TAAR1激动剂RO5263397干预线索诱导可卡因觅药行为重建的机制研究

Cocaine abuse remains a major public health problem for which there is currently no Food and Drug Administration-approved pharmacotherapy. Given the prominent role of dopaminergic system in the abuse-related behavioral effects of cocaine, preclinical and clinical studies have focused on the dopaminergic system in the development of potential medications to treat cocaine addiction. Despite some promising results, drugs that directly modulate dopaminergic system have only achieved limited success for the treatment of cocaine abuse either due to intolerable adverse effects or due to the lack of effectiveness. New targets that indirectly modulate dopaminergic system may provide a novel avenue for the development of cocaine addiction pharmacotherapy. Emerging evidence suggests that trace amine associated receptor 1 (TAAR1) is a novel target that modulates dopaminergic activity. First cloned in 2001, TAAR 1 has been increasingly recognized as a modulator of monoamine transporters and dopaminergic activity. Animal knockout studies suggest that TAAR1 is involved in behavioral effects of psychostimulants such as cocaine and methamphetamine. Recently several highly selective TAAR 1 agonists have been discovered. However, little is known of the impact of TAAR 1 agonists on abuse-related effects of cocaine. We first systematically assessed the effect of a TAAR1 agonist RO5263397 on a range of behavioral effects of cocaine. Our new studies revealed that RO5263397 reduced the expression of cocaine conditioned place preference, and attenuated cue- and cocaine prime-induced reinstatement of cocaine seeking behavior. Demand curve analysis showed that RO5263397 increased the elasticity of the cocaine demand curve, but did not change cocaine consumption. Besides, RO5263397 had no effect on cue-indeced reinstatement of sucrose seeking behavior. These data reveal essential neuromodulatory roles of TAAR 1 on cocaine abuse, and suggest that TAAR 1 may represent a novel drug target for the treatment of cocaine addiction. Based on our exciting preliminary data, proposed studies will identify the target brain region of RO5263397 via investigating the expression of TAAR1 and the release of DA in abuse-related brain regions, and further zoom in the D2 regulatory mechanism of RO5263397 applying D2 agonists and antagonists based on cocaine self-administration-extinction-reinstatement procedure. We will further uncover the negative modulatory mechanism of RO5263397 on cocaine addiction and the close interaction of TAAR1 and D2 dopamine receptors on cocaine addiction.

目前临床上还无FDA批准上市用于可卡因成瘾治疗的药物。最新研究表明，痕迹胺相关受体1（TAAR1）能够调控多巴胺能神经系统，这为可卡因成瘾的治疗提供了新的思路。初期研究发现，TAAR1激动剂RO5263397抑制大鼠条件性位置偏爱的表达；抑制线索和可卡因引燃诱导的大鼠觅药行为的重建；增加大鼠可卡因需求曲线的弹性；但不影响线索诱导的大鼠蔗糖觅食行为的重建。这提示RO5263397对可卡因成瘾行为，尤其对复吸、重建有显著的干预作用，TAAR1有望成为治疗可卡因复吸的新型药物靶点。我们将采用大鼠自我给药-消退-重建模型，进一步确认RO5263397的作用靶点确是TAAR1，并通过免疫组化和神经化学的方法确定RO5263397作用的关键脑区。在此基础上，采用D2受体激动剂和拮抗剂，从行为学角度论证RO5263397激活TAAR1后是否通过D2受体途径发挥作用，揭示TAAR1的多巴胺能神经调控机制。

目前临床上尚无FDA批准的用于治疗可卡因成瘾的药物。既往的研究表明，痕迹胺相关受体1（TAAR1）能够调控多巴胺能神经系统，这为可卡因成瘾的治疗提供了新的思路。我们在前期的研究中发现，TAAR1激动剂RO5263397抑制大鼠条件性位置偏爱的表达；抑制线索和可卡因引燃诱导的大鼠觅药行为的重建；增加大鼠可卡因需求曲线的弹性；但不影响线索诱导的大鼠天然奖赏行为的重建。这提示TAAR1激动剂RO5263397对可卡因成瘾行为，尤其对复吸、重建有显著的干预作用，TAAR1有望成为治疗可卡因复吸的新型药物靶点。我们采用大鼠自我给药-消退-重建模型，首先通过行为学实验验证了RO5263397的作用靶点为TAAR1，并通过免疫组化和western blot的方法进一步确定RO5263397作用的关键脑区。但是在研究过程中，我们发现同行实验室已经发表了同类TAAR1激动剂RO5166017的类似研究工作，因此，我们不得不放弃正在进行的研究工作，对研究计划进行了调整。有研究报道，痕迹胺水平的异常与临床上多种神经精神疾病的发病密切相关。我们推测TAAR1可能参与了精神分裂症、抑郁症和焦虑症等精神疾病的发病，因此我们对TAAR1激动剂在这些精神疾病中的作用进行初探。我们首先建立了大鼠精神分裂症模型，同时我们还建立了小鼠的抑郁和焦虑共患病模型，期望利用这些模型评估TAAR1激动剂在精神疾病中的治疗意义。