Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在本报告所述期间，就这一项目进行了少量的实验室工作。 此外，在本报告所述期间，该项目积压的实验室研究结果已进入出版阶段。 首先，使用一种新的额外的动物行为模型，我们报告说，我们的领先的概念验证多巴胺D3受体拮抗剂化合物SB 277011 A减少了C57 BL/J6小鼠的酒精狂欢样消耗。 第二，我们报道，SB 277011 A衰减药物或食物剥夺应激诱导的可卡因诱导的条件性位置偏爱在实验室大鼠的表达的再激活。 第三，我们报告说，SB 277011 A显着加速灭绝与可卡因诱导的位置偏好在实验室大鼠的环境线索。 第四，我们报告说，SB 277011 A不改变大鼠巴甫洛夫条件接近行为（符号跟踪与目标跟踪）。 第五，我们报道了一个新的和新颖的系列4-苯基哌嗪具有非常高的多巴胺D3受体亲和力和/或选择性。 该新化学系列的化合物19抑制小鼠中羟考酮诱导的过度运动，并抑制羟考酮诱导的运动敏化。 此外，用化合物19预处理剂量依赖性地抑制实验室大鼠中羟考酮诱导的条件性位置偏爱的获得。 第六，我们报告了左旋四氢巴马汀和低剂量纳洛酮的组合构成了预防可卡因寻求行为复发的有希望的新疗法。

During the present reporting period, modest laboratory work was conducted on this project. In addition, a backlog of laboratory findings on this project were brought forward to the publication stage during this reporting period. First, using a new additional animal behavioral model, we reported that our lead proof-of-concept dopamine D3 receptor antagonist compound SB277011A decreases binge-like consumption of ethanol in C57BL/J6 mice. Second, we reported that SB277011A attenuates drug- or food-deprivation stress-induced reactivation of the expression of cocaine-induced conditioned place preference in laboratory rats. Third, we reported that SB277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in laboratory rats. Fourth, we reported that SB277011A does not alter Pavlovian conditioned approach behaviors in rats (sign-tracking versus goal-tracking). Fifth, we reported on a new and novel series of 4-phenylpiperazines with exceptionally high dopamine D3 receptor affinities and/or selectivities. Compound 19 of this new chemical series inhibited oxycodone-induced hyperlocomotion in mice, and inhibited oxycodone-induced locomotor sensitization. In addition, pretreatment with compound 19 dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference in laboratory rats. Sixth, we reported that a combination of levo-tetrahydropalmatine and low dose naltrexone constitutes a promising new therapy for prevention of relapse to cocaine-seeking behavior.