Dopamine D₂/D₃ receptor binding of [¹²³I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging

Introduction: Epidepride is a compound with an affinity in picomolar range for D₂/D₃ receptors. The aim of this work was designed to investigate the diagnostic possibility of [¹²³I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model. Methods: Rats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3mg/kg/day) or saline for 4weeks. After 1-week administration of MK-801, rats in MK-801+risperidone group received risperidone (0.5mg/kg/day) intraperitoneally 15min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [¹²³I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain. Results: Risperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D₂R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [¹²³I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [¹²³I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively. Conclusions: We established a rat schizophrenia model by chronic MK-801 administration for 4weeks. [¹²³I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D₂R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [¹²³I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model.