Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: Differences in antagonist potency in previously ethanol-dependent versus nondependent rats
Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: Differences in antagonist potency in previously ethanol-dependent versus nondependent rats
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DOI：
10.1124/jpet.300.3.882
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发表时间：
2002-03-01
影响因子：
3.5
通讯作者：
Weiss, F
中科院分区：
文献类型：
--
作者：
Liu, X;Weiss, F
中皮质边缘多巴胺（DA）传递与乙醇行为的完成以及最近的激励-激励方面有关。本研究的目的是测试由乙醇相关的情境刺激诱导的乙醇寻求行为是否对 DA 传输的拮抗作用敏感。训练雄性 Wistar 大鼠自行口服 10% 乙醇，并将嗅觉辨别刺激与乙醇的可用性 (S+) 和无奖励 (S-) 联系起来。然后，通过抑制乙醇和相关的 S+ 来消除乙醇增强的操作反应。达到预定的灭绝标准后，进行恢复测试，其中仅向动物非偶然地提供S+或S-。暴露于 S+ 但不暴露于 S- 会在之前的活动杠杆处恢复响应。 D1 拮抗剂 R(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮平盐酸盐 (SCH23390; 5, 10, 50 杯/公斤 s.c.) 和 D2 拮抗剂艾氯必利 (5, 10, 50 杯/公斤 s.c.) 剂量依赖性地减少 S+ 诱导的响应并增加响应延迟。在对同一只大鼠进行的第二次测试中，从为期 12 天的乙醇蒸气吸入程序中撤出后 3 周，S' 的反应恢复功效保持不变。然而，两种 DA 拮抗剂抑制 S+ 诱导的药物寻求反应的效力显着增加。结果证实，与乙醇相关的环境刺激可靠地引发药物寻求行为，并表明这种效应需要激活 DA 神经传递。结果还表明，长期接触乙醇会导致 D1 和 D2 受体功能发生变化，从而导致对这些受体拮抗剂行为效应的敏感性增强。
Mesocorticolimbic dopamine (DA) transmission has been implicated in the consummatory and, more recently, the, incentive-motivational aspect of ethanol's actions. The purpose of this study was to test whether ethanol-seeking behavior induced by an ethanol-associated contextual stimulus is sensitive to antagonism of DA transmission. Male Wistar rats were trained to orally self-administer 10% ethanol and to associate olfactory discriminative stimuli with the availability of ethanol (S+) versus nonreward (S-). Ethanol-reinforced operant responding then was extinguished by withholding ethanol and the associated S+. After reaching a predetermined extinction criterion, reinstatement tests were conducted in which the animals were presented noncontingently with only the S+ or S-. Exposure to the S+ but not the S- reinstated responding at the previously active lever. The D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 5, 10, 50 mug/kg s.c.) and the D2 antagonist eticlopride (5, 10, 50 mug/kg s.c.) dose dependently decreased the number of S+-induced responses and increased response latency. During a second test, conducted in the same rats, 3 weeks after withdrawal from a 12-day ethanol vapor inhalation procedure, the response-reinstating efficacy of the S' remained unaltered. However, the potency of both DA antagonists to inhibit the S+-induced drug-seeking response was significantly increased. The results confirm that ethanol-related contextual stimuli reliably elicit drug-seeking behavior and suggest that this effect requires activation of DA neurotransmission. The results also indicate that chronic ethanol exposure produces changes in D1 and D2 receptor function that lead to enhanced sensitivity to the behavioral effects of antagonists for these receptors.