Neuroscience Research and Development Unit, Institut de Recherches Servier, 125 Chemin de ronde, Croissy-sur-Seine, Paris, France.
Psychopharmacology (Berl). 2013 Feb;225(3):579-94. doi: 10.1007/s00213-012-2845-3. Epub 2012 Sep 16.
Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.
代谢型谷氨酸 5 型受体（mGluR5）与 N-甲基-D-天冬氨酸（NMDA）受体物理和功能相互作用，同样控制认知过程，并被提议作为新型抗精神病药物的靶点。由于社会认知在精神分裂症中受损，并且 NMDA 受体拮抗剂如地卓西平会破坏这种认知，我们评估了其对 mGluR5 的潜在调节作用。mGluR5 正变构调节剂（PAMs）3-氰基-N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺（CDPPB）和 ADX47273 的急性给药（0.63-40mg/kg）可逆转成年大鼠延迟诱导的社会新颖性辨别（SND）障碍。CDPPB 的作用被 mGluR5 拮抗剂 2-甲基-6-(苯乙炔基)-吡啶（2.5-10mg/kg）阻断，并且在皮层内注射时也得到表达（0.63-10μg/侧），但在纹状体中没有。支持 mGluR5 和 NMDA 受体之间的相互关系，CDPPB 增强 SND 的作用被地卓西平（0.08mg/kg）阻断，而相反，地卓西平诱导的 SND 障碍被 CDPPB（10mg/kg）减弱。在成年时用苯环利定（10mg/kg，第 7-11 天）进行产后给药引起的 SND 缺陷可被 CDPPB 或 ADX47273 逆转，成年大鼠在第 8 周时出现这种苯环利定引起的认知障碍，并且在青少年时期用 CDPPB 进行慢性、亚临床治疗（每周 5-6 天，每天 10mg/kg）可防止成年大鼠出现 SND 缺陷，直到至少第 13 周。总之，通过 SND 程序评估，mGluR5 PAMs 通过在与 NMDA 受体相互作用中表达的作用促进社会认知，并在皮层中发挥作用。mGluR5 PAMs 不仅可以逆转，而且（在青春期给予时）还可以预防与精神分裂症发育模型相关的认知障碍的出现。
