NEUROBEHAVIORAL MECHANISMS OF DRUG ADDICTION

描述：(申请人摘要) 这项研究的长期目标是了解神经行为 毒品成瘾责任的决定机制及其合理性 开发药物治疗将作用于这些机制，以减少 或者消除上瘾的行为。这个实验室最近的研究已经 侧重于牛至生物碱(如牛至因)的神经药理学和 同系物(如18-甲氧基冠醚)及其与阿片类药物的相互作用 以及滥用兴奋剂的问题。该方法使用RAT并涉及到 静脉给药的自我给药及药效测定 大脑化学反应。体内微渗析与高效液相(高性能 高效液相色谱法)被用来检测细胞外生物来源的水平 离散脑中的胺(多巴胺、5-羟色胺)及其代谢物 地区。具体目标包括以下几个方面：(1)伊波甘的作用， 其代谢物Noribogaine和两个iboga生物碱同系物 [18-甲氧基冠醚和18-(N，N-二甲氨基乙基)冠醚] 将继续调查吗啡和可卡因的自我给药情况； 应该有可能开发出效力至少与 Ibogaine抑制药物自我给药，但更安全；iboga 代理商将根据获得的药物和正在进行的药物使用率进行评估 两种复吸模型和一种新口腔模型中的自我给药行为 尼古丁偏好模型。(2)可能的神经化学机制 同样的四种IBOGA制剂的假定的抗成瘾作用将 被研究。体内微渗析将被用来表征 IBOGA药物的神经化学作用及其受体机制的研究 也将在大鼠身上进行微透析 自我注射吗啡或可卡因与神经化学物质相关 以及特定治疗的行为影响。它被假设为 这些药物的独特药理作用来自于 Kappa阿片和NMDA受体以及5-羟色胺摄取部位。(3)使用 气相色谱-质谱法(GCMS)、分布和代谢 将对IBOGA试剂进行研究。据推测，从长期来看 这些药物的作用是由持续低水平的亲本介导的。 化合物和/或大脑不连续区域的活性代谢物。这 研究可能会为人类的成瘾障碍带来新的治疗方法。

DESCRIPTION: (Applicant's Abstract) The long-term goals of this research are an understanding of neurobehavioral mechanisms determining the addictive liabilities of drugs and the rational development of pharmacotherapies that will act on these mechanisms to reduce or eliminate addictive behavior. Recent research in this laboratory has focused on the neuropharmacology of iboga alkaloids (e.g., ibogaine) and congeners (e.g., 18-methoxycoronaridine) and their interactions with opioid and stimulant drugs of abuse. The methodology uses rats and involves measurement of intravenous drug self-administration and of drug effects on brain chemistry. In vivo microdialysis combined with HPLC (high performance liquid chromatography) is used to assay extracellular levels of biogenic amines (dopamine, serotonin) and their metabolites in discrete brain regions. Specific aims include the following: (1) The effects of ibogaine, its metabolite noribogaine and two iboga alkaloid congeners [18-methoxycoronaridine and 18-(N,N-dimethylaminoethyl)-coronaridine] on morphine and cocaine self-administration will continue to be investigated; it should be possible to develop agents that are at least as potent as ibogaine in suppressing drug self-administration but are much safer; iboga agents will be assessed on acquisition and on ongoing rates of drug self-administration behavior, in two models of relapse, and in a new oral model of nicotine preference. (2) Neurochemical mechanisms that might mediate putative anti-addictive effects of the same four iboga agents will be studied. In vivo microdialysis will be used to characterize the neurochemical actions of iboga agents and to define the receptor mechanisms mediating these effects; microdialysis will also be performed in rats self-administering morphine or cocaine in order to correlate neurochemical and behavioral effects of specific treatments. It is hypothesized that the unique pharmacology of these agents derives from a combination of actions at kappa opioid and NMDA receptors and at serotonin uptake sites. (3) Using GCMS (gas chromatography-mass spectrometry), the distribution and metabolism of the iboga agents will be studied. It is hypothesized that long-term effects of these agents are mediated by persistent low levels of the parent compounds and/or by active metabolites in discrete brain regions. This research may result in novel treatments for addictive disorders in humans.