Holtz Nathan A, Tedford Stephanie E, Persons Amanda L, Grasso Salvatore A, Napier T Celeste
Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Dept. of Psychiatry, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Oct 3;70:77-84. doi: 10.1016/j.pnpbp.2016.05.004. Epub 2016 May 20.
Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation-mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14-28days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2mg/kg/day) within 4h of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12-14days of infusion with 0.3mg/kg/day did not alter discounting, but increases were obtained with 1.2mg/kg/day pramipexole, with 67% of 1.2mg/kg/day-treated rats meeting categorical criteria for 'high risk-taking'. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact.
普拉克索和罗匹尼罗是多巴胺激动剂，在治疗神经病理学的运动障碍方面有效，例如帕金森病和不宁腿综合征。很大一部分接受治疗的患者会出现冲动/强迫行为。目前的治疗方法是减少剂量或换用其他多巴胺替代药物，而这两种方法都会削弱运动方面的益处。我们需要一种临床前模型，能够帮助确定多巴胺激动剂疗法的辅助治疗方法，这种方法可以减少冲动/强迫行为，同时又不干扰多巴胺激动剂的运动益处。为了实现这一目标，当前的研究采用了帕金森病大鼠模型，对长期给药的普拉克索进行行为学分析。这是通过雄性斯普拉格-道利大鼠完成的，其中：(i) 6-羟基多巴胺诱导的背外侧纹状体损伤导致帕金森病样运动不能，以前肢进行测量；(ii) 颅内自我刺激介导的概率折扣表明冲动性/冒险行为；(iii) 通过渗透微型泵连续给药两剂普拉克索，持续14 - 28天，以模拟缓释制剂实现的长期、稳定暴露。已知非典型抗抑郁药米氮平可减少大鼠与药物成瘾相关的行为；因此，我们通过确定米氮平对普拉克索诱导的运动改善与概率折扣的影响，在此证明了该模型的实用性。我们观察到，在植入泵给药0.3mg/kg/天的4小时内以及给药1.2mg/kg/天的1小时内，所测试的两种普拉克索剂量（0.3和1.2mg/kg/天）均减轻了纹状体损伤后的前肢运动不能。相比之下，0.3mg/kg/天输注12 - 14天未改变折扣情况，但1.2mg/kg/天的普拉克索剂量增加了折扣，1.2mg/kg/天治疗的大鼠中有67%符合“高冒险行为”的分类标准。在与普拉克索共同给药的14天期间，插入第二个输送米氮平的微型泵并未改变运动功能，但足以减轻冒险行为。这些结果揭示了普拉克索不同的概率折扣和抗运动不能特征，表明可以开发出在保留运动益处的同时减少冒险行为的药物治疗方法（例如米氮平治疗）。
