GLUTAMATE AGONISTS AND ANTAGONISTS--ROLE IN ADDICTION

本研究的两个总体目标是评估功能 兴奋性氨基酸突触在奖赏中的作用 精神兴奋剂和阿片类药物的（成瘾）作用， 新的药物，削弱这些滥用的奖励作用， 物质. 假设是神经元中的一个关键作用 介导这些药物作用的途径是增加 谷氨酸释放的核脑桥（N.ACC），激活 谷氨酸受体的AMPA亚型。 这一假设将由以下人员进行检验： 确定1）是否将AMPA受体的拮抗剂微量注射到 前扣带核减弱了精神兴奋剂和阿片类药物的奖赏效应 如通过条件性位置偏好测量的，2）AMPA激动剂是否 微注射到N.ACC产生类似的奖励效应， 精神兴奋剂和阿片类药物，以及3）是否对 精神兴奋剂药物和阿片类药物涉及增加 细胞外谷氨酸和天冬氨酸浓度 这种研究的一个主要限制因素是缺乏选择性 AMPA受体拮抗剂。 因此，我们计划合成新的 化合物并测试它们的AMPA拮抗剂活性。 策略是 合成基于两种重要先导化合物的类似物， 我们和其他人所做的结构-活性研究。 这两类化合物是：1）取代的邻酪氨酸和2）杂合的邻酪氨酸。 组合喹喔啉二酮化合物和喹喔啉二酮化合物的特征的分子， 兴奋毒素β-草酰氨基丙氨酸。 新的化合物将被测试 它们对兴奋性氨基酸受体的亲和力和选择性， 放射性配体结合技术，皮质楔手术将是 用于鉴定激动剂和拮抗剂。 最有力和最有效的 然后将测试化合物对抗这些效应的能力， 安非他明，可卡因和吗啡对运动活动的影响， 条件位置偏好范式 因此，拟议的研究具有 生物成分，应该提供更好的理解， 神经回路和机制涉及药物成瘾和和 化学成分提供了一种新的药理学的可能性， 治疗与吸毒成瘾有关的问题的战略。

The two overall objectives of this study are to evaluate the functional role of excitatory amino acid (glutamatergic) synapses in the rewarding (addicting) effects of psychostimulant and opioid drugs and to synthesize new drugs that attenuate the rewarding effects of these abused substances. The hypothesis is that a critical action in neuronal pathways that mediate the effects of these drugs is an increase in glutamate release in the nucleus accumbens (N.ACC), which activates the AMPA subtype of glutamate receptors. This hypothesis will be tested by determining 1) whether antagonists of AMPA receptors microinjected into the N.ACC attenuate the rewarding effects of psychostimulants and opioids as measured by conditioned place preference, 2) whether AMPA agonists microinjected into the N.ACC produce similar rewarding effects effects as the psychostimulant and opioid drugs, and 3) whether the responses to psychostimulant drugs and opioids involve an increase in the extracellular concentration of glutamic acid and aspartic acid in the N.ACC. A major limiting factor for such a study is the lack of selective antagonists of AMPA receptors. Therefore, we plan to synthesize new compounds and test them for AMPA antagonist activity. The strategy is to synthesize analogs based on two important lead compounds identified from the structure-activity studies that were done by ourselves and others. The two groups of compounds are: 1) substituted o-tyrosines and 2) hybrid molecules combining features of the quinoxalinedione compounds and the excitotoxin beta-oxalylaminoalanine. New compounds will be tested for their affinity and selectivity for excitatory amino acid receptors using radioligand binding techniques, and the cortical wedge procedure will be used to identify agonists and antagonists. The most potent and effective compounds will then be tested for their ability to antagonize the effects of amphetamine, cocaine, and morphine on locomotor activity and in the conditioned place preference paradigm. Thus, the proposed studies have a biological component that should provide greater understanding of neuronal circuits and mechanisms involved in drug addiction and and a chemical component that provides the possibility of a new pharmacological strategy for treating the problems associated with addicting drugs.