VanDierendonk D.R., Dire D.J., Baclofen and ethanol ingestion: A case report, J Emerg Med, 17, pp. 989-993, (1999)

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