Caprioli Daniele, Venniro Marco, Zhang Michelle, Bossert Jennifer M, Warren Brandon L, Hope Bruce T, Shaham Yavin
Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224
Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
J Neurosci. 2017 Jan 25;37(4):1014-1027. doi: 10.1523/JNEUROSCI.3091-16.2016.
We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D and D family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D and D receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation.
In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving.
我们最近建立了一种基于选择的自愿戒断后甲基苯丙胺渴求潜伏期的大鼠模型。在此，我们研究了背外侧纹状体（DLS）和背内侧纹状体（DMS）在这种潜伏期过程中的作用。我们训练大鼠自行摄取美味食物颗粒（6天，每天6小时）和甲基苯丙胺（12天，每天6小时）。然后，我们评估了在1天和21天戒断期后，在消退条件下对甲基苯丙胺寻求行为的复发情况。在两次测试之间，大鼠进行了19天的自愿戒断（使用甲基苯丙胺和食物之间的离散选择程序；每天20次试验）。我们使用原位杂交技术来测量测试后DMS和DLS中活性标记物Fos与Drd1和Drd2的共标记情况。基于原位杂交共标记结果，我们分别使用选择性多巴胺受体拮抗剂（SCH39166或雷氯必利）和道诺霉素02化学遗传失活程序，测试了DMS中D1和D2家族受体以及DMS神经元集群在“潜伏期”甲基苯丙胺寻求行为中的因果作用。自愿戒断21天后的甲基苯丙胺寻求行为比1天后更高（甲基苯丙胺渴求的潜伏期）。潜伏期反应与DMS中Fos表达增加相关，而与DLS中无关；Fos与Drd1和Drd2共标记。在戒断21天后，向DMS注射SCH39166或雷氯必利可选择性降低甲基苯丙胺寻求行为。在Fos - lacZ转基因大鼠中，在戒断第18天选择性失活复发测试激活的DMS中的Fos神经元，可降低第21天潜伏期甲基苯丙胺寻求行为。结果表明，DMS多巴胺D1和D2受体在自愿戒断后甲基苯丙胺渴求的潜期中发挥作用，且DMS神经元集群介导了这种潜伏期。
在人类成瘾者中，戒断通常是自我施加的，复发可能由暴露于诱导药物渴求的药物相关线索引发。我们最近建立了一种基于选择的自愿戒断后甲基苯丙胺渴求潜伏期的大鼠模型。在此，我们使用经典药理学、原位杂交、免疫组织化学和道诺霉素０２失活程序，证明了背内侧纹状体神经元集群在这种新型药物渴求潜期中的关键作用。
