DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

药物受体、神经递质和成瘾

• 批准号: 5201637
• 负责人: M KUHAR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201637
• 关键词: cocaine; dopamine transporter; drug addiction; drug administration rate /duration; drug receptors; drug withdrawal; laboratory mouse; limbic system; molecular site; neurophysiology; neurotransmitters; nucleus accumbens; receptor binding; receptor expression; reinforcer

An important focus of our laboratory is the elucidation of long term effects of drugs in the brain. We previously showed that repeated administration of cocaine followed by withdrawal for at least 10 days resulted in a downward regulation of the dopamine transporter protein. In a recent study, we sought to determine, as the previous work showed this down regulation occurred in the nucleus accumbens, whether or not the down regulation occurred in the shell or in the core of the nucleus accumbens. After preparing animals in the same way as previously described, we showed that the decrease occurred in the shell of this nucleus. This is not surprising as this is the limbic pathway and is the one associated mainly with reward and reinforcement. Another important issue in the field of addiction is the effect of rate of entry of drugs into the brain and its influence on abuse liability of these drugs. Intuitively, it seems obvious that drugs that enter the brain rapidly would be the most rewarding and reinforcing. Accordingly, we have developed a method, using in vivo receptor binding competition, that allows a calculation of the rate of entry of a substance into brain, but not only the rate of entry but also its occupancy of the transporter or receptor site. By using this method, we show that cocaine enters the brain quite rapidly as do some other compounds. However, interestingly, all of the RTI compounds enter the brain somewhat more slowly than cocaine, with quite a bit of variation. Some of the compounds do not occupy significant numbers of receptors for at least 15 minutes after intravenous injection. These results show that RTI compounds, which enter the brain more slowly than cocaine, might be good treatment medications, because a desirable property of treatment medications is that they enter the brain more slowly than cocaine; this would correspondingly reduce the abuse liability of these compounds. Secondly, it provides a mouse model by which rate of entry of drugs and occupancy of receptors can be determined. Furthermore, as it is an in vivo labeling model in the mouse, it certainly could be extended to nonhuman primates and humans utilizing brain imaging. Overall, results continue to be interesting and we continue to develop capabilities to look at additional variables in drugs of abuse and their physiological mechanisms.

我们实验室的一个重要重点是阐明长期的 药物对大脑的影响。 我们之前已经证明， 服用可卡因，然后停药至少10天 导致多巴胺转运蛋白的下调。 在最近的一项研究中，我们试图确定，正如以前的工作所显示的那样， 这种下调发生在丘脑核，无论是否 下调发生在核壳或核芯 伏隔核。 在以与先前相同的方式准备动物之后 描述，我们表明，减少发生在这个壳 原子核 这并不奇怪，因为这是边缘通路， 一个主要与奖励和强化有关的。 成瘾领域的另一个重要问题是速率的影响 药物进入大脑及其对滥用倾向的影响 这些药物。 直觉上，似乎很明显，药物进入 大脑的快速反应将是最有益和最强化的。 因此，委员会认为， 我们开发了一种方法，使用体内受体结合竞争， 它可以计算物质进入大脑的速率， 而且不仅是入境率， 或受体位点。 通过使用这种方法，我们表明，可卡因进入 大脑和其他化合物一样迅速。 然而，有趣的是， 所有的RTI化合物进入大脑的速度都比 可卡因，有很多不同的成分 有些化合物不 占据大量受体至少15分钟后， 静脉注射 这些结果表明，RTI化合物， 比可卡因进入大脑的速度慢，可能是很好的治疗方法 药物，因为治疗药物的理想性质是 它们进入大脑的速度比可卡因慢;这将 相应地降低了这些化合物的滥用倾向。 第二、 它提供了一种小鼠模型，通过该模型，药物的进入率和占用率 可以确定受体。 此外，由于它是一种体内 在小鼠中的标记模型，它当然可以扩展到非人类 灵长类动物和人类利用脑成像。 总的来说，结果仍然很有趣，我们继续发展 研究药物滥用及其 生理机制。