Mapping the central effects of ketamine in the rat using pharmacological MRI.
BACKGROUND
Ketamine induces, in both humans and rodents, behaviours analogous to some of the symptoms of schizophrenia.


OBJECTIVE
To utilise pharmacological magnetic resonance imaging (phMRI) techniques that identify changes in blood-oxygenation-level-dependent (BOLD) contrast to determine the temporal and spatial neuronal activation profile of ketamine in the rat brain.


METHODS
To obtain a pharmacodynamic profile of the drug, we assessed changes in locomotor activity after vehicle and 10 and 25 mg/kg ketamine. Separate animals were then anaesthetised and placed in a 4.7-T magnetic resonance (MR) system before receiving the same doses of ketamine during serial MR image acquisition. Subsequent statistical parametric mapping of the main effect of the drug was then undertaken to identify changes in BOLD contrast. Levels of gamma-aminobutyric acid (GABA) and dopamine (DA) in brain areas showing localised changes in BOLD contrast were then assessed via microdialysis.


RESULTS
Both doses of ketamine produced increases in BOLD image contrast in frontal, hippocampal, cortical and limbic areas. A further investigation of the release of DA and its metabolites in the nucleus accumbens, both in anaesthesised and freely moving rats, corroborated these findings. However, an investigation of GABA and DA levels in the ventral pallidum gave no indication of changes in activity.


CONCLUSIONS
Ketamine produced localised dose-dependent alterations in BOLD MR signal, which correlate with the pharmacodynamic profile of the drug. These results can be, at least, partially substantiated with complementary techniques but consideration must be given to the input function applied to the MR signal and the use of anaesthesia during phMRI experimentation.
Neuroimaging Research Group, Institute of Psychiatry, King's College, London, De Crespigny Park, London, SE5 8AF, UK. C.Littlewood@iop.kcl.ac.uk
Clare L
CL
Littlewood
Nicholas
N
Jones
Michael J
MJ
O'Neill
Stephen N
SN
Mitchell
Mark
M
Tricklebank
Steven C R
SC
Williams
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D004298:Dopamine