5-HT & Medication Development for Methamphetamine Abuse

5-羟色胺

• 批准号: 6684479
• 负责人: T. Celeste Napier
• 金额: $ 34.19万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-28 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684479
• 关键词: SDS polyacrylamide gel electrophoresis; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; biological signal transduction; drug abuse chemotherapy; drug addiction; drug screening /evaluation; drug withdrawal; electrophysiology; genetic transcription; laboratory rat; methamphetamine; neuropharmacology; neurotoxicology; neurotransmitter antagonist; serotonin; serotonin receptor; western blottings

DESCRIPTION (provided by applicant): Recent years have witnessed an alarming increase in the abuse of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict. To date, there is no pharmacotherapy that effectively reduces this relapse frequency. The Overall Objective of this grant is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for the human METH addict. Repeated, intermittent exposure of animals to drugs of abuse causes behavioral and neurobiological changes that may model the neuroadaptive processes that contribute to drug relapse in humans. Behavioral sensitization, characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse. However, the effects of a behaviorally sensitizing regimen of METH on cellular signaling and gene transcription have not been well studied. Our preliminary data demonstrate that (1) rats behaviorally sensitized to METH exhibit an upregulation of serotonin 5-HT2A/2C receptor -mediated signaling, and (2) post-withdrawal administration of the 5-HT2A/2C antagonist, mianserin, negates the sensitized motor behaviors established by METH. These findings direct our hypotheses that 1) increases in 5-HT2A/2C - function parallels METH-induced behavioral sensitization, and 2) 5-HT2A/2C antagonists can oppose behavioral sensitization and its associated neuroadaptive changes when the antagonists are administered after sensitized responding has developed. Experiments in Aim I will establish a METH dosing paradigm that exhibits an enduring behavioral sensitization (lasting 60 days after withdrawal) with a minimum of neurotoxicity to be used for the remaining studies. Aim II will determine the ability of three clinically available non-selective 5-HT2A/2C antagonists, mianserin, mirtazapine and ketanserin to negate METH-induced behavioral sensitization. The comparative effectiveness of antagonist administration at early and late stages of post-sensitization withdrawal will be ascertained. Aim Ill will establish, across time and brain region, changes in 5-HT receptor signaling, gene transcription (e.g., phosphorylated cAMP response element binding protein) and cellular physiology (e.g., in vivo electrophysiology with microiontophoresis) associated with persistent behavioral sensitization, and its attenuation as caused by post-withdrawal 5-HT antagonist treatments. Aim IV will ascertain the efficacy of newer, 5-HT2A or 5-HT2C -selective antagonists to negate METH-induced behavioral and cellular sensitization. These studies will provide new and important preclinical data for the development of medications targeted towards assisting the drug-withdrawn METH addict to stay drug free.

描述（由申请人提供）：近年来，甲基苯丙胺（METH）的滥用数量惊人地增加，甲基苯丙胺（METH）是一种强效精神运动兴奋剂，与戒毒成瘾者的高复发率相关。迄今为止，还没有药物疗法可以有效降低这种复发频率。这笔赠款的总体目标是确定临床前环境中的假定药物治疗，这些治疗可以迅速转化为人类冰毒成瘾者的戒断后药物治疗。动物反复、间歇性接触滥用药物会导致行为和神经生物学变化，这些变化可能会模拟导致人类药物复发的神经适应过程。行为敏化是冰毒和其他滥用药物的常见现象，其特点是运动行为持续增强，这种现象在停药后持续数周至数月。然而，METH 行为敏化方案对细胞信号传导和基因转录的影响尚未得到充分研究。我们的初步数据表明，(1) 对 METH 行为敏感的大鼠表现出血清素 5-HT2A/2C 受体介导的信号传导上调，(2) 停药后给予 5-HT2A/2C 拮抗剂米安色林，可消除 METH 建立的敏化运动行为。这些发现指导我们的假设：1）5-HT2A/2C 的增加 - 功能与 METH 诱导的行为敏化平行，2）当敏化反应出现后施用拮抗剂时，5-HT2A/2C 拮抗剂可以对抗行为敏化及其相关的神经适应性变化。 Aim I 中的实验将建立一种冰毒给药范例，该范例表现出持久的行为敏化（戒断后持续 60 天），且神经毒性最小，可用于其余研究。目标 II 将确定三种临床可用的非选择性 5-HT2A/2C 拮抗剂米安色林、米氮平和酮色林消除 METH 诱导的行为过敏的能力。将确定在致敏后戒断的早期和晚期阶段拮抗剂给药的相对有效性。 Aim Ill 将确定跨时间和大脑区域的 5-HT 受体信号传导、基因转录（例如，磷酸化 cAMP 反应元件结合蛋白）和细胞生理学（例如，微离子电渗疗法的体内电生理学）的变化，这些变化与持续的行为敏化及其由撤药后 5-HT 拮抗剂治疗引起的减弱有关。 Aim IV 将确定新型 5-HT2A 或 5-HT2C 选择性拮抗剂消除 METH 诱导的行为和细胞致敏作用的功效。这些研究将为开发旨在帮助戒毒的冰毒成瘾者摆脱毒品的药物开发提供新的重要临床前数据。