Kramer H K, Poblete J C, Azmitia E C
Department of Psychiatry, New York University Medical Center, Millhauser Labs, New York 10016, USA.
Neuropsychopharmacology. 1998 Oct;19(4):265-77. doi: 10.1016/S0893-133X(98)00027-X.
3, 4-methylenedioxymethamphetamine (MDMA or Ecstasy) is a substituted amphetamine whose acute and long-term effects on the serotonin system are dependent on an interaction with the 5-HT uptake transporter (SERT). Although much of the work dedicated to the study of this compound has focused on its ability to release monoamines, this drug has many important metabolic consequences on neurons and glial cells. The identification of these physiological responses will help to bridge the gap that exists in the information between the acute and neurotoxic effects of amphetamines. Substituted amphetamines have the ability to produce a long-term translocation of protein kinase C (PKC) in vivo, and this action may be crucial to the development of serotonergic neurotoxicity. Our earlier results suggested that PKC activation occurred through pre- and postsynaptic mechanisms. Because the primary site of action of these drugs is the 5-HT transporter, we now expand on our previous results and attempt to characterize MDMA's ability to translocate PKC within cortical 5-HT nerve terminals. In synaptosomes, MDMA produced a concentration-dependent increase in membrane-bound PKC (as measured by 3H-phorbol 12, 13 dibutyrate, 3H-PDBu) bindings sites. This response was abolished by cotreatment with the specific serotonin reuptake inhibitor (SSRI), fluoxetine, but not by the 5-HT2A/2C antagonist, ketanserin. In contrast, full agonists to 5-HT1A and 5-HT2 receptors did not produce significant PKC translocation. MDMA-mediated PKC translocation also requires the presence of extracellular calcium ions. Using assay conditions where extracellular calcium was absent prevented in vitro activation of PKC by MDMA. Prolonged PKC translocation has been hypothesized to contribute to the calcium-dependent neurotoxicity produced by substituted amphetamines. In addition, many physiological processes within 5-HT nerve terminals, including 5-HT reuptake and vesicular serotonin release, are susceptible to modification by PKC-dependent protein phosphorylation. Our results suggest that prolonged activation of PKC within the 5-HT nerve terminal may contribute to lasting changes in the homeostatic function of 5-HT neurons, leading to the degeneration of specific cellular elements after repeated MDMA exposure.
3,4-亚甲基二氧甲基苯丙胺（摇头丸）是一种取代苯丙胺，其对5-羟色胺系统的急性和长期影响取决于与5-羟色胺摄取转运体（SERT）的相互作用。尽管致力于该化合物研究的许多工作都集中在其释放单胺的能力上，但这种药物对神经元和神经胶质细胞有许多重要的代谢影响。识别这些生理反应将有助于弥合苯丙胺急性效应和神经毒性效应之间信息上的差距。取代苯丙胺能够在体内使蛋白激酶C（PKC）发生长期易位，这一作用可能对5-羟色胺能神经毒性的发展至关重要。我们早期的结果表明PKC激活是通过突触前和突触后机制发生的。由于这些药物的主要作用位点是5-羟色胺转运体，我们现在扩展我们之前的结果，并试图描述摇头丸在皮质5-羟色胺神经末梢内使PKC易位的能力。在突触体中，摇头丸使膜结合型PKC（通过3H-佛波醇12,13-二丁酸酯，3H-PDBu测量）结合位点呈浓度依赖性增加。与特异性5-羟色胺再摄取抑制剂（SSRI）氟西汀共同处理可消除这种反应，但5-HT2A/2C拮抗剂酮色林则不能。相比之下，5-HT1A和5-HT2受体的完全激动剂不会产生显著的PKC易位。摇头丸介导的PKC易位也需要细胞外钙离子的存在。在没有细胞外钙的检测条件下可阻止摇头丸在体外激活PKC。有人推测PKC的长期易位会导致取代苯丙胺产生钙依赖性神经毒性。此外，5-羟色胺神经末梢内的许多生理过程，包括5-羟色胺再摄取和囊泡5-羟色胺释放，都容易受到PKC依赖性蛋白磷酸化的影响。我们的结果表明，5-羟色胺神经末梢内PKC的长期激活可能导致5-羟色胺能神经元稳态功能的持久变化，导致反复接触摇头丸后特定细胞成分的退化。
