5-HT & Medication Development for Methamphetamine Abuse

5-羟色胺

• 批准号: 7348805
• 负责人: T. Celeste Napier
• 金额: $ 25.06万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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/7348805
• 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of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict.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characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse.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）的滥用出现了惊人的增长，甲基苯丙胺是一种强效精神兴奋剂，与戒毒成瘾者的药物复吸率高有关。到目前为止，还没有有效降低这种复发频率的药物治疗。该补助金的总体目标是在临床前环境中确定可以迅速转化为人类METH成瘾者戒断后药物治疗的假定药物治疗。反复、间歇性地将动物暴露于滥用药物会导致行为和神经生物学变化，这些变化可能模拟导致人类药物复发的神经适应过程。行为敏化，其特征是运动行为的持久增强，在药物停药后持续数周至数月，在METH和其他滥用药物中很常见。然而，METH的行为致敏方案对细胞信号传导和基因转录的影响尚未得到很好的研究。我们的初步数据表明：（1）对METH行为致敏的大鼠表现出血清素5-HT 2A/2C受体介导的信号传导的上调，和（2）戒断后给予5-HT 2A/2C拮抗剂米安色林，否定了由METH建立的致敏运动行为。这些发现指导了我们的假设：1）5-HT 2A/2C功能的增加与MET诱导的行为敏化平行，2）5-HT 2A/2C拮抗剂可以对抗行为敏化及其相关的神经适应性变化，当拮抗剂在敏化反应发生后给药时。目标I中的实验将建立一种METH给药模式，该模式表现出持久的行为致敏作用（停药后持续60天），神经毒性最小，可用于其余研究。目的II将确定三种临床上可用的非选择性5-HT 2A/2C拮抗剂米安色林、米氮平和酮色林否定MET诱导的行为敏化的能力。将确定致敏后戒断早期和晚期拮抗剂给药的比较有效性。目的III将建立跨时间和脑区域的5-HT受体信号传导、基因转录（例如，磷酸化cAMP应答元件结合蛋白）和细胞生理学（例如，体内电生理学与微离子电渗疗法）与持续行为敏化相关，以及其衰减由戒断后5-HT拮抗剂治疗引起。目的IV将确定新的5-HT 2A或5-HT 2C选择性拮抗剂的疗效，以否定甲基苯丙胺诱导的行为和细胞敏化。这些研究将提供新的和重要的临床前数据，用于开发药物，以帮助戒毒的METH成瘾者远离毒品。