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

Abstract

RATIONALE:

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.

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.

• Authors: Ming-Huan Chan, Pao-Hsiang Chiu, Jen-Hou Sou, Hwei-Hsien Chen
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 198 Issue 1 Pg. 141-8 (May 2008) ISSN: 0033-3158 [Print] Germany
• PMID: 18311557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-chloro-5-hydroxyphenylglycine
• 3,3'-difluorobenzaldazine
• Excitatory Amino Acid Antagonists
• Grm5 protein, mouse
• Hydrazines
• Phenylacetates
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• Ketamine
• Glycine

Topics

• Animals
• Behavior, Animal (drug effects)
• Cognition Disorders (chemically induced, drug therapy, psychology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• Hydrazines (pharmacology)
• Injections, Intraventricular
• Ketamine (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Motor Activity (drug effects)
• Phenylacetates (pharmacology)
• Postural Balance (drug effects)
• Psychomotor Performance (drug effects)
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (drug effects)
• Recognition, Psychology (drug effects)
• Reflex, Startle (drug effects)