Behavioral and Pharmacological Analysis of Drugs of Abuse

6.项目概要/摘要 所有类型的致幻剂都受到广泛的滥用，特别是青少年， 这个国家的年轻人。也许同样重要的是，这些药物可能 为最严重的精神疾病的病因学提供了线索。远景目标 目前的建议是描述致幻剂的行为和 最终目标是建立他们的行动机制。虽然他们是由一个 这两种药物的共同术语是致幻剂，它们代表不同的药理学实体。麦角 酸二乙基酰胺[LSD]在化学上和物理上与更简单的 以DMT和裸盖菇素为代表的吲哚胺。事实上，就一种假定的受体而言， 致幻剂的作用机制，LSD更类似于苯乙胺，如 美斯卡灵尽管如此，所有这些药物都通过α-肾上腺素能[5- 10] 羟色胺能]机制。直到最近， 苯环利定[PCP，天使尘]。然而，一个统一的能量-能量机制是 开始出现一种假设，即谷氨酸的释放可能代表了一种最终的共同点， 致幻剂的通道尽管如此，要说所有这些药物都以某种方式 在自然界中，多巴胺能受体掩盖了已知14种不同的多巴胺能受体的事实， 具有独特的神经解剖学分布和功能阵列。决定把重点放在 本文提出的关于5-HT_（2c）、5-HT_（7）、5-HT_（2_a）和5-HT_（2_a）~ d受体的建议，是基于对5-HT_（2_a）~（2_a）和5-HT_（2_a）~（2_a）受体的一些设想。 药理学和行为学证据，将这些受体与幻觉发生联系起来。的 主要的行为指标将继续是致幻剂对啮齿动物的刺激作用， 人们普遍认为这些影响在人类中具有显著的主观相关性。此外，本发明还提供了一种方法， 致幻剂将使用体内微透析来表征， 行为活动。预计综合所得数据将提供新的 了解迷幻剂的作用方式，尤其是那些容易被滥用的。在 此外，这些研究可能有助于我们了解最严重的精神疾病形式， 包括焦虑、抑郁和精神病在内的疾病。最后，互联网在 扩大对这些和其他俱乐部药物的兴趣，如MDMA [摇头丸]，特别是在 社会青年阶层的吸毒率是不可估量的，但几乎肯定会导致非法吸毒的增加。 这种可能性加上对药物治疗用途的持续兴趣， 裸盖菇素对这些药物进行了详细的药理学评估，这是非常重要的。

6. Project Summary/Abstract Hallucinogens of all types are subject to widespread abuse especially by adolescents and young adults in this country. Perhaps equally important is the possibility that these drugs may offer clues to the etiology of the most serious forms of mental illness. The long-term objectives of the present proposal are to characterize hallucinogens behaviorally and pharmacologically with the ultimate goal of establishing their mechanisms of action. Although they are united by a common term, hallucinogen, these drugs represent distinct pharmacological entities. Lysergic acid diethylamide [LSD] is chemically and pharmacologically quite different from the simpler indoleamines represented by DMT and psilocybin. Indeed, in terms of a presumed receptor mechanism of hallucinogenic action, LSD more closely resembles a phenethylamine such as mescaline. Nonetheless, all of these drugs are joined by prominent activity via serotonergic [5- hydroxytryptaminergic] mechanisms. Until recently, the same could not be said for phencyclidine [PCP, Angel Dust]. However, a unifying serotonergic-glutamatergic mechanism is beginning to emerge with the hypothesis that glutamate release may represent a final common pathway for hallucinogens. Nonetheless, to say that all of these drugs are somehow serotonergic in nature obscures the fact that 14 distinct serotonergic receptors are known, each with a distinct neuroanatomic distribution and array of functions. The decision to focus in the present proposal on, 5-HT2c, 5-HT7, 5-HT2~a,n d 5-HTqAr eceptors is based upon suggestive pharmacological and behavioral evidence, which links these receptors to hallucinogenesis. The primary behavioral index will continue to be the stimulus effects of hallucinogens in rodents, effects widely believed to have significant subjective correlates in humans. In addition, hallucinogens will be characterized using in vivo microdialysis to correlate glutamate release with behavioral activity. It is expected that integration of the resulting data will provide new understanding of the mode of action of hallucinogens, especially those subject to abuse. In addition, these studies may contribute to our understanding of the most serious forms of mental illness including anxiety, depression, and psychosis. Finally, the role of the internet in expanding interest in these and other club drugs such as MDMA [Ecstasy] especially among youthful segments of society is inestimable but will almost certainly lead to increased illicit use. This likelihood coupled with continued interest in the therapeutic use of agents such as psilocybin makes a detailed pharmacological assessment of these drugs of utmost importance.