对比新型多巴胺转运抑制剂 JJC8-088 和 JJC8-091 对猴子的强化作用:药物辅助治疗的潜在转化。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Mia I Allen, Omeed Rahimi, Bernard N Johnson, Jianjing Cao, Amy Hauck Newman, Michael A Nader
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引用次数: 0

摘要

尽管付出了巨大努力,但美国食品及药物管理局(FDA)仍未批准治疗可卡因使用障碍(CUD)的药物。缓解可卡因渴求和复吸的一种策略是提高多巴胺(DA)。DA转运抑制剂和释放剂d-苯丙胺已被证明可以减少可卡因自我给药,但它也有滥用的风险。最近,几种莫达非尼类似物减少了大鼠和猴子的可卡因自吸,其中包括在大鼠中被描述为 "类似可卡因 "的 JJC8-088,以及在大鼠中被描述为 "非典型 "且不自吸的 JJC8-091。本研究评估了这两种化合物在几种条件下对猴子的强化作用。在实验 1 中,四只有可卡因经验的雄性恒河猴在累进比率(PR)强化计划下自我注射了可卡因(0.001-0.3 毫克/千克/注射)、JJC8-088(0.001-0.3 毫克/千克/注射)和 JJC8-091(0.1-3.0 毫克/千克/注射)。这两种JJC化合物作为强化剂的强化强度与可卡因相当。虽然JJC8-091的效力低于可卡因,但JJC8-088和可卡因的效力相似。在实验 2 中,一只雄性和两只雌性对药物不敏感的犬科猴按照固定比例的食物强化时间表做出反应。三只猴子自我给药 JJC8-091 的比率均高于生理盐水。在实验 3 中,实验 2 中的猴子在同时进行的药物与食物选择范式下做出反应,并在这些条件下获得可卡因或 JJC8-091 。在剂量等于或高于实验 2 所用剂量对数单位的情况下,猴子选择可卡因而不是 JJC8-091 而不是食物。总之,这些结果表明,虽然 JJC8-091 在某些条件下可能具有强化作用,但在有替代强化物的情况下,其强化强度大大低于可卡因。意义声明 JJC8-088 和 JJC8-091 在减少大鼠和非人灵长类动物的可卡因自我给药方面具有疗效。这项研究发现,这两种化合物都能维持猴子在多种条件下的自我给药反应。这表明,JJC8-091 可能是一种可行的 CUD 候选药物,因为在人类群体中,吸毒的替代品通常是存在的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Contrasting the Reinforcing Effects of the Novel Dopamine Transport Inhibitors JJC8-088 and JJC8-091 in Monkeys: Potential Translation to Medication Assisted Treatment.

Despite considerable efforts, there remains no FDA-approved medications for cocaine use disorder (CUD). One strategy to mitigate cocaine craving and relapse is to elevate dopamine (DA). The DA transport inhibitor and releaser d-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogues reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as "cocaine like" in rats, and JJC8-091, characterized as "atypical" and not SA by rats. The present studies evaluated the reinforcing effects of both compounds in monkeys under several conditions. For Experiment 1, four male cocaine-experienced rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection), JJC8-088 (0.001-0.3 mg/kg/injection), and JJC8-091 (0.1-3.0 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For Experiment 2, one male and two females drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all three monkeys. In Experiment 3, monkeys from Experiment 2 responded under a concurrent drug vs. food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in Experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that while JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance Statement JJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration in rats and in nonhuman primates. This study found that both compounds maintained self-administration in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the self-administration session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may be a viable candidate for CUD since, in the human population, alternatives to drug use are often available.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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