The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter
The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter
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DOI：
10.1038/s41386-018-0209-3
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发表时间：
2018-11-01
影响因子：
7.6
通讯作者：
Collins, Gregory T.
中科院分区：
文献类型：
--
作者：
Gannon, Brenda M.;Baumann, Michael H.;Collins, Gregory T.
合成卡西酮是滥用“浴盐”制剂的常见成分，代表一大类结构相关的化合物，可作为可卡因样抑制剂或多巴胺 (DAT)、去甲肾上腺素 (NET) 和血清素 (SERT) 转运蛋白的苯丙胺样底物。临床前证据表明，某些卡西酮（例如 MDPV 和 α-PVP）是比典型的滥用兴奋剂药物（例如可卡因或甲基苯丙胺）更有效的强化剂。尽管这些卡西酮的增强效力与其抑制 DAT 的效力有关，但对其异常高增强效力的药理学决定因素知之甚少。为此，我们测试了这样的假设：卡西酮兴奋剂的增强效果与其相对于 SERT 对 DAT 的选择性呈正相关。大鼠脑突触体的摄取抑制测定用于直接比较 MDPV、MDPBP、MDPPP、α-PVP、α-PPP 和可卡因在 DAT、NET 和 SERT 时的效力，而大鼠静脉自我给药则用于使用渐进比率 (PR) 和行为经济程序来量化药物的相对增强效果。所有卡西酮在 DAT 上均比 NET 或 SERT 更有效，DAT 相对于 SERT 的选择性排序为 α-PVP > α-PPP > MDPV > MDPBP > MDPPP > 可卡因。这些合成卡西酮是比可卡因更有效的强化剂，并且通过 PR 和需求曲线分析确定的强化有效性测量与 DAT 对 SERT 的选择性高度相关。总之，这些研究提供了强有力且一致的证据，表明兴奋剂药物的滥用潜力是由 DAT 的摄取抑制介导的，而 SERT 的活性充当增强有效性的负调节剂。
Synthetic cathinones are common constituents of abused "bath salts" preparations and represent a large family of structurally related compounds that function as cocaine-like inhibitors or amphetamine-like substrates of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters. Preclinical evidence suggests that some cathinones (e.g., MDPV and alpha-PVP) are more effective reinforcers than prototypical stimulant drugs of abuse, such as cocaine or methamphetamine. Although the reinforcing potency of these cathinones is related to their potency to inhibit DAT, less is known about the pharmacological determinants of their unusually high reinforcing effectiveness. To this end, we tested the hypothesis that reinforcing effectiveness of cathinone stimulants is positively correlated with their selectivity for DAT relative to SERT. Uptake inhibition assays in rat brain synaptosomes were used to directly compare the potency of MDPV, MDPBP, MDPPP, alpha-PVP, alpha-PPP, and cocaine at DAT, NET, and SERT, whereas intravenous self-administration in rats was used to quantify relative reinforcing effectiveness of the drugs using progressive ratio (PR) and behavioral economic procedures. All cathinones were more potent at DAT than NET or SERT, with a rank order for selectivity at DAT over SERT of alpha-PVP > alpha-PPP > MDPV > MDPBP > MDPPP > cocaine. These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT. Together, these studies provide strong and convergent evidence that the abuse potential of stimulant drugs is mediated by uptake inhibition at DAT, with activity at SERT serving as a negative modulator of reinforcing effectiveness.