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）：本研究的总体目标是确定临床前环境中的假定药物治疗，该治疗可以快速转化为甲基苯丙胺（METH）成瘾的戒断后药物治疗。冰毒是一种越来越流行的精神兴奋药物，具有极高的滥用可能性。目前，冰毒成瘾无法治愈。事实上，绝大多数（高达 85%）接受现代戒毒康复的患者都会再次陷入强迫性吸毒状态。在老鼠身上，重复注射冰毒会引起行为过敏，而伴随这种行为的大脑适应被认为与冰毒成瘾者身上发生的情况相似。通过评估冰毒戒断后长期持续的过程，沃尔夫和纳皮尔的实验室已经确定了冰毒引起的行为敏化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 DA D1 拮抗剂 SCH 23390，可以逆转 METH 建立的致敏行为。 这些发现提出了以下假设：1) DA D1 功能的增加有助于 METH 诱导的致敏，2) 当在致敏反应出现后施用药物时，DA D1 拮抗剂或部分激动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，我们评估已知的 DA D1 拮抗剂或具有不同药理学特征的部分激动剂逆转 METH 诱导的致敏作用的功效。这些药物是 SCH 23390、结构相关的药物 SCH 39166 和结构不相关的药物 SKF 38393。提出了以下目标： 具体目标 I. 使用致敏后测试范例，我们将重复 SCH 23390 的试点行为研究，并且SCH 39166 和 SKF 38393 逆转 METH 诱导的行为过敏的能力将在大鼠中确定。 这些将指导 Aim II 中的实验。 具体目标二．在 METH 致敏的大鼠中，已知参与成瘾行为的大脑区域中的转录因子（激活的 CREB ​​和 delta Fos B）将被确定。 将确定目标 1 中确定的 DA D1 选择剂逆转这些影响的能力。 然后，将评估那些在生化标志物中表现出拮抗剂/部分激动剂诱导的 METH 诱导效应逆转的区域逆转神经元功能电生理测量的能力。这种独特的致敏后测试范例将有助于揭示测试化合物预防复发的治疗潜力。这些研究将有助于确定可以快速转化为冰毒成瘾者抗成瘾药物的药物治疗方法。 II 期 SBIR 的目标是通过内部 Solentix 药物发现工作，为冰毒成瘾治疗建立更多或新颖的候选药物。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以及随后新疗法的鉴定。