Mephedrone (4-methylmethcathinone (4-MMC)) (MEPH) is a new psychoactive substance (NPS) of the synthetic cathinone class. MEPH has a chiral center and exists as two enantiomers (R-,S-MEPH), yet stereospecific effects of MEPH have not been extensively investigated in preclinical assays. Because significant behavioral and neurochemical differences can exist between enantiomers, probing effects of stereochemistry on biological activity enables separation of adverse and therapeutic effects. Our prior work showed that R-MEPH, relative to S-MEPH, produced greater locomotor activation, place preference, and facilitation of brain reward thresholds in rodents. The present study sought to determine if MEPH enantiomers display stereospecific reward and reinforcement in rat self-administration assays. In Experiment 1, rats were trained to self-administer racemic MEPH (0.50 mg/kg/inf), and dose substitution effects of R-MEPH (0.50 mg/kg/inf) and S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) were examined. In Experiment 2, separate rats were trained to self-administer R-MEPH (0.25, 0.50, 2.00 mg/kg/inf) or S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) and were thereafter evaluated under progressive-ratio access conditions. Within this cohort, 50 kHz ultrasonic vocalizations (USVs) were recorded to measure potential differences in subjective positive affect associated with MEPH enantiomer self-administration. We identified enantiomer- and dose-dependent effects on infusions earned during self-administration following acquisition of racemic MEPH, with greatest infusions under low-effort, fixed-ratio 1 access conditions from low-dose S-MEPH self-administration. When taxed with progressive-ratio access conditions, rats trained to self-administer R-MEPH showed higher break points than those of rats trained to self-administer S-MEPH. Additionally, R-MEPH elicited greatest rates of 50 kHz USVs compared to S-MEPH. Taken together, these data suggest that the R-enantiomer of MEPH is primarily responsible for the rewarding, reinforcing, and motivational properties of racemic MEPH, which increases our understanding of stereospecific preferences pertaining to MEPH abuse.

中文翻译：

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自我给药大鼠中由卡西酮衍生的4-甲基甲卡西酮（甲氧麻黄酮）的强化和动机作用之间的立体选择性差异

甲氧麻黄酮（4-甲基甲卡西酮（4-MMC））（MEPH）是一种合成的卡西酮类的新型精神活性物质（NPS）。MEPH具有手性中心并以两种对映异构体（R-，S -MEPH）的形式存在，但尚未在临床前测定中广泛研究MEPH的立体特异性作用。因为对映异构体之间可能存在重大的行为和神经化学差异，所以立体化学对生物活性的探测作用可以分离不良作用和治疗作用。我们先前的工作表明，相对于S，R -MEPH-MEPH在啮齿动物中产生了更大的运动激活，位置偏爱和大脑奖励阈值的促进作用。本研究试图确定MEPH对映异构体在大鼠自我给药试验中是否显示立体特异性奖赏和增强作用。在实验1中，训练大鼠自我给予外消旋MEPH（0.50 mg / kg / inf）和R -MEPH（0.50 mg / kg / inf）和S -MEPH（0.25、0.50、2.00 mg / kg / inf）。在实验2中，训练了另一些大鼠自我给药R -MEPH（0.25、0.50、2.00 mg / kg / inf）或S-MEPH（0.25，0.50，2.00 mg / kg / inf），然后在渐进比进入条件下进行评估。在该队列中，记录了50 kHz超声发声（USV），以测量与MEPH对映体自我给药相关的主观积极影响中的潜在差异。我们确定了对映体和剂量依赖性效应对获得消旋MEPH后自我给药过程中获得的输注的影响，其中在低剂量，固定比率1的低剂量S -MEPH自我给药条件下，输注量最大。当以渐进比率进入条件征税时，训练为自我施用R -MEPH的大鼠显示出比接受自我管理S -MEPH的大鼠更高的断点。另外，R与S -MEPH相比，-MEPH引起的最大频率为50 kHz USV 。综上所述，这些数据表明，MEPH的R-对映异构体主要负责外消旋MEPH的奖励，增强和激励特性，这增加了我们对与MEPH滥用有关的立体定向偏好的理解。