Augmentation of drug reward by chronic food restriction: Behavioral evidence and underlying mechanisms
Augmentation of drug reward by chronic food restriction: Behavioral evidence and underlying mechanisms
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DOI：
10.1016/s0031-9384(02)00759-x
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发表时间：
2002-07-01
影响因子：
2.9
通讯作者：
Carr, KD
中科院分区：
文献类型：
--
作者：
Carr, KD
长期以来，人们都知道，长期限制食物和保持低体重会增加滥用药物的自我管理和运动激活效果。采用下丘脑外侧自我刺激(LHSS)频率-频率法，研究结果表明，长期限食可增强多种药物滥用的奖赏效应(即降低阈值)。此外，这种效应归因于神经底物的敏感性增加，而不是药物生物利用度或药代动力学的变化，因为当药物直接注射到侧脑室(脑室内)时，这种作用被保留下来。增加药物奖励的食物限制方案也增加了脑室内苯丙胺对边缘前脑多巴胺(DA)终末区域c-fos的诱导。直接DA受体激动剂的奖赏和运动激活效应因食物限制而增强，而苯丙胺增强的行为效应可被亚阈值剂量的D-1拮抗剂逆转，这一发现提示了DA受体功能增强的可能性。对DA受体介导的信号转导的初步研究，主要集中在D-2受体上，表明背侧纹状体受体与G蛋白之间的功能偶联(即喹比罗刺激的[S-35]GTP-γS结合)增加。与间歇应激或心理刺激治疗引起的行为敏感化不同，在诱导后无限期地持续，食物限制的增强效应在自由进食和体重增加的第一周内减弱。因此，内分泌激素和/或与摄食相关的神经肽的可能参与正在调查中，它们的水平随着脂肪储备的耗尽和再耗尽而动态变化。最初的试验仅限于急性治疗，目的是减轻食物限制大鼠的低胰岛素血症、低血浆蛋白血症和皮质酮水平升高的影响。所有这些治疗方法都没有减弱限食的行为影响。虽然已发现一种黑素皮质素受体激动剂可以增强药物奖赏，但黑素皮质素受体似乎并不介导食物限制的增强效应。对内分泌肥胖信号、摄食相关神经肽和多巴胺能信号转导的持续研究可能会进一步阐明药物滥用利用调节与生存相关行为的机制的方式，并有助于解释药物滥用和饮食失调的高共患率。(C)2002 Elsevier Science Inc.保留所有权利。
Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [S-35]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within I week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders. (C) 2002 Elsevier Science Inc. All rights reserved.