Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease.
Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease.
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DOI：
10.1016/j.pnpbp.2016.05.004
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发表时间：
2016-10-03
影响因子：
5.6
通讯作者：
Napier TC
中科院分区：
文献类型：
--
作者：
Holtz NA;Tedford SE;Persons AL;Grasso SA;Napier TC
普拉克索和罗匹尼罗是多巴胺激动剂，其有效治疗神经病理学的运动障碍，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改用替代多巴胺替代品，这两种方法都可能破坏运动益处。需要的是一个临床前模型，可以帮助确定多巴胺受体激动剂治疗的辅助治疗，减少冲动/强迫行为，而不干扰多巴胺受体激动剂的运动益处。为了实现这一目标，目前的研究实施了帕金森病大鼠模型，以行为分析长期给予普拉克索。这是用雄性Sprague-Dawley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产生帕金森病样运动不能，在前肢中测量，（ii）颅内自我刺激介导的概率折扣指示冲动/冒险，和（iii）通过渗透微型泵连续施用两个剂量的普拉克索14-28天以反映慢性、慢性或慢性的帕金森病样运动不能。使用延长释放制剂实现稳定暴露。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来证明模型效用。我们观察到，在泵植入后4小时内（分配0.3 mg/kg/天）和1小时内（分配1.2 mg/kg/天），两种试验剂量（0.3和1.2 mg/kg/天）的普拉克索均减轻了纹状体病变后的前肢运动不能。相比之下，以0.3 mg/kg/天剂量输注12-14天未改变折扣，但以1.2 mg/kg/天剂量普拉克索给药后，折扣增加，67%的1.2 mg/kg/天剂量给药大鼠符合“高风险”的分类标准。在与普拉克索联合给药的14天期间，插入第二个输送米氮平的微型泵并没有改变运动功能，但足以减轻冒险行为。这些结果揭示了普拉克索的不同概率折扣和抗运动不能特征，表明药物治疗（例如，米氮平治疗），可以减少冒险，同时保持运动益处不变。
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. Towards 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 14–28 days 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 4hr of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12–14 days 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 14 days 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.