Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat

Abstract

Rationale: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. Objectives: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. Method: Responses to 25 mg kg −1 S(+) isomer, R(−) isomer and racemic ketamine in independent groups of Sprague–Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. Results: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(−) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(−) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. Conclusions: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(−) isomer comparative to the racemate offers significant differences of interest.