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）：这项研究的总体目的是在临床前的环境中识别推定的药物治疗，这些药物可以迅速转化为甲基苯丙胺（METH）成瘾后的Drawdrdrawal药物治疗。甲基苯丙胺是一种越来越流行的精神刺激剂/致幻药，具有极高的滥用责任。目前，无法治愈甲基苯丙胺成瘾。的确，正在接受现代药物康复的患者中绝大多数（多达85％）重新恢复为强迫药物。在大鼠中，反复注射MET会引起行为敏化，并且伴随这种行为的大脑适应性被认为是模仿甲基苯丙胺成瘾者中发生的行为。通过评估在甲基苯丙胺提取后很长时间忍受的过程，沃尔夫和纳皮尔的实验室已经确定了在甲基苯甲酸甲酯诱导的行为敏化后，大脑中发生的生化和电生理变化的模式。他们的初步数据还表明，在5-HT2A/2C拮抗剂Mianserin的遗传后给药逆转了甲基甲基产生的敏感行为。这些发现指示了1）1）5-HT2A/2C功能的增加有助于甲基甲基诱导的敏化，而2）5-HT2A/2C拮抗剂可以逆转行为敏感性及其相关的神经适应性变化后，当拮抗剂被施用后施用后拮抗剂已发育后。对于当前的SBIR，我们构成了评估具有不同药理谱的已知5-HT2拮抗剂的功效，以反向甲基甲基化的敏化。这些药物是甲蛋白酶，结构相关的药物，米氮平和结构无关的药物酮酮。提出了以下目的：特定目标I使用敏感性测试范式，我们对米亚梅林的试验行为研究将被复制，并且在大鼠中将逆转甲氮平和酮酸甲氮平和酮类素的能力。这些将指导AIM II中的实验。具体目标II。在甲基敏化的大鼠中，将在已知与成瘾行为有关的大脑区域中确定5-HT2介导的转录因子（活化的Creb和Deltafos B）。将确定在AIM 1中鉴定出的5-HT2拮抗剂逆转这些影响的能力。然后，将评估那些显示拮抗剂引起的甲基化学标记中甲基甲基诱导作用逆转的区域，以评估其逆转神经元功能的电生理测量的能力。这种独特的敏感性测试范式将有助于揭示预防复发的测试化合物的治疗潜力。这些研究还将有助于确定可以快速转化为甲基苯丙胺瘾君子的抗瘾药物的药物治疗。 II期SBIR目标将是通过内部Solentix药物发现工作来建立其他或新颖的药物成瘾疗法。这项研究的结果将用于探索其他滥用药物的其他生物筛查，并随后鉴定出新的疗法。