de Groote L, Linthorst A C E
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Department of Clinical Science at South Bristol, University of Bristol, Whitson Street, Bristol BS1 3NY, UK.
Neuroscience. 2007 Sep 7;148(3):794-805. doi: 10.1016/j.neuroscience.2007.06.030. Epub 2007 Aug 10.
In the hippocampus, a brain structure critically important in the stress response, GABA controls neuronal activity not only via synaptic inhibition, but also via tonic inhibition through stimulation of extrasynaptic GABA receptors. The extracellular level of GABA may represent a major determinant for tonic inhibition and, therefore, it is surprising that its responsiveness to stress has hardly been investigated. To clarify whether hippocampal extracellular GABA levels change in response to acute stress, we conducted an in vivo microdialysis study in rats. We found that dialysate GABA levels respond to various neuropharmacological manipulations such as reuptake inhibition, elevated concentrations of K(+), tetrodotoxin and baclofen, indicating that a large proportion of hippocampal extracellular GABA depends on neuronal release and that GABA re-uptake plays a role in determining the extracellular levels of this neurotransmitter. Next, rats were exposed to a novel cage or to forced swimming in 25 degrees C water. Interestingly, these two stressors resulted in opposite effects. Novelty caused a fast increase in GABA (120% of baseline), whereas forced swimming resulted in a profound decrease (70% of baseline). To discriminate between the psychological and physical aspects (i.e. the effects on body temperature) of forced swimming, another group of animals was forced to swim at 35 degrees C. This stressor, like novelty, caused an increase in hippocampal GABA, suggesting a stimulatory effect of psychological stress. The effects of novelty could not be blocked by the corticotropin-releasing factor receptor antagonist D-Phe-CRF(12-41). These results are the first to demonstrate stressor-dependent changes in hippocampal extracellular GABA; an observation which may be of particular significance for GABAergic tonic inhibition of hippocampal neurons.
在海马体中，这是一种在应激反应中至关重要的脑结构，γ-氨基丁酸（GABA）不仅通过突触抑制来控制神经元活动，还通过刺激突触外GABA受体进行持续性抑制来实现。细胞外GABA水平可能是持续性抑制的主要决定因素，因此，令人惊讶的是，其对应激的反应性几乎未被研究过。为了阐明海马体细胞外GABA水平是否会因急性应激而发生变化，我们在大鼠身上进行了一项体内微透析研究。我们发现，透析液中的GABA水平会对各种神经药理学操作产生反应，如再摄取抑制、升高钾离子（K⁺）浓度、使用河豚毒素和巴氯芬，这表明海马体细胞外的GABA很大一部分依赖于神经元释放，并且GABA再摄取在决定这种神经递质的细胞外水平方面发挥着作用。接下来，将大鼠置于新笼子中或在25摄氏度的水中进行强迫游泳。有趣的是，这两种应激源产生了相反的效果。新奇环境导致GABA快速增加（达到基线的120%），而强迫游泳则导致显著下降（降至基线的70%）。为了区分强迫游泳的心理和生理方面（即对体温的影响），另一组动物被强迫在35摄氏度下游泳。这种应激源与新奇环境一样，导致海马体GABA增加，表明心理应激具有刺激作用。新奇环境的影响不能被促肾上腺皮质激素释放因子受体拮抗剂D-Phe-CRF(12 - 41)阻断。这些结果首次证明了海马体细胞外GABA水平会因应激源不同而发生变化；这一观察结果可能对海马体神经元的GABA能持续性抑制具有特别重要的意义。
