5-HT & Medication Development for Methamphetamine Abuse

描述（由申请人提供）：近年来，甲基苯丙胺（冰毒）的滥用呈惊人增长，甲基苯丙胺是一种强效精神运动兴奋剂，与药物戒断成瘾者的药物复发率高有关。到目前为止，还没有药物治疗可以有效地减少这种复发频率。这项拨款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人类冰毒成瘾者的戒断后药物治疗。反复、间歇性地暴露于滥用药物的动物会导致行为和神经生物学上的变化，这可能是导致人类药物复发的神经适应过程的模型。行为致敏是甲基苯丙胺和其他滥用药物的常见现象，其特征是在停药后持续数周至数月的运动行为持续增强。然而，甲基安非他明行为增敏方案对细胞信号传导和基因转录的影响尚未得到很好的研究。我们的初步数据表明：(1)对甲基苯丙胺致敏的大鼠表现出5-HT2A/2C受体介导的5-羟色胺信号传导上调，(2)戒断后给予5-HT2A/2C拮抗剂米安色林，可以消除甲基苯丙胺引起的致敏运动行为。这些发现指导了我们的假设：1)5-HT2A/2C功能的增加与meth诱导的行为致敏相似；2)5-HT2A/2C拮抗剂可以在致敏反应形成后给予拮抗剂，从而对抗行为致敏及其相关的神经适应性变化。Aim I的实验将建立一个甲基安非他明给药范例，该范例显示出持久的行为致敏（停药后持续60天），并将最小的神经毒性用于剩余的研究。Aim II将确定三种临床可用的非选择性5-HT2A/2C拮抗剂，米安色林，米氮平和酮色林对甲基苯丙胺诱导的行为致敏的能力。将确定在致敏后停药的早期和晚期使用拮抗剂的比较有效性。目的：研究5-羟色胺受体信号转导、基因转录（如cAMP反应元件结合蛋白磷酸化）和细胞生理（如微离子导入的体内电生理）与持续行为致敏相关的变化，以及停药后5-羟色胺拮抗剂治疗引起的行为致敏衰减。目的IV将确定新的5-HT2A或5-HT2C选择性拮抗剂对甲基苯丙胺诱导的行为和细胞致敏的有效性。这些研究将为开发药物提供新的和重要的临床前数据，以帮助戒断的冰毒成瘾者保持不吸毒。

DESCRIPTION (provided by applicant): Recent years have witnessed an alarming increase in the abuse of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict. To date, there is no pharmacotherapy that effectively reduces this relapse frequency. The Overall Objective of this grant is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for the human METH addict. Repeated, intermittent exposure of animals to drugs of abuse causes behavioral and neurobiological changes that may model the neuroadaptive processes that contribute to drug relapse in humans. Behavioral sensitization, characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse. However, the effects of a behaviorally sensitizing regimen of METH on cellular signaling and gene transcription have not been well studied. Our preliminary data demonstrate that (1) rats behaviorally sensitized to METH exhibit an upregulation of serotonin 5-HT2A/2C receptor -mediated signaling, and (2) post-withdrawal administration of the 5-HT2A/2C antagonist, mianserin, negates the sensitized motor behaviors established by METH. These findings direct our hypotheses that 1) increases in 5-HT2A/2C - function parallels METH-induced behavioral sensitization, and 2) 5-HT2A/2C antagonists can oppose behavioral sensitization and its associated neuroadaptive changes when the antagonists are administered after sensitized responding has developed. Experiments in Aim I will establish a METH dosing paradigm that exhibits an enduring behavioral sensitization (lasting 60 days after withdrawal) with a minimum of neurotoxicity to be used for the remaining studies. Aim II will determine the ability of three clinically available non-selective 5-HT2A/2C antagonists, mianserin, mirtazapine and ketanserin to negate METH-induced behavioral sensitization. The comparative effectiveness of antagonist administration at early and late stages of post-sensitization withdrawal will be ascertained. Aim Ill will establish, across time and brain region, changes in 5-HT receptor signaling, gene transcription (e.g., phosphorylated cAMP response element binding protein) and cellular physiology (e.g., in vivo electrophysiology with microiontophoresis) associated with persistent behavioral sensitization, and its attenuation as caused by post-withdrawal 5-HT antagonist treatments. Aim IV will ascertain the efficacy of newer, 5-HT2A or 5-HT2C -selective antagonists to negate METH-induced behavioral and cellular sensitization. These studies will provide new and important preclinical data for the development of medications targeted towards assisting the drug-withdrawn METH addict to stay drug free.