Drug- and reward-induced hedonic processing in humans

Project background and aims Drug abuse is an extremely costly problem. Existing treatments have low success rates. Despite the enormous research effort that has elucidated brain mechanisms of addiction in animal models (mainly rats and mice), no effective new treatment avenues have been uncovered for human addiction. This project was motivated by the persistent difficulties in treating addiction. We reasoned that an important missing link was to understand addiction-relevant mechanisms in the healthy human brain. One of the key neurochemical systems in addiction is the opioid system (popularly known as endorphins). The importance of endorphins has been shown both using rodent models as well as molecular imaging studies in addicted humans. This neurochemical system is also known for its role in pain relief. However, how endorphins work in the healthy, pain-free human brain was largely unknown at the time this project started. Thus, the major aim of the current project was to provide translational evidence of what the opioid system does in the healthy human brain, and to link the findings to existing evidence from rodent models and patient studies. Specifically, we aimed to map out how the healthy human opioid system modulates reward behaviours such as motivation to win money, appreciation (hedonics) of pleasant taste, stroking touch, and other people of varying attractiveness levels. Secondary aims focused on understanding the healthy human brain function of a related neurochemical, oxytocin, which has been implicated in a number of social processes that may influence addiction-related behaviours in humans too. Main results In sum, the findings from this project provides evidence that the healthy human opioid system modulates reward behaviour. Importantly, this modulation follows a specific pattern that is parallel to the evidence from rodent research. In rats - and as we have now shown in healthy young men - activation of the opioid system through drugs (morphine) stimulates motivation for highly valuable rewards without altering responses to less valuable stimuli. Conversely, blocking the brain's own endorphins reduces motivation for the highly valuable rewards without altering responses to less valuable stimuli. We find this pattern of opioid reward modulation across tasks and stimulus types, such as money, attractive faces and sweet tastes. This result is novel, as evidenced in part through the high-impact journals interested in publishing our work (Molecular Psychiatry and Neuropsychopharmacology are the highest-ranked journals in the psychiatry and psychopharmacology fields, respectively). As PI of the project, I have also spent research time on international collaborative projects that focus on related processes, notably the link between reward, pain and the opioid system. Several papers from these collaborations have also been published in high-impact outlets (two in PNAS, one in a top psychology journal, several in a top pain journal). In brief, the results of these collaborations point to very close neurobiological connections between reward and pain relief. Finally, the project also aimed to elucidate how oxytocin modulates reward-related behaviours of relevance to addiction. A strength of this branch of the project is our (so far) unique ability to compare how the oxytocin and opioid systems shape similar behaviors. Evidence from rodent models led to strong hypotheses in the literature that both oxytocin and opioids would increase the pleasure of a caress in humans; we find that this is not the case for either neurochemical system. We do find however that both oxytocin and opioids enhance how much people look at the eyes of others, a behavior linked to empathy.

Benzodiazepines and minor opiates are two of the most frequently prescribed addictive drugs, and abuse of these substances is associated with a range of adverse consequences, including anhedonia, or the loss of ability to experience pleasure, as well as p sychosocial problems. The understanding of the underlying neurobiological processes has made great progress in the past 30 years and several influential theories of addiction have been proposed, but these still rely heavily on findings from research on ro dents which have not been examined in humans, let alone in clinical populations. Thus, the primary objective of this project is to close this knowledge gap about drug- and reward-induced hedonic processes in humans. To this end, healthy human volunteers w ill be tested on a battery of reward tasks, involving both consummatory (taste, touch, money, relief) and conditioned stimuli to assess each individual's state and "hedonic capacity profile." Outcome measures are subjective ratings of hedonic experience, in combination with objective physiological measures of autonomic arousal, subconscious affective reactions, and brain activation assessed with functional MRI. Furthermore, pharmacological interventions will clarify the role of addictive drugs and endogen ous opioid and oxytonergic neurotransmitter signalling for the various reward processes. Understanding whether the role of these systems in human reward processing is homologous to that observed in rodent studies is essential for assessing current theorie s of addiction. A special focus is placed on the role of social functioning and social rewards with relevance to addiction, through the use of interpersonal touch paradigms as well as intranasal oxytocin administration. This project in healthy volunteers will form the basis for further research investigating these processes in human addiction.