Pes Romina, Godar Sean C, Fox Andrew T, Burgeno Lauren M, Strathman Hunter J, Jarmolowicz David P, Devoto Paola, Levant Beth, Phillips Paul E, Fowler Stephen C, Bortolato Marco
Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States; Dept. of Biomedical Sciences, Neuroscience Division, University of Cagliari, Italy.
Dept. of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States; Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, United States.
Neuropharmacology. 2017 Mar 1;114:77-87. doi: 10.1016/j.neuropharm.2016.11.014. Epub 2016 Nov 23.
Pramipexole (PPX) is a high-affinity D-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.
普拉克索（PPX）是一种高亲和力的D型多巴胺受体激动剂，用于治疗帕金森病（PD）和不宁腿综合征。最近的证据表明，PPX会增加易感患者出现问题赌博和冲动控制障碍的风险。尽管这些并发症的分子基础尚不清楚，但一些作者推测，PPX可能通过激活中脑边缘系统的突触前多巴胺受体来增加风险倾向，从而导致伏隔核（NAcc）中多巴胺释放减少。为了验证这种可能性，我们让大鼠接受一项专门设计的概率折扣任务，以捕捉对不利选项的反应。PPX在降低NAcc中多巴胺相位性释放的剂量（0.3毫克/千克/天，皮下注射）下增强了不利决策。为了测试多巴胺流出的这些变化是否是观察到的神经经济学缺陷的原因，将PPX与单胺耗竭剂利血平（RES）联合使用，利血平的低剂量（1毫克/千克/天，皮下注射）不影响基线运动和操作性反应。与我们的预测相反，RES出人意料地加剧了PPX对不利决策的影响，尽管它未能增强PPX诱导的多巴胺相位性释放减少。这些结果共同表明，PPX损害了概率损失的折扣，并且这种药物继发的冒险行为增强可能与中脑边缘多巴胺释放的动态变化无关。
