Sigma Ligands for the Treatment of Cocaine Overdose

描述(申请人提供)：可卡因比其他非法药物导致更严重的中毒和死亡，但目前还没有有效的可卡因滥用治疗方法。开发有效的反可卡因药物的一种策略是阻止可卡因进入其目标蛋白。在可卡因的众多作用部位中，S受体是一个很有希望的药物开发靶点。在我们早先资助的项目中，我们发现了20多种新型S受体拮抗剂，可以预防可卡因诱导的小鼠惊厥和死亡。这些最好的拮抗剂甚至可以在出现严重的可卡因过量症状后使用，以防止死亡。这些化合物以及针对Sigma受体的反义寡核苷酸也可以减弱可卡因诱导的运动活性，这表明它们可以阻断可卡因的行为毒性和精神运动刺激效应。最初资助的提案表明，Sigma受体的拮抗作用，特别是Sigma1亚型，可以防止可卡因的急性行为影响，现在是时候研究与成瘾更相关的其他可卡因相关行为了。因此，目前竞争性更新的目标是验证Sigma1受体拮抗可卡因的奖赏特性的假设，并开始确定参与这一保护作用的机制。因此，该项目的具体目标是：1)确认Sigma1受体的拮抗作用减弱可卡因的奖赏特性；2)确定参与Sigma1受体拮抗剂行为保护作用的基因；3)确定参与Sigma1受体拮抗剂行为保护作用的大脑区域。预计该项目的成果将有助于开发新的有效的可卡因滥用治疗方法。

DESCRIPTION (provided by applicant): Cocaine is responsible for more serious intoxications and deaths than other illicit drug, yet no effective treatments for cocaine abuse are currently available. One strategy for developing effective anti-cocaine agents is to block cocaine's access to its target proteins. Of the myriad of sites through which cocaine can act, s receptors are a promising target for drug development. In our earlier funded project, we identified over two-dozen novel s receptor antagonists that prevent cocaine-induced convulsions and lethality in mice. The best of these antagonists even prevent death when administered after the onset of symptoms of a severe cocaine overdose. These compounds, as well as antisense oligodeoxynucleotides against sigma receptors, also attenuate cocaine-induced locomotor activity, suggesting that they can block both the behavioral toxic and psychomotor stimulant effects of cocaine. With the initially funded proposal demonstrating that antagonism of sigma receptors, especially the sigma1 subtype, prevents the acute behavioral effects of cocaine, it is now time to investigate other cocaine-related behaviors that are more relevant to addiction. Therefore, the goal of the present competitive renewal is to validate the hypothesis that antagonism of sigma1 receptors attenuates the rewarding properties of cocaine and to begin defining the mechanisms involved in this protective action. Therefore, the specific aims of the project are: 1) To confirm that antagonism of sigma1 receptors attenuates the rewarding properties of cocaine, 2) To identify the genes that contribute to the behavioral protective actions of sigma1 receptor antagonists, and 3) To identify the brain regions that are involved in the behavioral protective actions of sigma1 receptor antagonists. It is anticipated that the results of this project will facilitate the development of new and effective treatments for cocaine abuse.