School of Dentistry (C.P.M., C.L.G., Y.H.S., P.S.C., G.R.H., A.E.F.), Interdepartmental Program in Neuroscience (C.P.M., C.L.G., G.R.H., A.E.F.), Center for Human Toxicology (D.J.A., D.G.W.), and Department of Pathology (D.G.W.), University of Utah, Salt Lake City, Utah.
School of Dentistry (C.P.M., C.L.G., Y.H.S., P.S.C., G.R.H., A.E.F.), Interdepartmental Program in Neuroscience (C.P.M., C.L.G., G.R.H., A.E.F.), Center for Human Toxicology (D.J.A., D.G.W.), and Department of Pathology (D.G.W.), University of Utah, Salt Lake City, Utah
J Pharmacol Exp Ther. 2020 Aug;374(2):273-282. doi: 10.1124/jpet.119.264895. Epub 2020 May 8.
Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are key regulators of both the abuse and neurotoxic potential of structurally and behaviorally related agents, the impact of MDPV on these transporters was investigated. Results revealed that a single in vivo MDPV administration rapidly (within 1 hour) and reversibly increased both rat striatal DAT and VMAT-2 activity, as assessed via [H]DA uptake in synaptosomes and synaptic vesicles, respectively, prepared from treated rats. There was no evidence of an MDPV-induced increase in plasmalemmal membrane DAT surface expression. Plasma concentrations of MDPV increased dose-dependently as assessed 1 hour after 2.5 and 5.0 mg/kg (s.c.) administration and returned to levels less than 10 ng/ml by 18 hours after 2.5 mg/kg (s.c.). Neither pretreatment with a D1 receptor (SCH23390), a D2 receptor (eticlopride), nor a nicotinic receptor (mecamylamine) antagonist attenuated the MDPV-induced increase in DAT activity. In contrast, eticlopride pretreatment attenuated both the MDPV-induced increase in VMAT-2-mediated DA uptake and an associated increase in cytoplasmic-associated vesicle VMAT-2 immunoreactivity. SCH23390 did not attenuate the MDPV-induced increase in VMAT-2 activity. Repeated MDPV injections did not cause persistent DAergic deficits, as assessed 7 to 8 days later. The impact of MDPV on striatal and hippocampal serotonergic assessments was minimal. Taken together, these data contribute to a growing pharmacological rubric for evaluating the ever-growing list of designer cathinone-related stimulants. The profile of MDPV compared with related psychostimulants is discussed. SIGNIFICANCE STATEMENT: Pharmacological characterization of the synthetic cathinone, 3,4-methylenedioxypyrovalerone (MDPV; commonly referred to as a "bath salt"), is critical for understanding the abuse liability and neurotoxic potential of this and related agents. Accordingly, the impact of MDPV on monoaminergic neurons is described and compared with that of related psychostimulants.
3,4-亚甲二氧基吡咯戊酮（MDPV）是一种滥用的合成苯丙胺，通常被称为“浴盐”。由于多巴胺（DA）转运体（DAT）和囊泡单胺转运体-2（VMAT-2）是结构和行为相关药物滥用和神经毒性潜力的关键调节剂，因此研究了 MDPV 对这些转运体的影响。结果表明，单次体内 MDPV 给药可迅速（1 小时内）和可逆地增加大鼠纹状体 DAT 和 VMAT-2 活性，分别通过用来自处理过的大鼠的突触体和突触小泡制备的[H]DA 摄取来评估。没有证据表明 MDPV 诱导的质膜 DAT 表面表达增加。通过在 2.5 和 5.0mg/kg（sc）给药后 1 小时评估，MDPV 的血浆浓度呈剂量依赖性增加，并且在 2.5mg/kg（sc）给药后 18 小时降至低于 10ng/ml 的水平。D1 受体（SCH23390）、D2 受体（eticlopride）或烟碱受体（mecamylamine）拮抗剂预处理均不能减轻 MDPV 诱导的 DAT 活性增加。相比之下，eticlopride 预处理可减轻 MDPV 诱导的 VMAT-2 介导的 DA 摄取增加以及相关的细胞质相关囊泡 VMAT-2 免疫反应性增加。SCH23390 不能减轻 MDPV 诱导的 VMAT-2 活性增加。7 至 8 天后再次 MDPV 注射不会引起持续的多巴胺能缺陷。MDPV 对纹状体和海马 5-羟色胺能评估的影响最小。总之，这些数据为评估不断增长的设计师苯丙胺相关兴奋剂的列表提供了越来越多的药理学依据。讨论了 MDPV 与相关精神兴奋剂的比较概况。
