A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist

doi:10.1073/pnas.012260599

A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist

Departments of ^*Psychiatry and ^†Neurology and Neurosurgery, ^‡Department of Radiology and Mallinckrodt Institute of Radiology, and ^∥Department of Anatomy and Neurobiology, School of Medicine, and ^¶School of Engineering, Washington University, 660 South Euclid Avenue, St. Louis, MO 63110

Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved November 1, 2002 (received for review May 7, 2002)

Abstract

Dopamine can induce fascinating, complex human behavioral states, including disinhibition, euphoria, or elaborate stereotypies, whereas dopamine deficiency can cause anxiety or sadness. Limited data suggest that these phenomena may involve dysfunction of orbital frontal cortex, cingulate cortex, or ventral striatum. The dopamine D3 receptor (D3R) has an anatomic distribution that suggests it could mediate these effects, but almost no data directly demonstrate the regional functional effects of D3R activation. We used quantitative positron emission tomography (PET), [¹⁵O]water, and the D3-preferring dopamine agonist pramipexole to identify D3-mediated regional cerebral blood flow (rCBF) responses in living primates. We studied seven normal baboons ventilated with 70% nitrous oxide, and analyzed results voxelwise in a common atlas space. At clinically relevant doses, pramipexole produced statistically robust decreases in rCBF in bilateral orbitofrontal cortex, thalamus, operculum, posterior and anterior (subgenual) cingulate cortex, and insula (in decreasing order of significance). Cortical areas related to movement were relatively unaffected, and rCBF did not change in cerebellum or visual cortex. The dose-response curve and duration of pramipexole's effects suggest that these rCBF responses indicate functional effects of a D3-preferring agonist. A D2-preferring agonist studied under the same conditions produced a quantitatively different pattern of responses. We conclude that a dopamine D3 receptor agonist preferentially affects brain activity in prefrontal and limbic cortex, and speculate that dopamine's effects on these regions via D3Rs may mediate some of the known psychiatric complications of dopamine deficiency or excess.

Footnotes

↵ § To whom correspondence should be addressed at: Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110-1093. E-mail: kevin{at}npg.wustl.edu.
This work was presented in part at the Society for Neuroscience Annual Meeting, November 18, 1996, and at the Joint Annual Meeting of the American Neuropsychiatric Association and Behavioral Neurology Society, February 3, 1998.
This paper was submitted directly (Track II) to the PNAS office.
↵ ** Camacho-Ochoa, M., Evans, D. L., Walker, E. L., Mattichak, S. & Piercey, M. F. (1994) Soc. Neurosci. Abstr. 20, 1355.
↵ †† Perlmutter, J. S., Rowe, C. C. & Lich, L. L. (1993) J. Cereb. Blood Flow Metab. 13, S286 (abstr.).
↵ ‡‡ Piercey, M. F., Smith, M. W., Haadsma-Svensson, S. R. & Hoffman, W. E. (1994) Soc. Neurosci. Abstr. 20, abstr. 555.10.
↵ ¶¶ Piercey, M. F., Moon, M. W., Hoffmann, W. E., Walters, R., Blanchet, P. J. & Bedard, P. J. (1992) Soc. Neurosci. Abstr. 18, 1081.
↵ §§ Black, K. J., Hershey, T., Hartlein, J. M., Carl, J. L. & Perlmutter, J. S. (2001) Mov. Disord. 16, S56 (abstr.).
Abbreviations:
1. D3R, dopamine D3 receptor
2. CBF, cerebral blood flow
3. rCBF, regional CBF
4. PET, positron emission tomography
5. FDG, [¹⁸F]fluorodeoxyglucose