纳曲酮对乙醇强化行为的抑制作用与乙醇诱导的伏隔核透析液多巴胺水平升高的减弱有关。
Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens.
作者信息
Gonzales R A, Weiss F
机构信息
Institute for Neuroscience, University of Texas at Austin, Austin, Texas 78712, USA.
出版信息
J Neurosci. 1998 Dec 15;18(24):10663-71. doi: 10.1523/JNEUROSCI.18-24-10663.1998.
The opiate antagonist naltrexone suppresses ethanol-reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simultaneous measures of the effects of naltrexone on dialysate dopamine levels in the NAcc and on operant responding for oral ethanol were used. Male Wistar rats were trained to self-administer ethanol (10-15%, w/v) in 0.2% (w/v) saccharin during daily 30 min sessions and were surgically prepared for intracranial microdialysis. Experiments began after reliable self-administration was established. Rats were injected with naltrexone (0.25 mg/kg, s.c.) or saline and 10 min later were placed inside the operant chamber for a 20 min waiting period with no ethanol available, followed by 30 min of access to ethanol. A transient rise in dialysate dopamine levels was observed during the waiting period, and this effect was not altered by naltrexone. Ethanol self-administration reliably increased dopamine levels in controls. Naltrexone significantly suppressed ethanol self-administration and prevented ethanol-induced increases in dialysate dopamine levels. Subsequent dose-effect analyses established that the latter effect was not merely a function of reduced ethanol intake but that naltrexone attenuated the efficacy of ethanol to elevate dialysate dopamine levels. These results suggest that suppression of ethanol self-administration by opiate antagonists is the result of interference with dopamine-dependent aspects of ethanol reinforcement, although possible additional effects via nondopaminergic mechanisms cannot be eliminated as a factor in opiate antagonist-induced reduction of ethanol intake.
阿片类拮抗剂纳曲酮可抑制动物的乙醇强化行为，并减少人类的乙醇摄入量。然而，这些作用背后的机制尚未完全明确。本实验旨在验证以下假设：纳曲酮通过干扰乙醇诱导的伏隔核（NAcc）多巴胺活性刺激，减弱乙醇的奖赏特性。实验同时测量了纳曲酮对NAcc透析液多巴胺水平以及口服乙醇操作性反应的影响。雄性Wistar大鼠在每日30分钟的实验时段内，于含0.2%（w/v）糖精的溶液中接受乙醇（10 - 15%，w/v）自我给药训练，并通过手术准备进行颅内微透析。在建立可靠的自我给药行为后开始实验。大鼠注射纳曲酮（0.25 mg/kg，皮下注射）或生理盐水，10分钟后放入操作性实验箱，等待20分钟，期间无乙醇供应，随后给予30分钟的乙醇接触时间。在等待期间观察到透析液多巴胺水平短暂升高，且该效应不受纳曲酮影响。对照组中，乙醇自我给药可靠地增加了多巴胺水平。纳曲酮显著抑制了乙醇自我给药，并阻止了乙醇诱导的透析液多巴胺水平升高。随后的剂量效应分析表明，后一种效应不仅仅是乙醇摄入量减少的结果，而是纳曲酮减弱了乙醇升高透析液多巴胺水平的效力。这些结果表明，阿片类拮抗剂对乙醇自我给药的抑制作用是干扰了乙醇强化过程中依赖多巴胺的方面，尽管通过非多巴胺能机制可能产生的其他效应不能排除是阿片类拮抗剂导致乙醇摄入量减少的一个因素。
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