Abstract
Neuroimaging techniques have been exploited to characterize the effect of N-methyl-d-aspartate (NMDA) receptor antagonists on brain activation in humans and animals. However, most preclinical imaging studies were conducted in anesthetized animals and could be confounded by potential drug-anesthetic interactions as well as anesthetic agents' effect on brain activation, which may affect the translation of these basic research findings to the clinical setting. The main aim of the current study was to examine the brain activation elicited by the infusion of a subanesthetic dose of ketamine using blood oxygenation level dependence (BOLD) pharmacological magnetic resonance imaging (phMRI) in awake rats. However, a secondary aim was to determine whether a behaviorally active metabotropic glutamate 2/3 receptor agonist, (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), could modulate the effects of ketamine-induced brain activation. Our data indicate that ketamine produces positive BOLD signals in several cortical and hippocampal regions, whereas negative BOLD signals were observed in regions, such as periaqueductal gray (PAG) (p < 0.05). Furthermore, pretreatment of LY379268 significantly attenuated ketamine-induced brain activation in a region-specific manner (posterior cingulate, entorhinal, and retrosplenial cortices, hippocampus CA1, and PAG). The region-specific brain activations observed in this ketamine phMRI study may afford a method of confirming central activity and dose selection in early clinical trials for novel experimental therapeutics.
Footnotes
This work was supported by Abbott Laboratories.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.173880.
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ABBREVIATIONS:
- MRI
- magnetic resonance imaging
- phMRI
- pharmacological MRI
- fMRI
- functional MRI
- BOLD
- blood oxygenation level dependence
- PD
- pharmacodynamic
- mGluR2/3
- metabotropic glutamate 2/3
- NMDA
- N-methyl-d-aspartate
- rCBV
- relative cerebral blood volume
- PAG
- periaqueductal gray
- EPI
- echo-planar imaging
- PCP
- phencyclidine
- LY379268
- (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid
- ROI
- regions of interest
- BINA
- biphenyl indanone-A.
- Received August 31, 2010.
- Accepted December 1, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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