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

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.

Fig. 1.

Selected focal decreases observed after 500 μg/kg pramipexole i.v. (t map in color overlaid on atlas image in grayscale). (A and B) Crosshairs at most significant decrease, atlas (13, 36, 15). (C) Cingulate cortex, atlas (1, 32, 12).

Fig. 2.

rCBF, right orbitofrontal prefrontal cortex. Dose–response curve for a region of interest centered at atlas (13, 36, 15), the voxel with the most significant rCBF decrease after 500 μg/kg pramipexole i.v. (mean ± SD).

Fig. 3.

Change in regional CBF over time, region of maximal decrease (prefrontal cortex). Regional CBF changes after 500 μg/kg pramipexole i.v. persist over the time interval observed. Each point corresponds to one PET scan. Data are from the region of interest described in Fig. 1 A and B and Fig. 2.

Fig. 4.

Relative rCBF “increases” after 500 μg/kg pramipexole i.v. as identified by spm99 (t map in color overlaid on atlas image in grayscale).

Fig. 5.

Absolute rCBF at peak relative “increase.” The relative increases in rCBF after 500 μg/kg pramipexole i.v. are actually regions protected from the widespread decrease in rCBF. Data are from an 8-mm-diameter spherical region centered at the peak relative increase.

Fig. 6.

Change in rCBF at three dose levels of a D3-preferring agonist (pramipexole, open circles and solid line) and a D2-preferring agonist (U91356a, filled squares and dashed line). Pramipexole doses were 5, 50, and 500 μg/kg, and U91356a doses were 1–2, 10–22, and 100–220 μg/kg. For both drugs, the doses were chosen a priori so that the intermediate dose approximated the reported antiparkinsonian dose in monkeys.