Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA.
Psychopharmacology (Berl). 2013 Jan;225(1):31-9. doi: 10.1007/s00213-012-2792-z. Epub 2012 Jul 14.
Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-D-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA(A) receptors.
The present study used a rodent model to compare the inhibition of NMDA and GABA(A) receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing.
Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats.
Reducing GABA(A) receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC.
These data demonstrate that, while tonic stimulation of NMDA and GABA(A) receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.
注意功能障碍是与精神分裂症等主要精神疾病相关的认知缺陷的标志。精神分裂症的认知缺陷归因于 N-甲基-D-天冬氨酸（NMDA）受体功能降低或γ-氨基丁酸（GABA）合成酶谷氨酸脱羧酶-67 的表达减少，这可能导致 GABA(A)受体的神经传递减弱。
本研究使用啮齿动物模型比较了 NMDA 和 GABA(A)受体以及 GAD 活性对注意力的抑制作用。我们测试了抑制这些蛋白质在全脑或在前扣带皮层（ACC）中的作用，ACC 是注意力处理的关键前额叶皮层区域。
大鼠在三选择序列反应时间任务（3-CSRT）上接受训练，这是一种注意力测试。在训练有素的大鼠中测量药物全身或 ACC 内注射对表现的影响。
用直接拮抗剂 SR95531（1 或 3ng/侧）或全身注射苯二氮䓬类反向激动剂 FG7142（5mg/kg）抑制 ACC 内的 GABA(A)受体功能会损害准确性并增加遗漏。使用 MK-801（分别为 3mg/kg 或 3μg）全身或 ACC 内抑制 NMDA 受体也会损害表现。即使给予高剂量，3-巯基丙酸抑制 GAD 对全身或 ACC 内给予时的 3-CSRT 准确性或遗漏均无影响。
这些数据表明，虽然 ACC 内 NMDA 和 GABA(A)受体的紧张刺激对注意力表现至关重要，但 GAD 活性的降低可能没有功能意义，也不表明 GABA 神经传递减少。
