LONG ACTING ANTICOCAINE THEAPY

美国出现了滥用可卡因的流行病。正在开发一种治疗可卡因滥用的替代治疗方法，其基础是阻断可卡因向多巴胺神经元摄取部位的分布。在这项建议中，将开发一种含有可卡因催化抗体的可注射微胶囊制剂，并在啮齿动物体内实验中评估其释放特性。更具体地说，在可生物降解的微囊中加入催化抗体Mab 15A10的有用性将通过测定在啮齿动物体内注射不同浓度的Mab 15A10后的血浆浓度-时间曲线下的面积、血浆半衰期和分布体积来评估。此外，从可生物降解的微囊中释放的单抗15A10的有效性将通过测量该配方改变急性和慢性每日注射可卡因产生的剂量-反应曲线的能力来评估。基本上，每天急性和长期注射不同剂量的可卡因改变运动活动、大脑中多巴胺和可卡因的浓度以及多巴胺D2和D1受体水平的能力将在有无含有单抗15A10的可生物降解微囊的存在和不存在的情况下被确定。将使用体外受体结合分析来测量啮齿动物基底节、杏仁核和尾壳核前内侧的脑组织中的多巴胺D2和D1受体。

An epidemic of cocaine abuse has occurred in the United States. An alternative therapeutic approach for treating cocaine abuse, based on interrupting the distribution of cocaine to the dopamine neuronal uptake sites, is being developed. In this proposal an injectable microcapsule formulation containing a catalytic antibody to cocaine will be developed and evaluated for release characteristics in rodent in vivo experiments. More specifically, the usefulness of incorporating the catalytic antibody, Mab 15A10, within biodegradable microcapsules will be assessed by determining the area under the plasma concentration-time curve, plasma half-lives, and the volume of distribution after injections of different concentrations of Mab 15A10 in rodents. In addition, the effectiveness of Mab 15A10 released from biodegradable microcapsules will be assessed by measuring the formulation's ability to shift dose-response curves produced by acute and chronic daily injections of cocaine. Basically, the ability of various doses of acute and chronic daily injections of cocaine to alter locomotor activity, brain concentrations of dopamine and cocaine, and dopamine D2 and D1 receptor levels will be determined in the presence and absence of biodegradable microcapsules containing Mab 15A10.Dopamine D2 and D1 receptor will be measured in rodent basal ganglia, amygdala, and brain tissue anterior and medial to the caudate putamen using in vitro receptor binding assays.