Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Service de Neurologie, CHU de Bordeaux, F-33604 Pessac, France.
Neurobiol Dis. 2013 Jan;49:79-86. doi: 10.1016/j.nbd.2012.08.005. Epub 2012 Aug 23.
Striatal D2 and D3 dopamine receptors are involved in mediating the reinforcing properties of natural rewards and drugs. In Parkinson's disease, while D2/3 dopamine agonists alleviate motor symptoms, behavioral addictions and withdrawal syndrome are reported in up to 15% of patients. The origin of such adverse effects is poorly understood but suggests that D2/3 agonists could possess reinforcing properties. We evaluated the reinforcing properties of the widely used D2/3 agonist, Pramipexole (PPX), in normal and parkinsonian rats. Intracerebroventricular injections of 6-OHDA induced a bilateral loss of tyrosine hydroxylase-positive cells in the substantia nigra (-51%) and ventral tegmental area (-31%). The animals were then allowed to self-administer intravenous PPX under fixed ratio and progressive ratio (PR) reinforcement schedules before being tested for extinction of PPX seeking. While parkinsonian were slower than sham rats in acquiring self-administration behavior, they later reached the same level of intake. The reinforcing value of PPX, as assessed during PR and extinction, was moderate in both groups. PPX heightened ∆FosB expression in dorsal striatum of lesioned rats and similar PR results involved different striatal subregions between groups. Altogether, our results show that drug-naïve rats self-administer PPX and that the dopaminergic lesion does not affect its reinforcing effects. While PPX reinforcing value was moderate in most rats, a subset of animals displayed a high number of responses and appeared to be particularly sensitive to this drug. These data suggest that PPX may not be responsible for the reported side-effects but rather call for further investigating the differential vulnerability among individuals.
纹状体 D2 和 D3 多巴胺受体参与介导自然奖赏和药物的强化作用。在帕金森病中，虽然 D2/3 多巴胺激动剂缓解了运动症状，但高达 15%的患者出现了行为成瘾和戒断综合征。这些不良反应的起源尚不清楚，但表明 D2/3 激动剂可能具有强化作用。我们评估了广泛使用的 D2/3 激动剂普拉克索（Pramipexole，PPX）在正常和帕金森病大鼠中的强化作用。6-羟基多巴胺（6-OHDA）脑室内注射导致黑质（-51%）和腹侧被盖区（-31%）中酪氨酸羟化酶阳性细胞的双侧丧失。然后，动物被允许在固定比率和递增比率（PR）强化方案下进行静脉内 PPX 自我给药，然后测试 PPX 寻求的消退。虽然帕金森病大鼠比假手术大鼠获得自我给药行为的速度较慢，但它们后来达到了相同的摄入量水平。在 PR 和消退期间评估的 PPX 强化值在两组中均为中等。PPX 增加了损伤大鼠背侧纹状体中 ∆FosB 的表达，并且两组之间的 PR 结果涉及不同的纹状体亚区。总的来说，我们的结果表明，未用药的大鼠会自行给予 PPX，而多巴胺能损伤不会影响其强化作用。虽然大多数大鼠的 PPX 强化值适中，但一部分动物表现出高反应次数，似乎对这种药物特别敏感。这些数据表明，PPX 可能不是导致报告的副作用的原因，而是需要进一步研究个体之间的差异易感性。
