Pei Yue, Mortas Patrick, Hoener Marius C, Canales Juan J
School of Psychology, University of Leicester, Leicester, United Kingdom; Department of Psychology, University of Canterbury, Christchurch, New Zealand.
Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Area, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Dec 3;63:70-5. doi: 10.1016/j.pnpbp.2015.05.014. Epub 2015 Jun 3.
The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction.
新发现的痕量胺相关受体1（TAAR1）已成为兴奋剂成瘾药物开发的一个有前景的靶点，因为它能够调节多巴胺（DA）功能并调节兴奋剂的作用。最近的研究结果表明，TAAR1激活可阻断可卡因的一些与滥用相关的生理和行为效应。然而，由于所测试的可卡因单位剂量范围非常有限，现有自我给药研究的结果尚无定论。在此，为了阐明TAAR1对可卡因奖赏和强化作用的影响，我们研究了TAAR1部分和完全激活对（1）可卡因自我给药的剂量反应曲线和（2）可卡因诱导的颅内自我刺激（ICSS）变化的影响。在第一个实验中，我们研究了选择性TAAR1完全和部分激动剂RO5256390和RO5203648对五种单位注射剂量可卡因（0.03、0.1、0.2、0.45和1mg/kg/输注）自我给药的影响。两种激动剂均诱导可卡因剂量反应曲线呈剂量依赖性下移，表明TAAR1部分和完全激活均降低了可卡因的强化效力。在第二个实验中，RO5256390和部分激动剂RO5263397剂量依赖性地阻止了可卡因诱导的ICSS阈值降低。综上所述，这些数据表明，在自我给药和ICSS模型中，TAAR1刺激可有效抑制可卡因的奖赏和强化作用，支持TAAR1作为可卡因成瘾药物发现靶点的候选资格。
