Dopamine agonist increases risk taking but blunts reward-related brain activity

Abstract

The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system.

Figure 1. Experimental paradigm.

Each trial of the lottery task comprised the presentation of two numbers, 25 and 5. Participants had to choose one of two numbers by pressing a corresponding button (left button for left number). One second after the participant's selection, the numbers changed color. Green indicated a win, red a loss. Thus, in the first (lower) example the subject incurred a loss of 25 Euro cent (while he could have won 5 Euro cent). The second (upper) example shows an infrequent “boost” trial in which gains were doubled. See the Materials and Methods section for further details.

Figure 2. Behavioral results.

The relationship between outcome in the previous trial and the probability of making a risky choice (choosing 25) is shown. Pramipexole significantly increased the probability of making a risky choice following an unexpected “boost+50” trial (left). The error bars denote ±1 standard error of mean.

Figure 3

(a) fMRI results (rostral basal ganglia). Axial slices at z = −3 showing voxels of greater activation for win (normal gain+boost) than loss trials in the ventral striatum after placebo and pramipexole. The time course of the BOLD response is shown for a ROI defined around voxel x = −15,y = −3,z = −3 in Talairach coordinates. Results are shown at p<0.001 uncorrected (n = 13). (b) fMRI results (midbrain). Axial slices at z = −8 showing the results of a conjunction analysis conducted to highlight those voxels where activation following unexpected high gains (boost+50 trials) was greater than the activation following normal gain trials and unexpected boost+10 trials after placebo and pramipexole. The time course of the BOLD response is shown for a ROI defined around voxel x = −4,y = −23,z = −8 in Talairach coordinates. Results are shown at p<0.0002 uncorrected (n = 13). In both panels (a and b), the color code is as follows: win trials (green; solid: 25 cent wins, dotted: 5 cent wins); loss trials (red; solid: 5 cent loss, dotted: 25 cent loss); boost trials (blue; solid: 50 cent wins, dotted: 10 cent wins).

Figure 4. fMRI results (cingulate gyrus).

Sagittal slices at x = −4 showing voxels of greater activation for win (normal gain+boost) than loss trials in the rostral anterior and posterior cingulate gyrus. Results are shown at p<0.001 uncorrected (n = 13).