Novel DA D1 treatments for METH post-addiction therapy

描述(由申请人提供)：这项研究的总体目标是确定在临床前环境中可以迅速转化为甲基苯丙胺(冰毒)成瘾的停药后药物治疗的假定药物治疗。冰毒是一种越来越受欢迎的精神刺激药物，具有极高的滥用风险。目前，冰毒成瘾还没有治愈方法。事实上，接受现代戒毒治疗的绝大多数(高达85%)的患者又回到了强迫吸毒的状态。在大鼠中，反复注射冰毒会导致行为敏感化，伴随这一行为的大脑适应被认为模仿了冰毒成瘾者的行为。通过评估冰毒戒断后持续很长时间的过程，沃尔夫和纳皮尔的实验室已经确定了冰毒诱导的行为敏化后大脑发生的生化和电生理变化的模式。他们的初步数据还显示，戒断后给予DA D 1拮抗剂SCH 23390，逆转了冰毒建立的致敏行为。这些发现提出假设：1)DA_1功能增强有助于冰毒致敏化；2)DA_1拮抗剂或部分激动剂在致敏反应形成后给药可逆转行为敏化及其相关的神经适应性改变。对于目前的SBIR，我们建议评估具有不同药理特征的已知DA D1拮抗剂或部分激动剂逆转冰毒诱导的致敏作用的效果。这些药物是SCH 23390，结构相关的药物SCH 39166和结构无关的药物SKF 38393。具体目标1.利用后敏化测试范式，我们将复制我们与SCH 23390的先导性行为研究，并将确定SCH 39166和SKF 38393逆转冰毒诱导的行为敏化的能力。在冰毒致敏大鼠中，转录因子(激活的CREB和Delta Fos B)将在已知与成瘾行为有关的大脑区域中被确定。将确定目标1中确定的DA D 1选择剂逆转这些影响的能力。然后将评估那些在生物化学标记物中显示拮抗剂/部分激动剂诱导的冰毒诱导效应逆转的区域，以确定其逆转神经功能的电生理测量的能力。这一独特的敏化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。这些研究将有助于确定可以迅速转化为冰毒成瘾者抗成瘾药物的药物治疗。第二阶段SBIR的目标将是通过Solentix内部的药物发现努力，为冰毒成瘾治疗建立更多或新的候选药物。这项研究的结果将被用来探索其他滥用药物的额外生物筛查，并随后确定新的治疗方法。

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.