Effect of GNTI, a kappa opioid receptor antagonist, on MK-801-induced hyperlocomotion and stereotypy in mice

Aim： To examine the effect of GNTI [5＇-guanidinyl-17-（cyclopropylmethyl）-6,7- dehydro-4,5ot-epoxy-3,14-dihydroxy-6,7-2＇,3＇-indolomorphinan], a selective antagonist for the kappa opioid receptor, in the MK-801 （dizocilpine maleate）-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia. Methods： Two doses of MK-801 （0.3 mg/kg and 0.6 mg/kg） were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis. Results： GNTI inhibited MK-801-induced hypeflocomotion and stereotypy. In particular, GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg vs 0.6 mg/kg MK-801. Conclusion： Antagonism of kappa opioid receptors attenuates MK-801-induced behavior, suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia. GNTI appears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.