Ahmed Serge H, Kenny Paul J
ILAR J. 2011;52(3):309-20. doi: 10.1093/ilar.52.3.309.
Cocaine addiction is a behavioral disorder defined by behavioral symptoms that set it apart from nondisordered forms of drug use. Here we review evidence in rats (the most frequently used animal model in the field) that it is possible, after extended (but not after limited) access to cocaine for self-administration, to selectively induce some of these behaviors: gradual escalation of cocaine intake, enhanced motivation for the drug despite increased costs (or negative consequences), and increased sensitivity to drug- and stress-primed craving-like behavior. Animals with extended drug use also present selective neurocognitive deficits (e.g., compromised working memory) that may impair their ability to regulate cocaine intake. In some rats, extended access to cocaine for self-administration is associated with loss of control over cocaine intake, as assessed by continued drug use despite the opportunity to make a different choice and to the exclusion of more natural and rewarding activities. These rats may represent the most advanced and severe stage on the path to cocaine addiction. Finally, comparisons of rats with extended versus limited access to cocaine for self-administration have recently revealed the existence of a new molecular pathway in the dorsal striatum (a brain region altered in cocaine-addicted humans) that causally and selectively controls cocaine intake. This pathway involves unforeseen homeostatic interactions between microRNAs (a class of nonprotein-coding RNAs) and some key molecular regulators of neuronal plasticity (e.g., MeCP2 and BDNF). This discovery provides an entirely new direction for the development of effective antiaddiction treatments.
可卡因成瘾是一种行为障碍，其行为症状使其有别于无紊乱形式的药物使用。在此，我们回顾了大鼠（该领域最常用的动物模型）的相关证据，即在延长（而非有限）获取可卡因用于自我给药后，有可能选择性地诱发其中一些行为：可卡因摄入量逐渐增加、尽管成本增加（或有负面后果）但对药物的动机增强，以及对药物和应激引发的渴望样行为的敏感性增加。长期使用药物的动物还存在选择性神经认知缺陷（例如，工作记忆受损），这可能会损害它们调节可卡因摄入量的能力。在一些大鼠中，延长获取可卡因用于自我给药与对可卡因摄入量失去控制有关，这是通过尽管有机会做出不同选择并排除更自然和有益的活动仍持续使用药物来评估的。这些大鼠可能代表了可卡因成瘾道路上最严重的阶段。最后，对延长获取可卡因用于自我给药与有限获取可卡因用于自我给药的大鼠进行比较，最近发现背侧纹状体（可卡因成瘾人类中发生改变的脑区）中存在一条新的分子途径，该途径因果性地且选择性地控制可卡因摄入量。这条途径涉及微小RNA（一类非蛋白质编码RNA）与神经元可塑性的一些关键分子调节因子（例如MeCP2和BDNF）之间意外的稳态相互作用。这一发现为开发有效的抗成瘾治疗提供了全新的方向。
