Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat.
BACKGROUND
Ketamine is a chiral molecule that is reported to model aspects of schizophrenia.


OBJECTIVE
To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions.


METHODS
Responses to 25 mg kg-1S(+) 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.
Littlewood
Clare L
CL
King's College London, Neuroimaging Research Group, Institute of Psychiatry, PO42 De Crespigny Park, London SE5 8AF, UK. C.Littlewood@iop.kcl.ac.uk
Cash
Diana
D
Dixon
Aisling L
AL
Dix
Sophie L
SL
White
Craig T
CT
O'Neill
Michael J
MJ
Tricklebank
Mark
M
Williams
Steven C R
SC
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects; D015331:Cohort Studies; D003847:Deoxyglucose; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000737:chemistry / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010100:Oxygen / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D013237:Stereoisomerism
D000778:Anesthetics, Dissociative; D000963:Antimetabolites; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D003847:Deoxyglucose; D005947:Glucose; D010100:Oxygen