Endogenous kynurenic acid regulates extracellular GABA levels in the rat prefrontal cortex
Endogenous kynurenic acid regulates extracellular GABA levels in the rat prefrontal cortex
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DOI：
10.1016/j.neuropharm.2014.02.019
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发表时间：
2014-07-01
影响因子：
4.7
通讯作者：
Ferraro, Luca
中科院分区：
文献类型：
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作者：
Beggiato, Sarah;Tanganelli, Sergio;Ferraro, Luca
色氨酸代谢物kynurenic acid （KYNA）是α 7烟碱乙酰胆碱受体（α 7nAChR）的内源性拮抗剂，在较高浓度下，可抑制嗜离子性谷氨酸受体。精神分裂症（SZ）患者的脑和脑脊液中可见KYNA水平升高，可能与SZ和其他精神疾病的认知缺陷有因果关系。由于涉及前额皮质（PFC） GABA能神经元的回路功能障碍可能在这些疾病中看到的认知障碍中起作用，我们研究了KYNA对该脑区域细胞外GABA的影响。通过反透析作用于清醒大鼠2小时，KYNA浓度依赖性和可逆性地降低了细胞外GABA水平，300 nM KYNA引起的最低点类似于基线浓度的45%。选择性甘氨酸(B)受体拮抗剂7-Cl-KYNA （100 nM）或AMPA/kainate受体拮抗剂CNQX （100 μ M）的反透析不能重复这种作用，并且可以通过加兰他明（5 μ M） （α - 7nAChR的正变构调节剂）的共同应用来阻止这种作用。相反，通过反透析(S)-4-（乙基磺酰基）苯甲酰丙氨酸（ESBA; 5 mM）抑制内源性KYNA形成，可可逆地增加PFC中的GABA水平，达到峰值，接近基线浓度的160%。共输注30nm KYNA可中和这种作用。综上所述，这些结果证明了内源性KYNA在pfc中双向控制gaba能神经传递中的作用。因此，KYNA的药理操作可能有助于治疗SZ中的gaba能损伤和其他涉及pfc的脑部疾病。版权所有。
The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) and, at higher concentrations, inhibits ionotropic glutamate receptors. Increases in KYNA levels are seen in brain and cerebrospinal fluid in individuals with schizophrenia (SZ) and may be causally related to cognitive deficits in SZ and other psychiatric diseases. As dysfunction of circuits involving GABAergic neurons in the prefrontal cortex (PFC) likely plays a role in the cognitive impairments seen in these disorders, we examined the effects of KYNA on extracellular GABA in this brain area. Applied to awake rats for 2 h by reverse dialysis, KYNA concentration-dependently and reversibly reduced extracellular GABA levels, with 300 nM KYNA causing a nadir of similar to 45% of baseline concentrations. This effect was not duplicated by reverse dialysis of the selective glycine(B) receptor antagonist 7-Cl-KYNA (100 nM) or the AMPA/kainate receptor antagonist CNQX (100 mu M), and was prevented by co-application of galantamine (5 mu M), a positive allosteric modulator of the alpha 7nAChR. Conversely, inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 5 mM) reversibly increased GABA levels in the PFC, reaching a peak of similar to 160% of baseline concentrations. Co-infusion of 30 nM KYNA neutralized this effect. Taken together, these results demonstrate a role for endogenous KYNA in the bi-directional control of GABAergic neurotransmission in the PFC. Pharmacological manipulation of KYNA may therefore be useful in the treatment of GABAergic impairments in SZ and other brain disorders involving the PFC. (C) 2014 Elsevier Ltd. All rights reserved.