Novel DA D1 treatments for METH post-addiction therapy

用于冰毒成瘾后治疗的新型 DA D1 疗法

• 批准号: 6643144
• 负责人: CLARK E TEDFORD
• 金额: $ 10.88万
• 依托单位: SOLENTIX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643144
• 关键词: SDS polyacrylamide gel electrophoresis; behavior test; brain; dopamine; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug design /synthesis /production; drug screening /evaluation; drug withdrawal; electrophysiology; histochemistry /cytochemistry; laboratory rat; methamphetamine; transcription factor; western blottings

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.

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，该药物可以迅速转化为甲基苯丙胺（METH）成瘾后的Drawdrawal药物治疗。甲基苯丙胺是一种日益流行的精神刺激药，具有极高的虐待责任。目前，无法治愈甲基苯丙胺成瘾。的确，接受现代药物康复的患者中绝大多数（多达85％）重新恢复为强迫毒品服用。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，DA D1拮抗剂SCH 23390的挥发后给药逆转了甲基甲基甲基苯丙胺所建立的敏感行为。 这些发现指示了1）DA D1功能增加的假设有助于甲基甲基诱导的致敏，而2）DA D1拮抗剂或部分激动剂可以逆转行为敏感性及其相关的神经适应性变化，而当敏化反应后施用了药物时。对于当前的SBIR，我们构成了评估已知的DA D1拮抗剂或部分激动剂具有不同药理学特征以反向甲基甲基诱导的敏化的功效。这些药物是SCH 23390，与结构相关的药物SCH 39166和与结构无关的药物SKF 38393。提出了以下目的：具体目的I.使用敏感性后测试范例，我们使用SCH 23390的试验后行为研究将被复制，并将其重复稳定性恢复到39166和SKF 38333333333333333333393老鼠。 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转录因子（激活的Creb和Delta FOS B）。 将确定AIM 1中确定的DA D1选择性剂的能力扭转这些效果。 然后将评估那些显示出拮抗剂/部分激动剂诱导的甲基化学标记作用逆转的区域，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。这些研究将有助于确定可以迅速转化为甲基苯丙胺瘾君子的抗死药物的药物治疗。 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。