Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex
Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex
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DOI：
10.1093/cercor/bhu096
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发表时间：
2015-09-01
期刊：
影响因子：
3.7
通讯作者：
Miller, Earl K.
中科院分区：
文献类型：
--
作者：
Puig, M. Victoria;Miller, Earl K.
多巴胺D2受体（D2R）在认知、情绪和运动中起主要作用。通过抗精神病药物阻断它们可以减少精神分裂症患者的幻觉和妄想行为，但通常不能减轻情感和认知功能障碍。前额叶皮层（PFC）表达D2R，并在精神分裂症中发生改变。我们研究了D2R如何调节猴子的行为和PFC功能。两只猴子学习新的和执行高度熟悉的视觉联想，其中每个线索都与向左或向右目标的扫视有关。我们记录了神经尖峰和局部场电位从多个电极，同时注射D2R拮抗剂依替氯必利在侧PFC。阻断前额叶D2R受损的联想学习和认知灵活性，减少动机，但留下的性能熟悉的协会完好无损。依替氯必利降低了前额叶神经元的扫视方向选择性，导致有关协会的神经信息减少，α振荡增加。这些结果，加上我们最近的研究，使用D1R拮抗剂，表明，D1R和D2R在灵长类动物的外侧PFC合作，以调节几个执行功能。我们的研究结果有助于深入了解为什么抗精神病药物对D2R具有强烈的拮抗作用，却不能改善精神分裂症患者的认知和情感缺陷。
Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia.