Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
Front Neural Circuits. 2014 May 28;8:57. doi: 10.3389/fncir.2014.00057. eCollection 2014.
In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.
在药物使用者中，仅与药物相关的线索就可以诱导背侧纹状体中的多巴胺释放。指导性线索激活来自多巴胺能和胆碱能神经元的传入信号，这些神经元被认为共同作用以支持运动学习和动机行为。这些神经调节影响的不平衡会损害正常的动作选择，从而可能导致病理性重复和强迫行为，如药物成瘾。多巴胺和乙酰胆碱对行为的影响既有拮抗作用，也有协同作用，具体取决于动物的状态和发挥作用的受体信号系统。背侧纹状体中的胆碱能中间神经元的半同步激活通过位于多巴胺末端的突触前烟碱型乙酰胆碱受体驱动多巴胺释放。已知烟碱受体阻断可减少精神运动兴奋剂诱导的异常重复行为（刻板行为）。相比之下，背侧纹状体中的突触后乙酰胆碱毒蕈碱受体阻断会加剧药物诱导的刻板行为，这说明了不同的乙酰胆碱受体也可能具有相反的作用。尽管已知在药物成瘾的动物模型中乙酰胆碱释放会发生改变，但预测这些变化是否会增强或减弱药物诱导的行为仍然是一个挑战。在这里，我们测量了 BAC 转基因小鼠中安非他命诱导的刻板行为，这些转基因小鼠表现出囊泡乙酰胆碱转运体（VAChT）的过度表达，从而导致乙酰胆碱释放增加。我们发现，与兄弟姐妹对照组相比，转基因小鼠中与药物相关的刻板行为（包括受限的嗅探和舔舐行为）大大增加，纹状体中的 VAChT 蛋白也是如此。这些发现表明，VAChT 介导的乙酰胆碱增加可能在加剧药物诱导的刻板行为和促进夸张的行为固定性方面至关重要。
