Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission
Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission
复制标题
DOI：
10.1007/s00213-011-2295-3
复制
发表时间：
2011-10-01
影响因子：
3.4
通讯作者：
Matsuda, Toshio
中科院分区：
文献类型：
--
作者：
Ago, Yukio;Araki, Ryota;Matsuda, Toshio
代谢型谷氨酸 (mGlu) 2/3 受体激动剂可抑制安非他明和苯环己哌啶诱导的过度运动。 mGlu2/3 受体激动剂的抗精神病作用机制是在低谷氨酸能模型中研究的，而不是在高多巴胺能模型中研究的。为了研究激动剂在高多巴胺能模型中的抗精神病作用机制，本研究考察了选择性 mGlu2/3 受体激动剂 MGS0028 对甲基苯丙胺诱导的抗精神病作用的影响。 小鼠前额皮质和伏核中的过度运动以及血清素、多巴胺、去甲肾上腺素和谷氨酸的细胞外水平增加。MGS0028的全身给药以剂量依赖性方式减弱甲基苯丙胺诱导的过度运动。微透析研究表明，MGS0028 显着抑制甲基苯丙胺诱导的前额皮质细胞外血清素水平增加，但不影响多巴胺和去甲肾上腺素水平，并且不影响甲基苯丙胺诱导的伏隔核细胞外胺水平增加。甲基苯丙胺不影响前额皮质和伏核的谷氨酸释放。将 MGS0028 局部应用到前额叶皮层还可以减弱甲基苯丙胺引起的过度运动，并增加前额叶皮层的细胞外血清素水平。此外，在用血清素合成抑制剂对氯苯丙氨酸预处理的小鼠中，MGS0028不会影响甲基苯丙胺诱导的过度运动。前额叶mGlu2/3受体的激活抑制了甲基苯丙胺对小鼠的精神运动兴奋作用，前额叶血清素能系统可能参与了这种作用。这一发现提供了前额叶 mGlu2/3 受体与血清素能系统功能耦合的证据。
Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model.To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice.Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor.Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.