Group II metabotropic and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats
Group II metabotropic and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats
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DOI：
10.1124/jpet.103.052027
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Markou, A
中科院分区：
文献类型：
--
作者：
Kenny, PJ;Gasparini, F;Markou, A
本研究探讨了离子型和代谢型谷氨酸受体在尼古丁戒断相关的脑奖赏功能缺陷中的作用，其指标是脑内自我刺激(ICSS)奖赏阈值的升高。第II组代谢性谷氨酸(MGluII)受体激动剂LY314582[LY354740([+]-2-氨基双环[3.1.0]己烷-2，6-二羧酸的外消旋混合物](2.5-7.5 mg/kg)可使尼古丁依赖而非对照组大鼠的ICSS阈值出现类似戒断样的升高，ICSS阈值是衡量奖赏功能的敏感指标。LY314582不影响响应延迟，这是ICSS范例中的一种性能衡量标准。双侧腹侧被盖区微量注射LY314582(10-100 ng/侧)同样可引起尼古丁依赖大鼠的剂量依赖性阈值升高。此外，单次注射mGluII受体拮抗剂LY341495(2S-2-氨基-2-[1S，2S-2-羧基环丙烷-1-基]-3[Xanth-9-yl]丙酸)(1 mg/kg)可降低自发戒断尼古丁大鼠的阈值升高。MGluII受体主要位于整个皮质边缘系统的谷氨酸能终末，在那里它们起抑制性自身受体的作用。为了研究mGluII受体是否通过减少谷氨酸能传递而参与尼古丁戒断，我们接下来研究了直接阻断突触后谷氨酸受体是否导致尼古丁依赖大鼠的戒断样奖赏缺陷。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯(AMPA)/海人藻酸受体拮抗剂2，3-二羟基-6-硝基-7-氨基甲酰苯并(F)喹恶啉(NBQX；0.01-1 mg/kg)可引起尼古丁依赖大鼠戒断样阈值的升高，而6-甲基-2-[苯乙炔基]-吡啶(MPEP；0.01-3 mg/kg)和地佐西平(MK-801；0.01-0.2 mg/kg)则不能。总体而言，这些数据表明，mGluII受体在尼古丁戒断相关的奖赏不足中发挥着重要作用。此外，mGluII受体很可能通过减少AMPA/海人藻酸受体上的谷氨酸传递来产生这种奖赏缺陷，至少部分是这样。
This study investigated the role of ionotropic and metabotropic glutamate receptors in the deficits in brain reward function, as measured by elevations in intracranial self-stimulation (ICSS) reward thresholds, associated with nicotine withdrawal. The group II metabotropic glutamate (mGluII) receptor agonist LY314582 [a racemic mixture of LY354740 ([+]-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid])] (2.5-7.5 mg/kg) precipitated withdrawal-like elevations in ICSS thresholds, a sensitive measure of reward function, in nicotine-dependent but not control rats. LY314582 did not affect response latencies, a measure of performance in the ICSS paradigm. Bilateral microinfusion of LY314582 (10-100 ng/side) into the ventral tegmental area likewise precipitated dose-dependent threshold elevations in nicotine-dependent rats. Furthermore, a single injection of the mGluII receptor antagonist LY341495 (2S-2-amino-2-[1S, 2S-2-carboxycyclopropan-1-yl]-3[xanth-9-yl] propionic acid) (1 mg/kg) attenuated the threshold elevations observed in rats undergoing spontaneous nicotine withdrawal. mGluII receptors are primarily located on glutamatergic terminals throughout the mesocorticolimbic system, where they act as inhibitory autoreceptors. To investigate whether mGluII receptors contributed to nicotine withdrawal by decreasing glutamatergic transmission, we next examined whether direct blockade of postsynaptic glutamate receptors precipitated withdrawal-like reward deficits in nicotine-dependent rats. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline (NBQX; 0.01-1 mg/kg) precipitated withdrawal-like threshold elevations in nicotine-dependent but not control rats, whereas 6-methyl-2-[phenylethynyl]-pyridine (MPEP; 0.01-3 mg/kg) and dizocilpine (MK-801; 0.01-0.2 mg/kg), antagonists at metabotropic glutamate 5 and N-methyl-D-aspartate receptors, respectively, did not. Overall, these data demonstrate that mGluII receptors play an important role in the reward deficits associated with nicotine withdrawal. Furthermore, it is likely that mGluII receptors generate this reward deficit, at least in part, by decreasing glutamate transmission at AMPA/kainate receptors.