Detection of the effects of dopamine receptor supersensitivity using pharmacological MRI and correlations with PET.
Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. (11)C-PET studies of ligands which bind to the dopamine transporter (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1, 5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding.
Nguyen
T V
TV
Department of Radiology, MGH-NMR Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Brownell
A L
AL
Iris Chen
Y C
YC
Livni
E
E
Coyle
J T
JT
Rosen
B R
BR
Cavagna
F
F
Jenkins
B G
BG
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000033:anatomy & histology / Q000098:blood supply / Q000378:metabolism; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects; D013563:Sympathectomy, Chemical; D013565:Sympatholytics; D014055:Tomography, Emission-Computed
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D016627:Oxidopamine; D000661:Amphetamine; D003042:Cocaine; D001058:Apomorphine