LONG ACTING ANTICOCAINE THEAPY

在美国，可卡因滥用已成为一种流行病。目前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。本研究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，将催化抗体Mab 15A10纳入可生物降解微胶囊的有效性将通过测定在啮齿动物体内注射不同浓度的Mab 15A10后血浆浓度-时间曲线下的面积、血浆半衰期和分布体积来评估。此外，从可生物降解微胶囊中释放的Mab 15A10的有效性将通过测量该制剂改变每日急性和慢性可卡因注射产生的剂量-反应曲线的能力来评估。基本上，在含有Mab 15A10的可生物降解微胶囊存在和不存在的情况下，将确定不同剂量的急性和慢性每日可卡因注射改变运动活动、大脑中多巴胺和可卡因浓度以及多巴胺D2和D1受体水平的能力。多巴胺D2和D1受体将在啮齿类动物基底神经节、杏仁核和尾状壳核前部和内侧的脑组织中使用体外受体结合测定。

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.