5-HT & Medication Development for Methamphetamine Abuse

描述(申请人提供)：近年来，甲基苯丙胺(冰毒)的滥用数量惊人地增加，这是一种强有力的精神运动兴奋剂，与戒毒成瘾者的高复吸率有关。到目前为止，还没有有效降低这种复发频率的药物疗法。这笔赠款的总体目标是确定在临床前环境中可以迅速转化为人类冰毒成瘾者停药后药物治疗的假定药物治疗。反复、间歇性地让动物接触滥用药物会导致行为和神经生物学变化，这些变化可能会模拟导致人类药物复发的神经适应过程。行为敏感化是冰毒和其他滥用药物的常见现象，其特征是运动行为的持久增强，并在停药后持续数周至数月。然而，冰毒的行为增敏疗法对细胞信号和基因转录的影响还没有得到很好的研究。我们的初步数据表明，(1)行为致敏的冰毒大鼠表现出5-HT2A/2C受体介导的信号上调，以及(2)戒断后给予5-HT2A/2C拮抗剂米安色林，可逆转冰毒所建立的致敏运动行为。这些发现指导了我们的假设：1)5-HT2A/2C功能的增加与冰毒诱导的行为敏化相似，2)5-HT2A/2C拮抗剂在敏化反应形成后给予5-HT2A/2C拮抗剂可以对抗行为敏化及其相关的神经适应性变化。AIM I的实验将建立一种冰毒剂量范例，该范例显示出持久的行为敏化(在戒断后持续60天)，并将神经毒性降至最低，用于剩余的研究。目的研究3种临床可用的非选择性5-HT2A/2C拮抗剂米安色林、米氮平和酮色林对冰毒诱导的行为敏化的拮抗作用。将确定在敏化后戒断的早期和后期给予拮抗剂的比较效果。目的建立持续行为敏化相关的5-羟色胺受体信号转导、基因转录(如磷酸化cAMP反应元件结合蛋白)和细胞生理学(如微离子导入体内电生理学)的变化，以及停用5-羟色胺拮抗剂引起的5-羟色胺受体信号和基因转录的变化。目的研究新型5-羟色胺2A或5-羟色胺2C选择性拮抗剂对冰毒诱导的行为和细胞敏化的影响。这些研究将提供新的和重要的临床前数据，以开发有针对性的药物，以帮助戒毒的冰毒成瘾者保持戒毒。

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of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict.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characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse.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.