Effects of positive allosteric modulators of the metabotropic glutamate receptor subtype 5 on ketamine-induced behavioral responses

• Main Authors: Pao-Hsiang Chiu, 邱保祥
• Other Authors: Hwei-Hsien Chen
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/86576787900808624606

碩士 === 慈濟大學 === 藥理暨毒理學研究所 === 95 === Metabotropic glutamate subtype 5 receptors have been suggusted to play a role in schizophrenia. Ketamine-induced behavioral changes in mice will be used as experimental model for schizophrenia, to determine if mGluR5 positive allosteric modulators attenuate ketamine-induced schizophrenia-like behavioral responses including locomotor hyperactivity, motor incoordination, disruption of the prepulse inhibition (PPI) of the startle reflex, deficits on learning and memory and social isolation. Mice received mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 5-50 nmole), mGluR5 positive allosteric modulators 3,3'-difluorobenzaldazine (DFB, 20-100 nmole) or vehicle 5 μl intracerebroventricularly (i.c.v.) 5 min prior to IP injection of saline or ketamine. The results showed that DFB and CHPG attenuated ketamine-induced hyperactivity, motor incoordination, learning and memory impairment and social isolation. However, CHPG (50 nmol) reversed the ketamine-induced disruption of the PPI, while DFB (up to 100 nmol) turned out to be ineffective. 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB, 100 nmole), a positive allosteric modulator of mGluR5 with higher potency and efficacy than DFB, reversed the ketamine-induced disruption of the PPI. In addition, the role of GSK-3 in ketamine-induced behavioral responses was also evaluated. GSK-3 inhibitor SB216763 (100 pnmol) attenuated ketamine-induced hyperactivity, motor incoordination and disruption of the PPI. These findings suggust that positive modulation of mGluR5 and GSK-3 inhibitor may provide novel approaches for treatment of psychiatric disorders.