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在临床前环境中确定可以快速转化为甲基苯丙胺（METH）成瘾戒断后药物治疗的假定药物治疗。甲基苯丙胺是一种越来越受欢迎的精神兴奋剂/致幻药物，具有极高的滥用倾向。目前，没有治愈METH成瘾的方法。事实上，绝大多数（高达85%）接受现代戒毒治疗的患者会重新陷入强迫性吸毒。在大鼠中，重复注射甲基苯丙胺会诱导行为敏感化，伴随这种行为的大脑适应被认为是模仿甲基苯丙胺成瘾者的行为。通过评估甲基苯丙胺戒断后持续很长时间的过程，沃尔夫和纳皮耶的实验室已经确定了甲基苯丙胺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。他们的初步数据还显示，停药后给予5-HT 2A/2C拮抗剂米安色林，逆转了METH建立的致敏行为。这些发现指导了以下假设：1）5-HT 2A/2C功能的增加有助于MET诱导的致敏; 2）当在致敏反应已经发展之后施用5-HT 2A/2C拮抗剂时，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，以评估已知的5-HT 2拮抗剂的疗效与不同的药理学概况，以扭转甲基苯丙胺诱导的敏化。这些药物是米安色林，结构上相关的药物，米氮平和结构上不相关的药物酮色林。提出了以下目标：具体目标一。使用致敏后试验范例，我们将重复米安色林的初步行为研究，并在大鼠中确定米氮平和酮色林逆转MET诱导的行为致敏的能力。这些将指导目标II中的实验。具体目标二。在MET致敏大鼠中，将在已知参与成瘾行为的脑区域中测定5-HT 2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-HT 2拮抗剂逆转这些效应的能力。然后评价那些在生化标志物中显示拮抗剂诱导的MET诱导效应逆转的区域逆转神经元功能的电生理学测量的能力。这种独特的致敏后测试范例将有助于揭示测试化合物用于预防复发的治疗潜力。这些研究也将有助于确定药物治疗，可以迅速转化为抗成瘾药物的甲基成瘾。第二阶段SBIR的目标是通过Solentix内部药物发现工作，为METH成瘾治疗建立额外或新型候选药物。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和随后的新疗法的鉴定。

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.