Katner S N, Weiss F
The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA.
Alcohol Clin Exp Res. 1999 Nov;23(11):1751-60.
Alcohol craving or automatic behavioral responses provoked by alcohol-related cues are thought to contribute to relapse risk in abstinent individuals. However, there is to date only limited direct experimental evidence that supports this hypothesis. The present study employed an operant response-reinstatement model to examine the effects of ethanol-associated environmental stimuli on alcohol-seeking behavior and extracellular dopamine (DA) levels in the nucleus accumbens (NAcc).
Male Wistar rats were prepared with intracerebral guide cannulae for microdialysis and trained to operantly self-administer ethanol in the presence of discrete olfactory discriminative stimuli (Sdelta's) signaling the availability of ethanol (10% w/v) versus a nonrewarding stimulus (a 50 microM quinine HCl solution). After the discrimination learning phase, responding for ethanol (and quinine) was extinguished by withholding the drinking solutions as well as the corresponding Sdelta's. After reaching and maintaining an extinction criterion of < or = 5 responses/session, the rats were exposed noncontingently to the ethanol and nonreward Sdelta's but without the availability of ethanol or quinine.
The ethanol Sdelta's, but not nonreward Sdelta's, elicited significant recovery of responding. Exposure to the operant chamber during a 20 min "waiting period" before presentation of the Ss's was associated with a small but significant increase in dialysate DA levels. Subsequent exposure to the ethanol Sdelta and onset of the reinstatement session was accompanied by a small but significant decrease in DA efflux. Exposure to the nonreward Sdelta did not alter DA levels.
The behavioral data confirm that ethanol-predictive discriminative stimuli reliably elicit ethanol-seeking behavior after extinction. The increase in DA efflux during the waiting period confirms earlier findings and suggests that anticipation of access to ethanol activates mesolimbic DA neurons. The decrease in DA efflux after onset of the reinstatement session in animals that were presented with the ethanol Sdelta's may reflect neurochemical events associated with the mismatch between the predicted (i.e., ethanol availability) and actual (i.e., absence of ethanol) stimulus events. This possibility is supported by the lack of changes in DA efflux in rats that were presented with the nonreward Sdelta's, a test condition that did not involve such a mismatch. Overall, the findings provide further evidence for a role of conditioning processes in the control of alcohol-seeking behavior and, by extension, support the hypothesis that conditioned responses to drug-related stimuli may be an important factor in chronic alcohol abuse and relapse.
酒精相关线索引发的酒精渴望或自动行为反应被认为会增加戒酒者复发的风险。然而，迄今为止，仅有有限的直接实验证据支持这一假设。本研究采用操作性反应恢复模型，以检验乙醇相关环境刺激对伏隔核（NAcc）中觅酒行为和细胞外多巴胺（DA）水平的影响。
雄性Wistar大鼠植入用于微透析的脑内引导套管，并训练其在离散嗅觉辨别刺激（Sdelta's）存在的情况下操作性自我给药乙醇，该刺激表明有乙醇（10% w/v）可供使用，而不是无奖励刺激（50 microM盐酸奎宁溶液）。在辨别学习阶段后，通过停止提供饮用溶液以及相应的Sdelta's，对乙醇（和奎宁）的反应被消除。在达到并维持<或 = 5次反应/会话的消退标准后，大鼠被非条件性地暴露于乙醇和无奖励Sdelta's，但没有乙醇或奎宁可供使用。
乙醇Sdelta's而非无奖励Sdelta's引发了反应的显著恢复。在呈现刺激之前的20分钟“等待期”内暴露于操作性条件箱与透析液DA水平的小幅但显著增加有关。随后暴露于乙醇Sdelta和恢复阶段的开始伴随着DA流出的小幅但显著减少。暴露于无奖励Sdelta并未改变DA水平。
行为数据证实，乙醇预测性辨别刺激在消退后可靠地引发觅酒行为。等待期内DA流出的增加证实了早期发现，并表明对获取乙醇的预期激活了中脑边缘DA神经元。在呈现乙醇Sdelta's的动物中，恢复阶段开始后DA流出的减少可能反映了与预测（即乙醇可用性）和实际（即无乙醇）刺激事件之间不匹配相关的神经化学事件。在呈现无奖励Sdelta's的大鼠中DA流出缺乏变化支持了这一可能性，这一测试条件不涉及这种不匹配。总体而言，这些发现为条件作用过程在控制觅酒行为中的作用提供了进一步证据，进而支持了对药物相关刺激的条件反应可能是慢性酒精滥用和复发的重要因素这一假设。
