Pei Yui, Lee Jungah, Leo Damiana, Gainetdinov Raul R, Hoener Marius C, Canales Juan J
Behavioural Neuroscience, Department of Psychology, University of Canterbury, Christchurch, New Zealand.
Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy.
Neuropsychopharmacology. 2014 Sep;39(10):2299-308. doi: 10.1038/npp.2014.88. Epub 2014 Apr 11.
The trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in addiction because of its ability to regulate dopamine (DA) transmission. We tested in rats the efficacy of RO5203648 and RO5256390, partial and full TAAR1 agonists, respectively, in models of cocaine relapse. Using a model of context-induced relapse, both RO5203648 and RO5256390 dose-dependently suppressed cocaine seeking after a 2-week period of withdrawal from chronic cocaine self-administration. In a model of extinction-reinstatement, RO5203648 completely inhibited cocaine-primed reinstatement of cocaine seeking. At doses that effectively suppressed cocaine seeking neither RO5203648 nor RO5256390 altered responding maintained by a natural reward. Moreover, fast scan cyclic voltammetry data showed that RO5203648 prevented cocaine-induced DA overflow in the nucleus accumbens without altering DA half-life, suggesting that the partial TAAR1 agonist attenuated cocaine-stimulated DA overflow by mechanisms other than direct interference with DA uptake. Collectively, these data provide strong evidence in support of TAAR1 as a neuropharmacological target for the treatment of cocaine addiction.
由于能够调节多巴胺（DA）传递，痕量胺相关受体1（TAAR1）已成为成瘾药物开发的一个有前景的靶点。我们在大鼠中测试了RO5203648和RO5256390（分别为TAAR1部分激动剂和完全激动剂）在可卡因复发模型中的疗效。使用情境诱导复发模型，在从慢性可卡因自我给药戒断2周后，RO5203648和RO5256390均剂量依赖性地抑制了可卡因觅求行为。在消退-复吸模型中，RO5203648完全抑制了可卡因引发的可卡因觅求行为的复吸。在有效抑制可卡因觅求行为的剂量下，RO5203648和RO5256390均未改变由自然奖励维持的反应。此外，快速扫描循环伏安法数据表明，RO5203648可防止可卡因诱导伏隔核中的DA溢出，而不改变DA半衰期, 这表明TAAR1部分激动剂通过直接干扰DA摄取以外的机制减弱了可卡因刺激的DA溢出。总体而言，这些数据为支持TAAR1作为治疗可卡因成瘾的神经药理学靶点提供了有力证据。
