Pharmacological MRI in awake rats predicts selective binding of alpha4beta2 nicotinic receptors.
Neuronal nicotinic receptors are the subject of intensive research focused on developing novel therapies for drug abuse, neurocognitive disorders, neurodegenerative diseases, and pain. In this study, we have applied pharmacological magnetic resonance imaging (phMRI) in awake rats to map functional brain responses to the selective alpha(4)beta(2) nicotinic receptor agonists, A-85380, and ABT-594. Moreover, we have validated our methods by comparison with autoradiography using [(3)H]-A-85380 and [(3)H]-ABT-594. Under awake conditions (no anesthesia during scanning) where rats were habituated to the imaging environment, both compounds increased regional cerebral blood volume (rCBV) across multiple brain regions that closely matched regional brain receptor distribution with the same tritiated compounds. In addition, regional ABT-594-induced rCBV changes under awake conditions were also derived and characterized using a pharmacological model. Area-under-curve and maximum rCBV changes in brain were found to be dose-related and region-specific, and corresponded well with the known preclinical behavioral profile of this drug. In contrast, under conditions of alpha-chloralose anesthesia where physiological variables were maintained within normal ranges, increases in rCBV induced by ABT-594 were primarily restricted to some cortical areas and did not agree well with autoradiography data. Our data demonstrate the utility of using phMRI in awake animals to characterize selective pharmacological action but also highlight an important confound (anesthesia) that is rarely considered in preclinical phMRI studies.
Chin
Chih-Liang
CL
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Pauly
James R
JR
Surber
Bruce W
BW
Skoubis
Pamela D
PD
McGaraughty
Steve
S
Hradil
Vincent P
VP
Luo
Yanping
Y
Cox
Bryan F
BF
Fox
Gerard B
GB
D000818:Animals; D001384:Azetidines / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D008279:Magnetic Resonance Imaging; D008297:Male; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology*
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; C104288:A 85380; D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D014316:Tritium