Kenny Paul J, Gasparini Fabrizio, Markou Athina
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Pharmacol Exp Ther. 2003 Sep;306(3):1068-76. doi: 10.1124/jpet.103.052027. Epub 2003 Jun 12.
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.
本研究调查了离子型和代谢型谷氨酸受体在脑奖赏功能缺陷中的作用，该缺陷通过颅内自我刺激（ICSS）奖赏阈值升高来衡量，与尼古丁戒断有关。II型代谢型谷氨酸（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）使尼古丁依赖但非对照大鼠的ICSS阈值出现类似戒断的升高，ICSS阈值是奖赏功能的一项敏感指标。LY314582不影响反应潜伏期，反应潜伏期是ICSS范式中一项关于行为表现的指标。向腹侧被盖区双侧微量注射LY314582（10 - 100 ng/侧）同样使尼古丁依赖大鼠的阈值出现剂量依赖性升高。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-[黄嘌呤-9-基]丙酸）（1 mg/kg）可减弱在经历自发尼古丁戒断的大鼠中观察到的阈值升高。mGluII受体主要位于整个中脑皮质边缘系统的谷氨酸能终末，在那里它们作为抑制性自身受体发挥作用。为了研究mGluII受体是否通过减少谷氨酸能传递导致尼古丁戒断，我们接下来检查了直接阻断突触后谷氨酸受体是否会在尼古丁依赖大鼠中引发类似戒断的奖赏缺陷。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸受体拮抗剂2,3-二羟基-6-硝基-7-氨磺酰基苯并[f]喹喔啉（NBQX；0.01 - 1 mg/kg）使尼古丁依赖但非对照大鼠的阈值出现类似戒断的升高，而代谢型谷氨酸5受体拮抗剂6-甲基-2-[苯乙炔基]-吡啶（MPEP；0.01 - 3 mg/kg）和N-甲基-D-天冬氨酸受体拮抗剂地卓西平（MK-801；0.01 - 0.2 mg/kg）则不会。总体而言，这些数据表明mGluII受体在与尼古丁戒断相关的奖赏缺陷中起重要作用。此外，mGluII受体很可能至少部分地通过减少AMPA/海人藻酸受体处的谷氨酸传递来产生这种奖赏缺陷。
