Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice

• DOI: 10.1007/s00213-008-1103-1
• Publication Date: 2008-03-03T07:09:13Z
• Authors: Ming-Huan Chan; Pao-Hsiang Chiu; Jen-Hou Sou; Hwei-Hsien Chen
• Keywords: Male; 0301 basic medicine; Mice, Inbred ICR; Reflex, Startle; Behavior, Animal; Receptor, Metabotropic Glutamate 5; Glycine; Recognition, Psychology; Motor Activity; Receptors, Metabotropic Glutamate; Mice; 03 medical and health sciences; Hydrazines; Animals; Ketamine; Cognition Disorders; Excitatory Amino Acid Antagonists; Postural Balance; Psychomotor Performance; Injections, Intraventricular; Phenylacetates

Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate receptor function. Our previous findings demonstrated that the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the antagonist 2-methyl-6-(phenylethynyl)-pyridine can reduce and enhance the ketamine anesthesia, respectively.The purpose of this study was to examine whether CHPG and positive allosteric modulator 3,3'-difluorobenzaldazine (DFB) can reverse ketamine-induced behavioral responses including locomotor hyperactivity, motor incoordination, sensorimotor gating deficit, and learning impairment.Mice were pretreated with CHPG (5-50 nmol,) or DFB (40-100 nmol) followed by ketamine administration. Locomotor activity, rotarod test, prepulse inhibition (PPI) of acoustic startle test, and novel object recognition test were examined.CHPG and DFB had no effect on these behaviors when administered alone. Both of them attenuated the locomotor hyperactivity, motor incoordination, and cognitive impairment induced by ketamine. However, the ketamine-induced PPI deficit was reversed by CHPG (50 nmol) but not by DFB (up to 100 nmol). CHPG and DFB have distinct potency and efficacy in attenuating ketamine-induced behavioral response.These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.