DOPAMINE RELEASE INDUCED BY 4-METHYLAMINOREX

新型兴奋剂4-methylaminorex（4-MAX;2-amino-4-methyl-5- 苯基恶唑啉;街道名称“U4 Euh”最近作为一种 滥用药物。 吸毒者描述了4- MAX就像安非他明和可卡因一样，4-MAX是自我- 猴子用类似可卡因的方式给药 其实恰恰 秘密市场，4-MAX经常被毒贩歪曲为 可卡因或安非他明 非法制造的4-MAX已被 被佛罗里达，加州和宾夕法尼亚州当局没收。 由于 由于这种物质滥用的可能性很大，4- MAX被分配到受控药物的附表1药物类别。 1987年10月的物质法。 当局担心， 这种化合物的合成和前体的可获得性将导致 更广泛地滥用4 MAX 尽管如此， 它对中枢神经系统的药理作用 的 有限的数据表明，4-MAX具有兴奋剂，厌食和 拟交感神经特性类似于那些充分表征的 兴奋剂安非他明 安非他明主要通过其 作用于大脑多巴胺和去甲肾上腺素系统。 现存的不足 4-MAX上的生化和行为数据也与 假设4-MAX是通过与 大脑多巴胺系统 4 Max存在于四种异构形式中， 在效力上。 本提案的总体目标是考察 我们的异构体的4-MAX诱导释放的 神经递质多巴胺从选定的前脑结构， 自由活动的老鼠 将通过微透析收集样品 技术，并在样品中的多巴胺含量将定量 通过高效液相色谱法（HPLC）分析。 中脑 腹侧被盖区（A10）的多巴胺神经元具有不同的 比多巴胺神经元的生化和生理特性 发现于邻近的黑质区域（A9）。 因此，多巴胺 将在几个不同的前脑区域检查释放， 选择性地由这两种多巴胺中的一种神经支配 神经元 这一点很重要，因为与安非他明不同， 表明4-MAX对电气性能有不同影响 这两种多巴胺神经元的放电活动。 在 选择性实验观察刺激诱导的行为 变化将与多巴胺的同步测量相关 release. 此外，4-MAX诱导释放的机制 将检测多巴胺的含量。 在所有拟议的研究中， 4-MAX的效果将与原型的效果进行比较。 兴奋剂安非他明 我们的方法应该产生关于 4-MAX异构体对多巴胺神经元的作用 大脑，这将有助于我们了解4-MAX的作用模式。

The novel stimulant drug 4-methylaminorex (4-MAX;2-amino-4-methyl-5- phenyloxazoline; street name "U4Euh" has recently gained attention as a drug of abuse. Drug users have described the subjective effects of 4- MAX to be like those of amphetamine and cocaine, and 4-MAX is self- administered by monkeys in a manner similar to cocaine. IN fact, on the clandestine market, 4-MAX is often misrepresented by drug dealers as cocaine or amphetamine. Illegally manufactured 4-MAX has been confiscated by authorities in Florida, California and pennsylvania. Due to the high potential for abuse of this substance, the cis isomer of 4- MAX was assigned to the schedule 1 drug category of the Controlled Substances Act in October, 1987. Authorities fear that the ease of synthesis of this compound and the accessibility of precursors will lead to more widespread abuse of 4-MAX. Nonetheless, very little is known about its pharmacological actions on the central nervous system. The limited data available suggest that 4-MAX has stimulant, anorectic and sympathomimetic properties similar to those of the well characterized stimulant amphetamine. Amphetamine primarily exerts its effects via its action on brain dopamine and norepinephrine systems. The scant existing biochemical and behavioral data available on 4-MAX are also consistent with the hypothesis that 4-MAX produces its effects by interacting with brain dopamine systems. 4 Max exists in four isomeric forms which vary in potency. The overall goal of this proposal is to examine the ability of the our isomers of 4-MAX to induce the release of the neurotransmitter dopamine from selected forebrain structures in the awake freely moving rat. The samples will be collected by microdialysis technique, and dopamine content in the samples will be quantitatively analyzed by high performance liquid chromatography (HPLC). Midbrain dopamine neurons in the ventral tegmental area (A10) have different biochemical and physiological characteristics than dopamine neurons found in the adjacent substantia nigra region (A9). Hence, dopamine release will be examined in several different forebrain areas which are selectively innervated by only one of these two populations of dopamine neurons. This is important since, unlike amphetamine, preliminary data indicate that 4-MAX has a differential effect on the electrical discharge activity of these two populations of dopamine neurons. In selected experiments observations of stimulant-induced behavioral changes will be correlated with simultaneous measures of dopamine release. In addition, the mechanism by which 4-MAX induces the release of dopamine will be examined. In all of the proposed studies the effects of 4-MAX will be compared to the effects of the prototypical stimulant amphetamine. Our approach should yield important data about the action of the isomers of 4-MAX on dopamine-containing neurons in the brain, which will help us to understand the mode of action of 4-MAX.