Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

Midbrain dopaminergic neurons projecting to the ventral striatum code for reward magnitude and probability during reward anticipation and then indicate the difference between actual and predicted outcome. It has been questioned whether such a common system for the prediction and evaluation of reward exists in humans. Using functional magnetic resonance imaging and a guessing task in two large cohorts, we are able to confirm ventral striatal responses coding both reward probability and magnitude during anticipation, permitting the local computation of expected value (EV). However, the ventral striatum only represented the gain-related part of EV (EV ϩ ). At reward delivery, the same area shows a reward probability and magnitude-dependent prediction error signal, best modeled as the difference between actual outcome and EV ϩ . In contrast, loss-related expected value (EV Ϫ ) and the associated prediction error was represented in the amygdala. Thus, the ventral striatum and the amygdala distinctively process the value of a prediction and subsequently compute a prediction error for gains and losses, respectively. Therefore, a homeostatic balance of both systems might be important for generating adequate expectations under uncertainty. Prevalence of either part might render expectations more positive or negative, which could contribute to the pathophysiology of mood disorders like major depression.

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/ Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.is critical to motivational and reward-related functions of the brain, including adaptation through reinforcement learning (1, 2) and decision making (3). Considerable interindividual differences with respect to decision making have been observed (4), and it has been speculated that genetic variability in the dopaminergic system could be related to these differences (5, 6). In addition, interindividual variation in dopaminergic function has been hypothesized as a major factor contributing to inheritable personality traits (7) and addiction (8). However, little is known about how variation in DA-related genes modulates the described physiological properties of the dopaminergic reward system (1-3, 9, 10) and how such physiological variation affects reward processing. To bridge this gap between genetics and behavior, we combined genetics and personality assessment with fMRI measures of brain activation as an intermediate (endo)phenotype (11,12), an approach based on the assumption that brain activation is causally more directly linked to genotype than is behavior (12).In the study of individual differences in DA system physiology, a useful conceptual distinction is often made between tonic and phasic dopaminergic neurotransmission (13,14). In the striatum, a basal level of extracellular DA results from tonic, slow, and irregular ''background'' firing of dopaminergic neurons originating in the ventral tegmental area. By contrast, burst firing of ventral tegmental area neurons induces phasic DA release, a me...

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use.