Selective potentiation of (*4)3(*2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.
Selective potentiation of (*4)3(*2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.
复制标题
(*4)3(*2)2 烟碱乙酰胆碱受体的选择性增强可增加大鼠前额叶乙酰胆碱和尼古丁诱发的谷氨酸瞬变的幅度。
DOI：
10.1016/j.bcp.2013.09.005
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发表时间：
2013
影响因子：
5.8
通讯作者：
Grunnet,Morten
中科院分区：
文献类型：
--
作者：
Grupe,Morten;Paolone,Giovanna;Jensen,AndersA;Sandager-Nielsen,Karin;Sarter,Martin;Grunnet,Morten
前额叶谷氨酸释放是通过激活丘脑谷氨酸能传入通路上的α4β2*烟碱乙酰胆碱受体（nAChRs）介导线索检测过程，从而有助于注意力表现。然而，对于α4β2 nAChR (α4)2(β2)3和（α4）3(β2)2的高灵敏度和低灵敏度（LS）化学计量学分别对这些过程的贡献知之甚少。本研究采用谷氨酸敏感微电极和（α4）3(β2)2选择性正变构调节剂（PAM） NS9283，研究了LS α4β2 nAChR在大鼠内侧前额叶皮层（mPFC）谷氨酸释放中的作用。首先，生理相关ACh浓度通过HEK293细胞中的（α4）3(β2)2nAChR引起的信号被NS9283增强，符合NS9283作为PAM的分类。在脲麻醉大鼠中，NS9283的前额叶内压射能诱发谷氨酸能瞬态。重要的是，这种谷氨酸释放通过去除记录区域的胆碱能投射而减弱。这一发现表明NS9283的作用依赖于内源性乙酰胆碱，再次与PAM的作用一致。然后，我们进行微透析，以证明在尿素麻醉的对照大鼠细胞外乙酰胆碱的存在。虽然可以检测到，但这些水平明显低于清醒的大鼠。最后，全身给药NS9283 （3.0 mg/kg）后，低浓度尼古丁局部压射引起的谷氨酸能瞬态振幅显著增强。综上所述，我们的研究结果表明，LS α4β2 nAChR PAM如NS9283可能增强皮层中谷氨酸能神经传递的胆碱能调节，从而可能减轻一系列脑部疾病常见的注意力障碍。
Prefrontal glutamate release evoked through activation of α4β2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the α4β2 nAChR, (α4)2(β2)3and (α4)3(β2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (α4)3(β2)2-selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS α4β2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC). Firstly, the signaling evoked by physiologically relevant ACh concentrations through the (α4)3(β2)2nAChR in HEK293 cells was potentiated by NS9283, consistent with the classification of NS9283 as a PAM. In urethane-anesthetized rats, intra-prefrontal pressure ejections of NS9283 evoked glutamatergic transients. Importantly, this glutamate release was attenuated by removal of cholinergic projections to the recording area. This finding indicates that the effects of NS9283 depend on endogenous ACh, again consistent with effects of a PAM. We then conducted microdialysis to demonstrate the presence of extracellular ACh in urethane-anesthetized control rats. While detectable, those levels were significantly lower than in awake rats. Finally, the amplitudes of glutamatergic transients evoked by local pressure ejections of a low concentration of nicotine were significantly augmented following systemic administration of NS9283 (3.0 mg/kg). In conclusion, our results indicate that a LS α4β2 nAChR PAM such as NS9283 may enhance the cholinergic modulation of glutamatergic neurotransmission in the cortex, thereby perhaps alleviating the attentional impairments common to a range of brain disorders.