5-HT & Medication Development for Methamphetamine Abuse

5-羟色胺

基本信息

批准号：
7282521
负责人：
T. Celeste Napier
金额：
$ 33.14万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-28 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7282521
关键词：
Abstinence Agonist Animals Attenuated Behavior Behavioral Biochemical Brain Brain region CREB1 gene Cell physiology Class Cyclic AMP-Responsive DNA-Binding Protein Data Development Dopamine Dose Electrophysiology (science)End Point Exhibits Frequencies Genetic Transcription Grant HTR2A gene Human Incidence Ketanserin Ligands MDL 100907 Measures Mediating Methamphetamine Mianserin Mirtazapine Modeling Motor Neurobiology Neuronal Plasticity Neurons Pattern Personal Satisfaction Pharmaceutical Preparations Pharmacotherapy Phase Process Protocols documentation Psychological reinforcement Rat-1 Rattus Receptor Signaling Regulation Relapse Relative (related person)Research Personnel Rewards Serotonin Serotonin Antagonists Signal Transduction Staging Testing Therapeutic Thinking Time Toxic effect Translating Treatment Protocols Up-Regulation Week Withdrawal addiction attenuation behavioral sensitization cellular sensitization comparative effectiveness day design disorder later incidence prevention drug craving drug of abuse drug relapse in vivo indexing methamphetamine exposure neurotoxicity pre-clinical programs psychosocial receptor relating to nervous system research study response serotonin receptor transcription factor

项目摘要

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of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict.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characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse.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）滥用滥用，这是一种有效的精神运动刺激剂，这是与药物 - 毒品中瘾君子的高发病率相关的有效的刺激剂。迄今为止，还没有有效降低这种复发频率的药物疗法。该赠款的总体目的是在临床前的环境中识别推定的药物治疗，该药物可以迅速转化为人类甲基苯丙胺成瘾者的WithDrawal药物治疗。反复的，间歇性暴露于滥用药物中会导致行为和神经生物学变化，这些变化可能会模拟有助于人类药物复发的神经适应过程。行为敏化的特征是，在撤回药物后数周至数月的运动行为的持久增强是对甲基苯丙胺和其他滥用药物的共同点。然而，尚未对甲基苯丙胺行为敏化方案的影响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）在行为上对甲基的大鼠表现出5-羟色胺5-HT2A/2C受体介导的信号传导的上调，以及（2）（2）在滴加后给药的5-HT2A/2C拮抗剂Mianserin，Mianserin，Mianserin，否定了甲基甲基甲基甲基甲酸酯行为。这些发现指出了我们的假设，即1）在5-HT2A/2C的功能中增加了甲基甲基甲基甲基诱导的行为敏化，而2）5-HT2A/2C拮抗剂可以反对行为敏感性及其相关的神经适应性变化，而当拮抗剂响应后拮抗剂被施加了拮抗剂时。 AIM I将建立一种甲基剂量范式，表现出持久的行为敏化（戒断后60天），其神经毒性最少用于其余研究。 AIM II将确定三种临床可用的非选择性5-HT2A/2C拮抗剂，米亚梅林，米氮平和酮类蛋白否定甲基甲基甲基甲基苯酚诱导的行为敏化的能力。将确定拮抗剂在早期和晚期戒断的拮抗剂戒断的比较有效性。 AIM IL将在时间和大脑区域内建立5-HT受体信号，基因转录（例如，磷酸化的cAMP反应元件结合蛋白）和细胞生理学（例如，在体内电生理学与微动噬菌体）与持久的行为敏化相关，并通过持久的行为敏化以及其衰减为eTternation而引起的postentuniation and Wed-Wintawal Draws presention 5-Htrawal 5-HT-Htagonist。 AIM IV将确定较新的，5-HT2A或5-HT2C选择性拮抗剂的疗效，以消除甲基甲基苯酚诱导的行为和细胞敏化的功效。这些研究将为开发旨在协助毒品毒品成瘾者保持无药物的药物的开发提供新的重要临床前数据。