Blocking central opiate function modulates hedonic impact and anterior cingulate response to rewards and losses

Abstract

Reward processing is linked to specific neuromodulatory systems with a dopaminergic contribution to reward learning and motivational drive being well established. Neuromodulatory influences on hedonic responses to actual receipt of reward, or punishment, referred to as experienced utility are less well characterized, although a link to the endogenous opioid system is suggested. Here, in a combined functional magnetic resonance imaging-psychopharmacological investigation, we used naloxone to block central opioid function while subjects performed a gambling task associated with rewards and losses of different magnitudes, in which the mean expected value was always zero. A graded influence of naloxone on reward outcome was evident in an attenuation of pleasure ratings for larger reward outcomes, an effect mirrored in attenuation of brain activity to increasing reward magnitude in rostral anterior cingulate cortex. A more striking effect was seen for losses such that under naloxone all levels of negative outcome were rated as more unpleasant. This hedonic effect was associated with enhanced activity in anterior insula and caudal anterior cingulate cortex, areas implicated in aversive processing. Our data indicate that a central opioid system contributes to both reward and loss processing in humans and directly modulates the hedonic experience of outcomes.

Figure 1.

A, Gambling task 1. Subjects had to choose a left or right wheel of fortune pressing a right or a left key. Each gamble had the same possible outcomes with an expected value of £0. The win and loss outcomes in each gamble varied from £1 to £10, making it possible to measure responses related to outcome magnitude. Subjects rated how they experienced the outcome of each gamble on a visual analog scale (VAS) from −100 (highest imaginable unpleasantness) to 100 (highest imaginable pleasantness). B, C, Behavioral results. The ratings of the subjects for all outcomes in the placebo and the naloxone day (B). Although treatment did not show any significant difference for overall reward outcomes, a significant effect was observed for the losses in that losses were experienced as more unpleasant after naloxone treatment with 10 of the 13 subjects showing this effect (C).

Figure 2.

Loss processing under placebo and naloxone. A, For placebo, loss versus zero outcome block showed increased activity in midcaudal and rostral ACC, bilateral insula, and visual cortex/precuneus. B, The same areas were activated in the naloxone condition. C, Testing for an interaction (including the parameter estimates) indicated greater activation for loss versus zero outcome blocks in caudal ACC, bilateral insula, subgenual ACC, precuneus, and extrastriate visual cortex under naloxone compared with placebo treatment. Error bars indicate SEM.

Figure 3.

Naloxone effect on outcome magnitude. A, B, Activity in rACC and PCC correlated with the outcome magnitude independent of value (from £1 to £10 for both rewards and losses) for both placebo (A) and naloxone (B) treatment. C, The effect was attenuated in rACC after naloxone treatment and was evident both for losses and rewards. Error bars indicate SEM. Pl, Placebo; Nal, naloxone.

Figure 4.

Naloxone effect on outcome magnitude for pleasure ratings and rACC activity in rewards and losses. A, B, Naloxone had a more negative effect the larger the reward outcome magnitude was both for affective ratings and activity in rACC. A, For the behavioral ratings, this was manifest in a positive correlation between the treatment difference [placebo (Pl) vs naloxone (Nal)] in hedonic ratings for each reward outcome (y-axis) and the outcome (x-axis) (Spearman's ρ: r = 0.728; p < 0.005). Thus, larger outcome magnitudes were experienced as less pleasurable under naloxone compared with placebo. This effect was mirrored by a reward outcome magnitude-related activity in rACC after placebo treatment that was attenuated after naloxone treatment (B). C, D, Although no significant behavioral effects of treatment were observed for the different magnitudes in losses (C), a similar effect was observed in the rACC (D). Here, the outcome magnitude of loss was attenuated after naloxone treatment. Thus, the correlation between activity in rACC and loss outcome magnitude (£1–£10) was suppressed by naloxone. Note that the observed magnitude effect in rACC was independent of positive or negative value.