Pramipexole (PPX) is a D2 and D3 dopamine receptor agonist approved for clinical use, which is associated with a higher risk of impulse-control disorders. Using a rat model, we recently found that low doses of the monoamine-depleting agent reserpine (RES; 1 mg/kg/day, SC) dramatically increased the untoward effects of PPX (0.3 mg/kg/day, SC) on probability discounting, a key impulsivity function. To further understand the neurobehavioral mechanisms underlying these effects, we first tested whether the combination of PPX and RES may lead to a generalized enhancement in risk taking, as tested in the suspended wire-beam paradigm. The association of RES and PPX did not augment the proclivity of rats to cross the bridge in order to obtain a reward, suggesting that the effects of RES and PPX on probability discounting do not reflect a generalized increase in impulsivity. We then studied what receptors mediate the effects of PPX in RES-treated rats. The combination of RES and PPX increased membrane expression and binding of D3, but not D2 dopamine receptors, in the nucleus accumbens. However, the behavioral effects of PPX and RES were not reduced by acute treatments with the D2/D3 receptor antagonist raclopride (0.01-0.05 mg/kg, SC), the highly selective D2 receptor antagonist L-741,626 (0.1-1 mg/kg, SC) or the D3 receptor antagonists GR 103691 (0.1-0.3 mg/kg, SC) and SB 277011A (1-10 mg/kg, SC). These findings collectively suggest that the effects of PPX in probability discounting do not reflect generalized enhancements in impulsivity or acute dopamine D2 or D3 receptor activation.

中文翻译：

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急性 D2 或 D3 受体拮抗作用不能逆转普拉克索对概率贴现的不利影响

普拉克索 (PPX) 是一种批准用于临床的 D2 和 D3 多巴胺受体激动剂，它与更高的冲动控制障碍风险有关。使用大鼠模型，我们最近发现低剂量的单胺消耗剂利血平（RES；1 mg/kg/天，SC）显着增加了 PPX（0.3 mg/kg/天，SC）对概率折扣的不利影响，一个关键的冲动函数。为了进一步了解这些影响背后的神经行为机制，我们首先测试了 PPX 和 RES 的组合是否会导致风险承担的普遍增强，正如在悬浮线束范式中所测试的那样。RES 和 PPX 的关联并没有增加大鼠过桥以获得奖励的倾向，表明 RES 和 PPX 对概率贴现的影响并不反映冲动性的普遍增加。然后，我们研究了哪些受体在 RES 治疗的大鼠中介导 PPX 的作用。RES 和 PPX 的组合增加了伏隔核中 D3 的膜表达和结合，但不增加 D2 多巴胺受体。然而，使用 D2/D3 受体拮抗剂雷氯必利 (0.01-0.05 mg/kg, SC)、高选择性 D2 受体拮抗剂 L-741,626 (0.1-1 mg/kg) 急性治疗并未降低 PPX 和 RES 的行为影响, SC) 或 D3 受体拮抗剂 GR 103691 (0.1-0.3 mg/kg, SC) 和 SB 277011A (1-10 mg/kg, SC)。这些发现共同表明，PPX 在概率折扣中的影响并不反映冲动或急性多巴胺 D2 或 D3 受体激活的普遍增强。