Discipline of Pharmacology, University of Sydney, Sydney, Australia.
Nat Neurosci. 2011 Oct 30;14(12):1548-54. doi: 10.1038/nn.2940.
Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.
神经递质转运体可以通过调节神经递质浓度间接影响神经元兴奋性，或者通过转运体电流直接影响神经元兴奋性。目前尚未描述转运体电流的生理或病理生理学作用。我们发现，在啮齿动物阿片类戒断期间，GABA 转运体 1（GAT-1）阳离子电流直接增加了导水管周围灰质（PAG）中的 GABA 能神经元兴奋性和突触 GABA 释放。相比之下，GAT-1 并未通过调节细胞外 GABA 浓度间接改变 GABA 受体反应。值得注意的是，我们发现 GAT-1 诱导的 GABA 能活性增加有助于 PAG 介导的许多阿片类戒断症状。综上所述，这些数据支持了这样一种假设，即 GAT-1 活性通过直接过度兴奋 GABA 能 PAG 神经元和神经末梢直接产生阿片类戒断症状，这可能增强了 GABA 能对 PAG 输出神经元的抑制作用。这些数据提供了迄今为止的最佳证据，表明神经递质转运体电流的失调对于阿片类戒断所基于的适应性可塑性非常重要。
