Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data.
The metabolic activation resulting from direct dopaminergic stimulation can be detected using auto-radiography, positron emission tomography (PET) or, potentially, fMRI techniques. To establish the validity of the latter possibility, we have performed a number of experiments. We measured the regional selectivity of two different dopaminergic ligands: the dopamine release compound D-amphetamine and the dopamine transporter antagonist 2 beta-carbomethoxy-3 beta-(4-fluoropheny) tropane (CFT). Both compounds led to increased signal intensity in gradient echo images in regions of the brain with high dopamine receptor density (frontal cortex, striatum, cingulate cortex > > parietal cortex). Lesioning the animals with unilaterally administered 6-hydroxydopamine (6-OHDA) led to ablation of the phMRI response on the ipsilateral side; control measurements of rCBV and rCBF using bolus injections of Gd-DTPA showed that the baseline rCBV and rCBF values were intact on the lesioned side. The time course of the BOLD signal changes paralleled the changes observed by microdialysis measurements of dopamine release in the striatum for both amphetamine and CFT; peaking at 20-40 min after injection and returning to baseline at about 70-90 min. Signal changes were not correlated with either heart rate, blood pressure or pCO2. Measurement of PET binding in the same animals showed an excellent correlation with the phMRI data when compared by either measurements of the number of pixels activated or percent signal change in a given region. The time course for the behavioral measurements of rotation in the 6-OHDA lesioned animals correlated with the phMRI. These experiments demonstrate that phMRI will become a valuable, noninvasive tool for investigation of neurotransmitter activity in vivo.
Chen
Y C
YC
Department of Radiology, Massachusetts General Hospital, USA.
Galpern
W R
WR
Brownell
A L
AL
Matthews
R T
RT
Bogdanov
M
M
Isacson
O
O
Keltner
J R
JR
Beal
M F
MF
Rosen
B R
BR
Jenkins
B G
BG
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D017551:Microdialysis / Q000379:methods*; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed / Q000379:methods*
D018663:Adrenergic Agents; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D016627:Oxidopamine; D003042:Cocaine; D003913:Dextroamphetamine; D004298:Dopamine