COMPARATIVE STUDY
JOURNAL ARTICLE

Xanomeline modulation of the blood oxygenation level-dependent signal in awake rats: development of pharmacological magnetic resonance imaging as a translatable pharmacodynamic biomarker for central activity and dose selection

Scott Baker, Chih-Liang Chin, Ana M Basso, Gerard B Fox, Gerard J Marek, Mark Day
Journal of Pharmacology and Experimental Therapeutics 2012, 341 (1): 263-73
22267203
In vivo translational imaging techniques, such as positron emission tomography and single-photon emission-computed tomography, are the only ways to adequately determine that a drug engages its target. Unfortunately, there are far more experimental mechanisms being tested in the clinic than there are radioligands, impeding the use of this risk-mitigating approach in modern drug discovery and development. Pharmacological magnetic resonance imaging (phMRI) offers an approach for developing new biomarkers with the potential to determine central activity and dose selection in animals and humans. Using phMRI, we characterized the effects of xanomeline on ketamine-induced activation on blood oxygen level-dependent (BOLD) signal. In the present studies, xanomeline alone dose-dependently increased the BOLD signal across several regions of interest, including association and motor and sensory cortical regions. It is noteworthy that xanomeline dose-dependently attenuated ketamine-induced brain activation patterns, effects that were antagonized by atropine. In conclusion, the muscarinic 1/4-preferring receptor agonist xanomeline suppressed the effects of the N-methyl-D-aspartate channel blocker ketamine in a number of brain regions, including the association cortex, motor cortex, and primary sensory cortices. The region-specific brain activation observed in this ketamine challenge phMRI study may provide a method of confirming central activity and dose selection for novel antipsychotic drugs in early clinical trials for schizophrenia, if the data obtained in animals can be recapitulated in humans.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
22267203
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"