Biopsychology Area, Department of Psychology, University of Michigan, Ann Arbor, Michigan 48109 and
School of Life, Health and Chemical Sciences, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, United Kingdom MK76AA.
J Neurosci. 2018 Jan 3;38(1):60-73. doi: 10.1523/JNEUROSCI.2458-17.2017. Epub 2017 Nov 20.
Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus-response (S-R) habits. This has supported the notion of addiction as a "drug habit," and has led to considerable advances in our understanding of the neurobiological basis of such behavior. However, to procure such drugs as cocaine, addicts often require considerable ingenuity and flexibility in seeking behavior, which, by definition, precludes the development of habits. To better model drug-seeking behavior in addicts, we first developed a novel cocaine self-administration procedure [puzzle self-administration procedure (PSAP)] that required rats to solve a new puzzle every day to gain access to cocaine, which they then self-administered on an intermittent access (IntA) schedule. Such daily problem-solving precluded the development of S-R seeking habits. We then asked whether prolonged PSAP/IntA experience would nevertheless produce "symptoms of addiction." It did, including escalation of intake, sensitized motivation for drug, continued drug use in the face of adverse consequences, and very robust cue-induced reinstatement of drug seeking, especially in a subset of "addiction-prone" rats. Furthermore, drug-seeking behavior continued to require dopamine neurotransmission in the core of the nucleus accumbens (but not the dorsolateral striatum). We conclude that the development of S-R seeking habits is not necessary for the development of cocaine addiction-like behavior in rats. Substance-use disorders are often characterized as "habitual" behaviors aimed at obtaining and administering drugs. Although the actions involved in consuming drugs may involve a rigid repertoire of habitual behaviors, evidence suggests that addicts must be very creative and flexible when trying to procure drugs, and thus drug seeking cannot be governed by habit alone. We modeled flexible drug-seeking behavior in rats by requiring animals to solve daily puzzles to gain access to cocaine. We find that habitual drug-seeking isn't necessary for the development of addiction-like behavior, and that our procedure doesn't result in transfer of dopaminergic control from the ventral to dorsal striatum. This approach may prove useful in studying changes in neuropsychological function that promote the transition to addiction.
药物自我给药模型通常需要动物反复做出相同的反应（例如，压杆或鼻戳）以获取和服用药物。根据其设计，此类程序通常会产生受刺激-反应（S-R）习惯控制的行为。这支持了成瘾是一种“药物习惯”的观点，并促使我们在理解此类行为的神经生物学基础方面取得了相当大的进展。然而，为了获取可卡因等药物，成瘾者通常需要在寻求行为方面表现出相当的创造力和灵活性，而根据定义，这排除了习惯的形成。为了更好地模拟成瘾者的觅药行为，我们首先开发了一种新的可卡因自我给药程序[拼图自我给药程序（PSAP）]，该程序要求大鼠每天解决一个新的拼图以获得可卡因，然后他们根据间歇性访问（IntA）时间表进行自我给药。这种日常的解决问题行为排除了 S-R 寻求习惯的形成。然后，我们询问长期的 PSAP/IntA 体验是否会产生“成瘾症状”。事实证明，这会导致摄入增加、对药物的动机增强、即使面对不良后果仍继续使用药物，以及非常强烈的线索诱导的觅药行为恢复，特别是在一部分“易成瘾”大鼠中。此外，觅药行为仍然需要伏隔核核心中的多巴胺神经传递。我们得出的结论是，S-R 寻求习惯的形成不是大鼠产生可卡因样成瘾行为的必要条件。物质使用障碍通常被描述为旨在获取和使用药物的“习惯性”行为。尽管摄入药物所涉及的行为可能涉及一套僵化的习惯性行为，但有证据表明，成瘾者在试图获取药物时必须非常有创造力和灵活性，因此觅药行为不能仅由习惯来控制。我们通过要求动物每天解决谜题来获取可卡因，从而在大鼠中模拟了灵活的觅药行为。我们发现，习惯性觅药对于成瘾样行为的发展不是必需的，而且我们的程序不会导致多巴胺能控制从腹侧纹状体转移到背侧纹状体。这种方法可能有助于研究促进成瘾过渡的神经心理功能变化。
