Abstract

Background

Reexposure to methamphetamine with a single “priming dose” can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril “molecular container” calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats.

Methods

Male Long-Evans rats were trained to self-administer i.v. methamphetamine (0.06 mg/kg/infusion). Following 10 days of stable self-administration, rats underwent extinction training and were subsequently tested on a multi-phase reinstatement procedure. Drug-primed reinstatement sessions (0.3 mg/kg methamphetamine, i.v.) were preceded by either saline or calabadion-2 (130 mg/kg). Additional reinstatement tests were conducted after administration of yohimbine (1.0 mg/kg, i.v.) to define the pharmacological specificity of calabadion-2.

Results

Pretreatment with calabadion-2 significantly attenuated methamphetamine-induced reinstatement of responding. Cal2 did not affect drug-seeking behavior stimulated by the pharmacological stressor yohimbine, indicating a mechanism of action specific to methamphetamine.

Conclusions

These results demonstrate the effectiveness of calabadion-2 in a preclinical model relapse-like behavior. With further structural optimization, molecular containers may provide a novel and efficacious pharmacokinetic approach to relapse prevention for methamphetamine-dependent individuals.

中文翻译：

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帕金森病的幻视和冲动控制障碍。

摘要

背景

使用单一“初始剂量”重新接触甲基苯丙胺会引发强烈的渴望并促使依赖甲基苯丙胺的个体复发。无环葫芦[n]uril“分子容器”calabadion-2 在体外显示出对甲基苯丙胺的高亲和力结合和螯合，并减弱其对大鼠的运动刺激作用。本研究调查了用 calabadion-2 进行预处理是否足以防止在大鼠中通过初始剂量的甲基苯丙胺恢复药物寻求。

方法

雄性 Long-Evans 大鼠被训练自行静脉注射甲基苯丙胺（0.06 毫克/公斤/输注）。在稳定自我给药 10 天后，大鼠接受了灭绝训练，随后在多阶段恢复程序中进行了测试。药物引发的恢复会话（0.3 毫克/千克甲基苯丙胺，静脉注射）之前是生理盐水或 calabadion-2（130 毫克/千克）。在施用育亨宾 (1.0 mg/kg, iv) 后进行了额外的恢复试验，以确定 calabadion-2 的药理学特异性。

结果

用calabadion-2 预处理显着减弱了甲基苯丙胺诱导的响应恢复。Cal2 不影响由药理学压力源育亨宾刺激的寻药行为，表明对甲基苯丙胺具有特异性作用机制。

结论

这些结果证明了 calabadion-2 在临床前模型复发样行为中的有效性。通过进一步的结构优化，分子容器可以为甲基苯丙胺依赖者提供一种新的、有效的药代动力学方法来预防复发。