Impairments of probabilistic response reversal and passive avoidance following catecholamine depletion

Abstract

Catecholamines, particularly dopamine, have been implicated in various aspects of the reward function including the ability to learn through reinforcement and to modify flexibly responses to changing reinforcement contingencies. We examined the impact of catecholamine depletion (CD) achieved by oral administration of alpha-methyl-paratyrosine (AMPT) on probabilistic reversal learning and passive avoidance (PA) in 15 female subjects with major depressive disorder in full remission (RMDD) and 12 healthy female controls. The CD did not affect significantly the acquisition phase of the reversal learning task. However, CD selectively impaired reversal of the 80-20 contingency pair. In the PA learning task, CD was associated with reduced responding toward rewarding stimuli, although the RMDD and control subjects did not differ regarding these CD-induced changes in reward processing. Interestingly, the performance decrement produced by AMPT on both of these tasks was associated with the level of decreased metabolism in the perigenual anterior cingulate cortex. In an additional examination using the affective Stroop task we found evidence for impaired executive attention as a trait abnormality in MDD. In conclusion, this study showed specific effects of CD on the processing of reward-related stimuli in humans and confirms earlier investigations that show impairments of executive attention as a neuropsychological trait in affective illness.

Figure 1

Probabilistic Response Reversal Task: Number of errors by treatment and pair and learning phase. As expected, the numbers of errors were higher in the 100:0 pair trials than in the probabilistic 80:20 pair trials (p<0.001); and there were more errors in the reversal phase than in the acquisition phase (p<0.001). In the reversal phase of the 80:20 pair trials, errors were more frequent following catecholamine depletion than under placebo (drug by pair by phase interaction, p<0.05).

Figure 2

Passive Avoidance learning task: Number of omission of responses to rewarded stimuli by treatment and block. Following catecholamine depletion, subjects were less likely to respond to S+ stimuli in the later blocks (7–10) relative to the earlier blocks (1–4, p<0.01), while under placebo subject did not show such an influence of the blocks on the number of omission errors (drug by block interaction, p<0.05).

Figure 3

Affective Stroop Task: Error rates by group and condition. As expected, subjects made a greater number of errors as numerical distance between the target and distracter information decreased (p<0.05). In addition, the fully remitted subjects with MDD made significantly more errors for distance 2 (p <0.05; group by distance interaction, p<0.05)

Figure 4

Placement of the perigenual anterior cingulate cortex (ACC) region-of-interest (ROI) in the horizontal plane. The crosshair is placed over the pregenual ACC within the left perigenual ACC ROI. In this voxel, CD-induced change in brain metabolism correlated with CD-induced errors in the reward learning tasks: the greater the extent to which metabolism in perigenual ACC decreased under CD, the greater the number of 80:20 reversal errors occurred under CD relative to placebo (r = −0.52; p < 0.01) and the more often good stimuli were missed in blocks 7 to 10 relative to blocks 1 to 4 under CD versus placebo (r = −0.46; p < 0.05).