Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists.
BACKGROUND
Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry.


OBJECTIVE
We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry.


METHODS
We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography.


RESULTS
D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques.


CONCLUSIONS
MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum.
Choi
Ji-Kyung
JK
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA.
Mandeville
Joseph B
JB
Chen
Y Iris
YI
Grundt
Peter
P
Sarkar
Susanta K
SK
Newman
Amy H
AH
Jenkins
Bruce G
BG
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001810:Blood Volume; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000187:drug effects* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology
D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D009570:Nitriles; D011725:Pyridines; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D013764:Tetrahydronaphthalenes; C031349:7-hydroxy-2-N,N-dipropylaminotetralin