Carter Kevin, Dickerson Jon, Schoepp Darryle D, Reilly Melinda, Herring Nicole, Williams Jon, Sallee Floyd R, Sharp James W, Sharp Frank R
Department of Neurology, University of Cincinnati, Cincinnati, OH 45267, USA.
Neuropharmacology. 2004 Dec;47(8):1135-45. doi: 10.1016/j.neuropharm.2004.08.018.
The non-competitive NMDA receptor antagonists, including PCP (phencyclidine), ketamine, and MK-801 (dizocilpine) produce psychosis in humans and injure neurons in retrosplenial cortex in adult rodent brain. This study examined the effects of the metabotropic mGlu2/3 agonist LY379268 and antagonist LY341495 on cortical injury produced by systemic MK-801 (1 mg/kg i.p.) in adult female rats. Systemic injections of mGlu2/3 agonist LY379268, but not mGlu2/3 antagonist LY341495, decreased the injury in the retrosplenial cortex produced by systemic MK-801 as assessed by Hsp70 induction. Bilateral injections of LY379268, but not vehicle, into retrosplenial cortex or bilateral injections of LY379268 into anterior thalamus also decreased the injury in retrosplenial cortex produced by systemic MK-801. The data show that bilateral activation of mGlu2/3 glutamate receptors in cortex or anterior thalamus decreases the neuronal injury in retrosplenial cortex produced by systemic MK-801. Because antipsychotic medications decrease cortical injury produced by NMDA antagonists in rodents and decrease psychosis in humans, mGlu2/3 agonists that decrease cortical injury produced by NMDA antagonists in rodents might be evaluated for decreasing psychosis in people.
非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，包括苯环己哌啶（PCP）、氯胺酮和MK-801（地佐环平）可在人类中引发精神病，并损伤成年啮齿动物大脑压后皮质中的神经元。本研究检测了代谢型谷氨酸受体mGlu2/3激动剂LY379268和拮抗剂LY341495对成年雌性大鼠全身注射MK-801（1毫克/千克，腹腔注射）所致皮质损伤的影响。通过热休克蛋白70（Hsp70）诱导评估发现，全身注射mGlu2/3激动剂LY379268可减轻全身注射MK-801所致的压后皮质损伤，而mGlu2/3拮抗剂LY341495则无此作用。向压后皮质双侧注射LY379268而非溶剂，或向前丘脑双侧注射LY379268，也可减轻全身注射MK-801所致的压后皮质损伤。数据表明，皮质或前丘脑中mGlu2/3谷氨酸受体的双侧激活可减轻全身注射MK-801所致的压后皮质神经元损伤。由于抗精神病药物可减轻啮齿动物中NMDA拮抗剂所致的皮质损伤，并减轻人类的精神病症状，因此，或许可以评估在啮齿动物中减轻NMDA拮抗剂所致皮质损伤的mGlu2/3激动剂对减轻人类精神病症状的作用。
