Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists
- 207 Downloads
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.
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.
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.
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.
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.
KeywordsCortical layers Dopamine D3 receptor Hippocampus Hypothalamus Infralimbic cortex Limbic circuitry MRI Nucleus accumbens Subiculum
This work was supported by NIH/NIDA DA16187-06.
- Chen YI, Choi JK, Xu H, Ren J, Andersen SL, Jenkins BG (2010) Pharmacologic neuroimaging of the ontogeny of dopamine receptor function. Dev Neurosci Jun 3, epub ahead of printGoogle Scholar
- Collins GT, Truccone A, Haji-Abdi F, Newman AH, Grundt P, Rice KC, Husbands SM, Greedy BM, Enguehard-Gueiffier C, Gueiffier A, Chen J, Wang S, Katz JL, Grandy DK, Sunahara RK, Woods JH (2009) Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice. J Pharmacol Exp Ther 329:210–217CrossRefPubMedGoogle Scholar
- Grundt P, Prevatt KM, Cao J, Taylor M, Floresca CZ, Choi JK, Jenkins BG, Luedtke RR, Newman AH (2007) Heterocyclic analogues of N-(4-(4-(2, 3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: potential substance abuse therapeutic agents. J Med Chem 50:4135–4146CrossRefPubMedGoogle Scholar
- Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N, N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci U S A 89:8155–8159CrossRefPubMedGoogle Scholar
- Meador-Woodruff (1994) Update on dopamine receptors. Ann Clin Psychiatry 6:79–90Google Scholar
- Neisewander JL, Fuchs RA, Tran-Nguyen LT, Weber SM, Coffey GP, Joyce JN (2004) Increases in dopamine D3 receptor binding in rats receiving a cocaine challenge at various time points after cocaine self-administration: implications for cocaine-seeking behavior. Neuropsychopharmacology 29:1479–1487CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
- Rabiner EA, Slifstein M, Nobrega J, Plisson C, Huiban M, Raymond R, Diwan M, Wilson AA, McCormick P, Gentile G, Gunn RN, Laruelle MA (2009) In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: studies in non-human primates and transgenic mice. Synapse 63:782–793CrossRefPubMedGoogle Scholar
- Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC, Hadley MS, Hunter AJ, Jeffrey P, Jewitt F, Johnson CN, Jones DN, Medhurst AD, Middlemiss DN, Nash DJ, Riley GJ, Routledge C, Stemp G, Thewlis KM, Trail B, Vong AK, Hagan JJ (2000) Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 294:1154–1165PubMedGoogle Scholar
- Schwarz AJ, Gozzi A, Reese T, Heidbreder CA, Bifone A (2007) Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D3 receptor antagonist SB277011A. Magn Reson Imaging 25:811–820CrossRefPubMedGoogle Scholar
- Zaharchuk G, Mandeville JB, Bogdanov AA Jr, Weissleder R, Rosen BR, Marota JJ (1999) Cerebrovascular dynamics of autoregulation and hypoperfusion. An MRI study of CBF and changes in total and microvascular cerebral blood volume during hemorrhagic hypotension. Stroke 30:2197–2204, discussion 2204-5PubMedGoogle Scholar