Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors
Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors
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DOI：
10.1038/sj.npp.1300818
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发表时间：
2006-03-01
影响因子：
7.6
通讯作者：
Lavin, A
中科院分区：
文献类型：
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作者：
Andrews, GD;Lavin, A
尽管哌醋甲酯 (MPH) 是一种儿茶酚胺能再摄取阻滞剂，用于治疗注意力缺陷/多动症，但缺乏有关其作用的细胞基础的信息。为了解决这个问题，我们使用全细胞膜片钳记录来研究各种儿茶酚胺受体在 MPH 诱导的皮质神经元兴奋性变化中的作用。我们将多巴胺或去甲肾上腺素受体拮抗剂与 MPH 联合沐浴，作用于位于边缘下和边缘前额皮质深层的锥体细胞。单独应用 MPH (10 μM) 可以增加从幼年大鼠获得的切片中的皮质细胞兴奋性。当在记录之前用利血平耗尽儿茶酚胺时，这种 MPH 介导的兴奋性增加就会消失，这表明需要突触前单胺成分。拮抗剂研究进一步表明，α-2 去甲肾上腺素能受体的刺激介导 MPH 诱导的内在兴奋性增加。多巴胺 D1 受体在 MPH 的作用中没有发挥可观察到的作用。因此，我们认为 MPH 的作用是增加 PFC 中的儿茶酚胺能张力，从而通过可能包括激活位于中间神经元中的 α-2 肾上腺素受体的机制介导锥体细胞的去抑制来增加皮质兴奋性。
Although methylphenidate (MPH), a catecholaminergic reuptake blocker, is prescribed for attention-deficit/hyperactivity disorder, there is a dearth of information regarding the cellular basis of its actions. To address this issue, we used whole-cell patch-clamp recordings to investigate the roles of various catecholamine receptors in MPH-induced changes in cortical neuron excitability. We bath-applied dopamine or noradrenaline receptor antagonists in combination with MPH to pyramidal cells located in deep layers of the infralimbic and prelimbic prefrontal cortices. Application of MPH (10 mu M) by itself increased cortical cell excitability in slices obtained from juvenile rats. This MPH-mediated increase in excitability was lost when catecholamines were depleted with reserpine prior to recording, demonstrating the requirement for a presynaptic monoamine component. Antagonist studies further revealed that stimulation of alpha-2 noradrenergic receptors mediates the MPH-induced increase in intrinsic excitability. Dopamine D1 receptors played no observable role in the actions of MPH. We therefore propose that MPH is acting to increase catecholaminergic tone in the PFC, and thereby increases cortical excitability by mediating the disinhibition of pyramidal cells through mechanisms that may include activation of alpha-2 adrenoreceptors located in interneurons.