Dopamine D1-Like Receptor Agonist and D2-Like Receptor Antagonist (-)-Stepholidine Reduces Reinstatement of Drug-Seeking Behavior for 3,4-Methylenedioxypyrovalerone (MDPV) in Rats
Dopamine D1-Like Receptor Agonist and D2-Like Receptor Antagonist (-)-Stepholidine Reduces Reinstatement of Drug-Seeking Behavior for 3,4-Methylenedioxypyrovalerone (MDPV) in Rats
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DOI：
10.1021/acschemneuro.7b00510
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Liu-Chen, Lee-Yuan
中科院分区：
文献类型：
--
作者：
Hicks, Callum;Huang, Peng;Liu-Chen, Lee-Yuan
精神兴奋剂强化是通过刺激多巴胺（DA）D1样和D2样受体介导的，这表明具有双重DA受体机制的药物治疗剂可能有助于管理精神兴奋剂滥用。（-）-千金藤定（L-SPD）是一种具有D1样受体激动剂和D2样受体拮抗剂功能的中药提取物。L-SPD已被证明可以减弱海洛因的增强作用;然而，它对合成卡西酮3，4亚甲基二氧基吡咯戊酮（MDPV）的影响尚未被研究。目前的研究确定了L-SPD对静脉内自我给药（NSA）和条件性位置偏爱（CPP）范式中MDPV寻求行为恢复的影响。为了确定LSPD的影响是否是特定于精神兴奋剂强化，我们还研究了它对蔗糖寻求行为的影响。采用自发活动试验，我们测试了L-SPD的自发活动效果，以及其对MDPV诱导的活动过度的影响。一系列体外结合和功能测定的结果证实L-SPD具有D1样受体激动剂和D2样受体拮抗剂的功能。在行为实验中，L-SPD剂量依赖性地减弱了NSA模型中MDPV寻求行为的线索加上MDPV引发的恢复。最高剂量的L-SPD也减弱了MDPV引发的MDPV CPP恢复，以及线索诱导的蔗糖寻求恢复。L-SPD没有显著的运动效应，并且不调节MDPV诱导的强烈的多动。目前的研究结果首次显示，MDPV具有强大的恢复作用，L-SPD可以降低MDPV的恢复作用。这些结果确立了DA受体在MDPV的觅药行为中的作用。
Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (-)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-seeking behavior in the drug intravenous self-administration (NSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of LSPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-seeking behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPVinduced hyperactivity. The results of a battery of in vitro binding and functional assays confirmed that L-SPD functioned as a D1 like receptor agonist and D2-like receptor antagonist. In behavioral experiments, L-SPD dose-dependently attenuated cue plus MDPV-primed reinstatement of MDPV-seeking behavior in the NSA model. The highest dose of L-SPD also attenuated MDPVprimed reinstatement of MDPV CPP, as well as cue-induced reinstatement of sucrose-seeking. L-SPD had no significant locomotor effects, and did not modulate the robust hyperactivity induced by MDPV. The current findings show for the first time a robust reinstatement effect with MDPV, which can be reduced by L-SPD. These results establish a role for DA receptors in drug-seeking behavior for MDPV.