Novel 5-HT treatments for METH post-addiction therapy

描述（由申请人提供）：本研究的总体目标是确定临床前假定的药物治疗方法，这些药物治疗方法可以迅速转化为戒断后的药物治疗，以治疗甲基苯丙胺（冰毒）成瘾。甲基苯丙胺是一种日益流行的精神兴奋剂/致幻药物，具有极高的滥用风险。目前，还没有治愈冰毒成瘾的方法。事实上，绝大多数（高达85%）接受现代药物康复治疗的患者又重新开始强迫性服药。在大鼠中，反复注射冰毒会引起行为敏感，而伴随这种行为的大脑适应被认为是模仿冰毒成瘾者的行为。通过评估戒断冰毒后持续很长时间的过程，Wolf和Napier的实验室已经确定了在冰毒诱导的行为致敏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，逆转了由冰毒建立的致敏行为。这些发现指导了以下假设：1)5-HT2A/2C功能的增加有助于甲基甲醚诱导的致敏；2)在致敏反应形成后使用5-HT2A/2C拮抗剂可以逆转行为致敏及其相关的神经适应性变化。对于目前的SBIR，我们提出评估具有不同药理特征的已知5-HT2拮抗剂对逆转甲基苯丙胺诱导的致敏的功效。这些药物是结构相关药物米安色林，结构相关药物米氮平和结构不相关药物酮色林。1 .使用致敏后试验范式，我们的米安色林试点行为研究将被复制，米氮平和酮色林逆转甲基苯丙胺诱导的大鼠行为致敏的能力将被确定。这些将指导Aim II的实验。具体目标二。在冰毒致敏的大鼠中，5- ht2介导的转录因子（激活的CREB和delta afos B）将在已知参与成瘾行为的大脑区域中确定。在Aim 1中鉴定的5-HT2拮抗剂逆转这些效应的能力将被确定。那些在生化标记中显示出拮抗剂诱导的甲基安非他明诱导效应逆转的区域将被评估其逆转神经元功能电生理测量的能力。这种独特的敏化后测试模式将有助于揭示测试化合物预防复发的治疗潜力。这些研究也将有助于确定药物治疗，可以迅速转化为对冰毒成瘾者的抗成瘾药物。II期SBIR的目标将是通过内部Solentix药物发现工作，建立新的或新的药物候选物，用于冰毒成瘾治疗。这项研究的结果将用于探索其他药物滥用的其他生物筛选和随后的新疗法的确定。

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.