STIMULANT ABUSE BEHAVIOR AND PHARMACOKINETICS

本研究旨在研究两种操作性[（例如，DRL时间表，静脉内自我给药（S-A）]和无条件行为（例如，自发活动），以研究可卡因和d-甲基苯丙胺（d-MA）药代动力学（PK）对它们各自药效学（PD）的影响。 尽管这两种兴奋剂表现出相似的药理学作用和滥用倾向，但它们在PK特征上明显不同;可卡因是短效的，而d-MA是长效的。 PK/PD建模方法将用于描述和预测两种兴奋剂的药理学反应的时间过程，以研究PK是否在药物成瘾和依赖中起关键作用。 低速率和高速率操作性行为（模拟人类中常见的两种活动水平）将用于确定任何观察到的浓度-效应关系是否可推广至广泛的行为模式。 PK和PD的整合允许将应答划分为PK和PD组分，并预测新出现的PD事件的时程，例如，致敏/耐受（S/T）的发展。 用植入双导管（颈静脉和股动脉）的大鼠进行的实验将确定使用各种剂量方案（例如，急性、反复、暴饮暴食、剂量递增-暴饮暴食模式）。 在明确定义的PK条件下，在各种稳态可卡因或d-MA浓度（CSS）下，可通过PD模型轻松定量表征S/T发展的时间过程。此外，还将研究药物浓度升高至CSS水平的速率对S/T发展速率和程度的影响。 S/T被认为是药物成瘾行为模型的重要组成部分。 关键时间点的识别对于研究S/T的潜在机制至关重要，不仅可以导致药物成瘾的合理药物治疗的发展，而且可以在脆弱阶段实施干预。研究还将关注PK因素（例如，可卡因蛋白结合部分）在食物限制方案下影响增强的静脉内药物S-A，这反过来可以识别产生成瘾易感性的因素。 众所周知，咖啡因可以增强可卡因的强化作用和其他作用。在推断其他PD机制之前，将研究PK的作用，以探索急性和慢性给药方案下咖啡因和可卡因之间相互作用的机制。

This research aims to examine both operant [(e.g., DRL schedule, i.v. self-administration (S-A)] and unconditioned behaviors (e.g., locomotor activity) to study the consequences of cocaine and d-methamphetamine (d-MA) pharmacokinetics (PK) on their respective pharmacodynamics (PD). Although the two stimulants exhibit similar pharmacological effects and abuse liability, they differ distinctly in PK profiles; cocaine is short acting and d- MA is long acting. The PK/PD modeling approach will be used to describe and predict the time course of the pharmacological response for the two stimulants to investigate whether PK play a key role in drug addiction and dependence. Both low- and high- rate operant behaviors, which model two activity levels routinely seen in humans, will be used to determine whether any observed concentration-effect relation is generalizable to a wide range of behavior patterns. The integration of PK and PD allows partitioning of the response into PK and PD components and the prediction of the time course of an emerging PD event, e.g., the development of sensitization/tolerance (S/T). Experiments with rats implanted with dual catheters (jugular vein and femoral artery) will determine the concentration-effect relations after constant-rate i.v. infusion using various dose regimens (e.g., acute, repeated, binge, escalating dose-binge pattern). The time course of S/T development can be readily characterized quantitatively by PD model(s) under various steady-state cocaine or d-MA concentrations (CSS) in well-defined PK conditions. Furthermore, the effects of rate of rise in drug concentration to a CSS level on the rate and extent of S/T development will be investigated. S/T is considered an important component in the behavioral model of drug addiction. The identification of critical time points is crucial for the investigation of the underlying mechanism(s) of S/T and may lead not only to the development of rational pharmacotherapies for drug addiction but also to the implementation of intervention at a vulnerable stage. Studies will also focus on whether and how PK factors (e.g., fraction of cocaine protein binding) effect the enhanced i.v. drug S-A under a food-limited regimen, which in turn may identify factors that produce vulnerability to addiction. Caffeine is known to potentiate the reinforcing and other effects of cocaine. The role of PK will be investigated to explore the mechanism of the interaction between caffeine and cocaine under acute- and chronic-dose regimens before other PD mechanism(s) are inferred.