Novel DA D1 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对甲基苯丙胺（冰毒）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，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，戒断后给予DA D1拮抗剂SCH 23390，逆转了甲基安非他明建立的致敏行为。这些发现为以下假设提供了依据：1)DA D1功能的增加有助于甲基甲醚诱导的致敏；2)DA D1拮抗剂或部分激动剂在致敏反应形成后使用，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，我们提出评估已知的具有不同药理学特征的DA D1拮抗剂或部分激动剂对逆转冰毒诱导的致敏的功效。药物为SCH 23390、结构相关药物SCH 39166和结构无关药物SKF 38393。1 .使用致敏后试验范式，我们将重复使用SCH 23390进行的实验性行为研究，并在大鼠中确定SCH 39166和SKF 38393逆转冰毒诱导的行为致敏的能力。这些将指导Aim II的实验。具体目标二。在冰毒致敏的大鼠中，转录因子（激活的CREB和δ Fos B）将在已知参与成瘾行为的大脑区域中确定。在Aim 1中确定的DA D1选择性药物逆转这些效应的能力将被确定。在生化标记中显示拮抗剂/部分激动剂诱导的逆转甲基苯丙胺诱导效应的那些区域，然后将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。这些研究将有助于确定药物治疗方法，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 a post-withdrawal pharmacotherapy for methamphetamine (METH) addiction. METH is an increasingly popular psychostimulant drug with an extremely high abuse liability. Presently, there is no cure for METH addiction. Indeed, the overwhelming majority (up to 85 percent) 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 DA D1 antagonist, SCH 23390, reversed the sensitized behaviors established by METH. These findings directed the hypotheses that 1) increases in DA D1 function contribute to METH-induced sensitization, and 2) DA D1 antagonists or partial agonists can reverse behavioral sensitization and its associated neuroadaptive changes when the agents are administered after sensitized responding has developed. For the present SBIR, we pose to evaluate the efficacy of known DA D1 antagonists or partial agonists with differing pharmacological profiles to reverse METH-induced sensitization. The drugs are SCH 23390, the structurally related drug SCH 39166 and the structurally unrelated drug SKF 38393. The following aims are proposed: Specific Aim I. Using a post-sensitization test paradigm, our pilot behavioral study with SCH 23390 will be replicated and the ability of SCH 39166 and SKF 38393 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, transcription factors (activated CREB and delta Fos B) will be determined in brain regions known to be involved in addictive behaviors. The ability of the DA D1 selective agents identified in Aim 1 to reverse these effects will be ascertained. Those regions showing an antagonist/partial agonist-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 will help identify drug treatments 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.