Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA.
Psychopharmacology (Impact Factor: 3.99). 09/2010; 212(1):59-72. DOI: 10.1007/s00213-010-1924-6
Source: PubMed

ABSTRACT 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.

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    • "The D2-like family includes D2, D3 and D4 receptors that interact with G i or G 0 proteins (Neve et al., 2004). DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas (Choi et al., 2010) that have been found to be critically involved in reward-related learning induced by drugs of abuse (Di Chiara and Imperato, 1988; Nestler, 2005; Stuber et al., 2005; Hyman et al., 2006; Schultz, 2010). This expression pattern has sparked numerous studies on the role of this receptor in drug-induced behaviors and motivated intense efforts in drug discovery (Parsons et al., 1996; Pilla et al., 1999; Heidbreder et al., 2005; Micheli and Heidbreder, 2008; Heidbreder and Newman, 2010; Spanagel and Vengeliene, 2013). "
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    • "Indeed, the time course for the CBV change induced with cocaine in the hypothalamus matches well with the time course produced by administration of the D3 agonist 7-OHDPAT (compare time courses in Fig. 6 with Fig. 9) and both responses are larger in the saline-yoked animals than in the cocaine SA animals. We recently showed that 7-OHDPAT produces negative CBV changes in hypothalamus whereas the D3 selective antagonist PG-01037 produces positive changes in the hypothalamus (Choi et al., 2010). Therefore, these data suggest that measurement of cocaine-induced signal changes in hypothalamus may produce a readout on the status of D3 receptors, although this concept requires further proof. "
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