Psychopharmacology

, Volume 212, Issue 1, pp 59–72

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

  • Ji-Kyung Choi
  • Joseph B. Mandeville
  • Y. Iris Chen
  • Peter Grundt
  • Susanta K. Sarkar
  • Amy H. Newman
  • Bruce G. Jenkins
original investigation

Abstract

Rationale

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.

Objectives

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.

Keywords

Cortical layers Dopamine D3 receptor Hippocampus Hypothalamus Infralimbic cortex Limbic circuitry MRI Nucleus accumbens Subiculum 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ji-Kyung Choi
    • 1
  • Joseph B. Mandeville
    • 1
  • Y. Iris Chen
    • 1
  • Peter Grundt
    • 2
  • Susanta K. Sarkar
    • 3
  • Amy H. Newman
    • 2
  • Bruce G. Jenkins
    • 1
  1. 1.Athinoula A. Martinos Center for Biomedical Imaging, Department of RadiologyMassachusetts General Hospital and Harvard Medical SchoolCharlestownUSA
  2. 2.Medicinal Chemistry SectionNational Institute on Drug Abuse-Intramural Research Program, National Institutes of HealthBaltimoreUSA
  3. 3.Medicine Development, Oncology R&DGlaxoSmithKlineCollegevilleUSA

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