Novel 5-HT treatments for METH post-addiction therapy

用于冰毒成瘾后治疗的新型 5-HT 疗法

基本信息

批准号：
6643227
负责人：
CLARK E TEDFORD
金额：
$ 10万
依托单位：
SOLENTIX BIOSCIENCES, INC.
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：
2003-05-01 至 2003-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6643227
关键词：
SDS polyacrylamide gel electrophoresis behavior test behavioral habituation /sensitization cAMP response element binding protein drug abuse chemotherapy drug addiction drug addiction antagonist electrophysiology fos protein histology ketanserin laboratory rat methamphetamine relapse /recurrence serotonin serotonin inhibitor technology /technique development western blottings

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this research is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for methamphetamine (METH) addiction. Methamphetamine is an increasingly popular psychostimulant/hallucinogenic drug with an extremely high abuse liability. Presently, there is no cure for METH addiction. Indeed, the overwhelming majority (up to 85%) of patients undergoing modern day drug rehabilitation relapse back into compulsive drug taking. In rats, repeated injections of METH induce behavioral sensitization, and the brain adaptations that accompany this behavior are thought to emulate those that occur in the METH addict. By evaluating processes that endure long after METH withdrawal, Wolf and Napier's laboratories have identified a pattern of biochemical and electrophysiological changes that occur in the brain following METH-induced behavioral sensitization. Their preliminary data also have revealed that post-withdrawal administration of the 5-HT2A/2C antagonist, mianserin, reversed the sensitized behaviors established by METH. These findings directed the hypotheses that 1) increases in 5-HT2A/2C function contribute to METH-induced sensitization, and 2) 5-HT2A/2C antagonists can reverse behavioral sensitization and its associated neuroadaptive changes when the antagonists are administered after sensitized responding has developed. For the present SBIR, we pose to evaluate the efficacy of known 5-HT2 antagonists with differing pharmacological profiles to reverse METH-induced sensitization. The drugs are mianserin, the structurally related drug, mirtazapine and the structurally un-related drug ketanserin. The following aims are proposed: Specific Aim I. Using a post-sensitization test paradigm, our pilot behavioral study with mianserin will be replicated and the ability mirtazapine and ketanserin to reverse METH-induced behavioral sensitization will be ascertained in rats. These will direct the experiments in Aim II. Specific Aim II. In METH-sensitized rats, 5-HT2-mediated transcription factors (activated CREB and deltaFos B) will be determined in brain regions known to be involved in addictive behaviors. The ability of the 5-HT2 antagonist identified in Aim 1 to reverse these effects will be ascertained. Those regions showing an antagonist-induced reversal of METH-induced effects in biochemical markers will then be evaluated for its ability to reverse electrophysiological measures of neuronal function. This distinctive post-sensitization test paradigm will help reveal the therapeutic potential of test compounds for relapse prevention. These studies also will help identify drug treatment that can be rapidly translated into anti-addiction medication for the METH addict. The phase II SBIR goals will be to establish additional or novel drug candidates for METH addiction therapy through internal Solentix drug discovery efforts. The results of this research will be utilized to explore additional biological screens for other drugs of abuse and subsequent identification of novel therapies.

描述（由申请人提供）：本研究的总体目标是确定临床前环境中的假定药物治疗，这些治疗可以快速转化为甲基苯丙胺（METH）成瘾的戒断后药物治疗。甲基苯丙胺是一种日益流行的精神兴奋剂/致幻药物，具有极高的滥用可能性。目前，冰毒成瘾无法治愈。事实上，绝大多数（高达 85%）接受现代戒毒康复的患者会再次陷入强迫性吸毒状态。在老鼠身上，重复注射冰毒会引起行为过敏，而伴随这种行为的大脑适应被认为与冰毒成瘾者身上发生的情况相似。通过评估冰毒戒断后长期持续的过程，沃尔夫和纳皮尔的实验室已经确定了冰毒引起的行为敏化后大脑中发生的生化和电生理变化模式。他们的初步数据还显示，停药后给予 5-HT2A/2C 拮抗剂米安色林，可逆转 METH 建立的致敏行为。这些发现提出了以下假设：1) 5-HT2A/2C 功能的增加有助于 METH 诱导的敏化，2) 当敏化反应发生后施用拮抗剂时，5-HT2A/2C 拮抗剂可以逆转行为敏化及其相关的神经适应性变化。发达。对于目前的 SBIR，我们评估了具有不同药理学特征的已知 5-HT2 拮抗剂逆转 METH 诱导的致敏作用的功效。这些药物是米安色林、结构相关的药物米氮平和结构不相关的药物酮色林。提出以下目标：具体目标 I. 使用致敏后测试范例，我们将复制米安色林的试点行为研究，并在大鼠中确定米氮平和酮色林逆转冰毒诱导的行为致敏的能力。这些将指导 Aim II 中的实验。具体目标二。在 METH 致敏的大鼠中，将在已知参与成瘾行为的大脑区域中测定 5-HT2 介导的转录因子（激活的 CREB 和 deltaFos B）。将确定目标 1 中确定的 5-HT2 拮抗剂逆转这些影响的能力。然后，将评估那些在生化标志物中表现出拮抗剂诱导的 METH 诱导效应逆转的区域逆转神经元功能电生理测量的能力。这种独特的致敏后测试范例将有助于揭示测试化合物预防复发的治疗潜力。这些研究还将有助于确定可以快速转化为冰毒成瘾者的抗成瘾药物的药物治疗。 II 期 SBIR 的目标是通过内部 Solentix 药物发现工作，为冰毒成瘾治疗建立更多或新颖的候选药物。这项研究的结果将用于探索其他滥用药物的额外生物筛选以及随后新疗法的鉴定。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mirtazapine treatment after conditioning with methamphetamine alters subsequent expression of place preference.

用甲基苯丙胺调节后的米氮平治疗改变了随后的位置偏好表达。

DOI：
发表时间：
2009-01-01
期刊：
影响因子：
4.2
作者：
Herrold, Amy A;Shen, Fei;Graham, Martin P;Harper, Laura K;Specio, Sheila E;Tedford, Clark E;Napier, T Celeste
通讯作者：
Napier, T Celeste

Mirtazapine alters cue-associated methamphetamine seeking in rats.

米氮平改变大鼠中与线索相关的甲基苯丙胺寻找。