Rewards are central for goal-directed behavior as they induce approach behavior toward valued outcomes (Schultz, 2015). Theoretical models distinguish between behavioral dimensions of rewards, such as the motivational drive to obtain rewards (‘wanting’) versus the hedonic pleasure associated with reward consumption (‘liking’), whereby ‘wanting’ and ‘liking’ refer to preconscious, rather than conscious, mental states (Berridge, 1996; Berridge and Kringelbach, 2015; Berridge et al., 2009). Dysfunctions in wanting and liking of rewards belong to the core symptoms to addiction, which can be conceptualized as a wanting-dominated state with deficits in switching to liked non-drug rewards (Berridge and Robinson, 2016; Berridge et al., 2009). It is thus important to obtain a better understanding of the human brain mechanisms underlying wanting and liking. Previous animal research suggested that wanting and liking relate to dissociable neurochemical mechanisms (Berridge and Kringelbach, 2015; Berridge and Valenstein, 1991): Dopaminergic activity is thought to modulate the wanting component of rewards, but not liking (Berridge and Valenstein, 1991). In contrast, the opioidergic system has later been associated with both wanting and liking (Berridge and Kringelbach, 2015). Human studies support the hypothesized link between dopaminergic activation and cue-triggered wanting (Hebart and Gläscher, 2015; Soutschek et al., 2020b; Weber et al., 2016) as well as the motivation to work for rewards (Cawley et al., 2013; Chong et al., 2015; Korb et al., 2020; Skvortsova et al., 2017; Soutschek et al., 2020a; Venugopalan et al., 2011; Westbrook et al., 2020; Zénon et al., 2016). Noteworthy, two of these studies suggest that dopamine changes only experimental measures of wanting (motivation to work for rewards), but not self-reported wanting ratings (Korb et al., 2020; Venugopalan et al., 2011).

Consistent with animal findings, pharmacological manipulations of the opioid system affected both wanting and liking aspects of rewards in humans (Buchel et al., 2018; Chelnokova et al., 2014; Eikemo et al., 2016). Less is known, however, about the neuroanatomical basis of human wanting and liking. Both dopaminergic and opioidergic neurons project to reward circuits in the striatum as well as to the prefrontal cortex (Delay-Goyet et al., 1987; Lidow et al., 1991), and recent neuroimaging findings suggest that these regions indeed play a role in processing of wanting and liking (Weber et al., 2018). In particular, the ventral striatum appears to encode the currently behaviorally relevant reward dimension and dynamically switch functional connectivity with wanting- and liking-encoding prefrontal regions (Weber et al., 2018; such frontostriatal gating constitutes one possibility how dopamine [and by extension opioids] can affect functions involving prefrontal cortex and the striatum; Cools, 2011). This is also in line with the view that wanting and liking are preferentially represented in partially distinct subregions of the striatum (which are in turn connected to different input and output regions; Peciña, 2008). Thus, processing of wanting and liking appears to be dissociable on both a neurochemical and an anatomical basis. However, it remains unknown how pharmacological and connectivity-related brain mechanisms interact. We investigated whether frontostriatal connectivity related to motivational and hedonic judgements is modulated by dissociable neurotransmitter systems.

To test this hypothesis, the current study investigated the impact of pharmacologically manipulating dopaminergic and opioidergic systems on the neural processing of wanting and liking information. This study was part of a larger project investigating also the roles of opioidergic and dopaminergic activity for reward impulsivity (Weber et al., 2016). Here, we administered a task that allows distinguishing between wanting and liking dimensions of valued goods and assessed how pharmacologically reducing dopaminergic (using the dopamine antagonist amisulpride) or opioidergic neurotransmission (with the opioid antagonist naltrexone) changes frontostriatal connectivity related to parametric wanting and liking judgements. We hypothesized that, on a behavioral level, reducing opioid receptor activation will reduce both wanting and liking (Buchel et al., 2018; Chelnokova et al., 2014; Eikemo et al., 2016), whereas reduced dopaminergic neurotransmission will selectively affect wanting (Cawley et al., 2013; Korb et al., 2020; Venugopalan et al., 2011). We further hypothesized that on a neural level the behavioral effects of the pharmacological manipulations are mirrored by changes in frontostriatal connectivity related to wanting and liking information (Weber et al., 2018). In particular, we expected that frontostriatal connectivity during wanting judgements is modulated by opioidergic and dopaminergic activation (as these neurotransmitters have been related to the processing of wanting), whereas frontostriatal connectivity during liking judgements should be reduced after reduction of opioidergic neurotransmission.

In animal models, the wanting and liking dimensions of rewards are processed by partly distinct brain regions and neurotransmitter systems, but in humans it remained unclear so far how opioidergic and dopaminergic systems orchestrate the processing of wanting and liking. The current findings provide evidence for dissociable roles of opioidergic neurotransmission in processing the two dimensions of rewards on both a behavioral and a neural level. Behaviorally, lowering opioidergic activation with naltrexone selectively reduced wanting, not liking, ratings for non-consumable goods. On a neural level, this reduction in wanting was reflected by changes in DLPFC-striatum connectivity: When wanting judgements were required, DLPFC-striatum connectivity was significantly stronger for the behaviorally relevant wanting ratings than for the irrelevant liking dimension of rewards.

Importantly, wanting-related functional coupling between DLPFC and striatum was significantly stronger under naltrexone than under placebo. This is consistent with recent findings relating opioid receptor inhibition with increased connectivity between the prefrontal control system and reward circuits (Elton et al., 2019; Lim et al., 2019) and suggesting prefrontal kappa opioid receptors to mediate the impact of naltrexone on drug craving in alcohol use disorder (de Laat et al., 2019). Through corticostriatal loops, the striatum receives input from several cortical regions and can prioritize processing of behaviorally relevant information (Frank, 2011). DLPFC provides inhibitory input to the striatum and was shown to reduce wanting-related activation in the striatum (Dong et al., 2020; Koob and Volkow, 2010), consistent with the importance of frontostriatal loops for self-control (van den Bos et al., 2014). According to this view, the observed positive relationship between wanting ratings and DLPFC-striatum connectivity might indicate that DLPFC exerts top-down control over striatal representations of wanting predominantly for highly wanted items, whereas there may be less need for inhibitory top-down control for less desired goods (van den Bos et al., 2014). By strengthening DLPFC-striatum connectivity, naltrexone enhances top-down processes predominantly for highly wanted items, which would explain why lower wanting under naltrexone is associated with stronger DLPFC-striatum connectivity even though in the placebo group functional DLPFC-striatum coupling is increased for highly wanted items. In any case, because we observed no significant brain-behavior mediation effect (p = 0.06), the stronger DLPFC-striatum connectivity under naltrexone should not be interpreted as the cause for the changes in behavioral ratings under naltrexone. It is further worth noting that in the current study we observed significant effects predominantly in the left hemisphere. In the literature on frontostriatal connectivity during reward processing, both left- and right-lateralized effects were reported (van den Bos et al., 2014; van den Bos et al., 2015; Yuan et al., 2017). We therefore do not make any claims regarding whether this result pattern represents just a power issue or a truly lateralized effect.

Contrary to our hypotheses, we did not observe effects of naltrexone on liking or amisulpride effects on wanting. Interestingly, however, a recent study observed no influences of opioid and dopamine antagonists on self-report wanting and liking ratings but only on experimental measures of these reward dimensions (Korb et al., 2020). In fact, previous studies reporting effects of dopaminergic manipulations on wanting operationalized wanting with experimental measures rather than self-report (Soutschek et al., 2020a; Soutschek et al., 2020b; Weber et al., 2016), while studies using self-report ratings observed no or only weak effects of pharmacological manipulations (Case et al., 2016; Ellingsen et al., 2014; Løseth et al., 2019). In line with our previous study (Weber et al., 2018), we had decided to use self-report ratings to avoid the issue that implicit measures of liking such as face muscle activity are more open to alternative interpretations (Pool et al., 2016), but we acknowledge that implicit measures might be more sensitive to pharmacological interventions. Moreover, given that in our study participants had to provide liking ratings without being able to actually consume or handle the items, our measurements might have been less sensitive than those of other studies assessing the liking of consumed rewards (Buchel et al., 2018; Chelnokova et al., 2014; Eikemo et al., 2016). It is also worth noting that it has recently been suggested that amisulpride shows, if any, only weak effects on BOLD signal changes in the reward system (Grimm et al., 2020). We note though that in the same sample of participants amisulpride showed significant effects on tasks for cue reactivity and delay discounting (Weber et al., 2016), which were administered 2.5 hr after drug intake (while the rating task started 1 hr after drug intake). Due to this difference in timing, it is thus not possible to decide whether the different amisulpride effects on these tasks can be explained by different sensitivities of these tasks to dopaminergic manipulations or by the time course of amisulpride effects. In any case, one should thus be careful with interpreting these unexpected null findings as being inconsistent with previous pharmacological results manipulating dopaminergic activity with different compounds than amisulpride.

Interestingly, the ROI analysis provided some evidence for amisulpride effects on wanting at the neural level, as amisulpride increased wanting-related DLPFC-striatum connectivity, similar to the findings for naltrexone. However, the impact of amisulpride on wanting-related frontrostriatal connectivity (gating) needs to be interpreted with caution, given the lack of significant amisulpride effects on behavior.

Our findings have important implications for clinical research, given that dysfunctions in wanting and liking are prevalent in several psychiatric disorders. Substance use disorders, for example, are characterized by increased wanting of drugs as reflected in craving symptoms (Berridge, 2012; Edwards, 2016), and craving has been linked to impairments in prefrontal top-down control over the striatum (Feil et al., 2010). Naltrexone is approved in several countries for the treatment of alcohol use disorder (Krystal et al., 2001; Srisurapanont and Jarusuraisin, 2005) and opioid dependence (Johansson et al., 2006) and was shown to reduce relapse risk and craving specifically in alcohol use disorder. Consistent with the view that naltrexone reduces the salience of drug cues by strengthening prefrontal activation (Courtney et al., 2016), we speculate that the beneficial effects of naltrexone on alcohol use and craving might be explained by increased top-down control of DLPFC over striatal wanting signals as a consequence of opioid receptor inhibition (but see Nestor et al., 2017). Our results may thus improve the understanding of neural mechanisms underlying pharmacological treatments of dysfunctional wanting in substance use disorders.

Several limitations are worth mentioning. First, we did not assess wanting and linking prior to drug administration, such that we cannot control for potential baseline differences in wanting and liking between drug groups. Thus, it remains possible that the non-significant effects of amisulpride on wanting and of naltrexone on liking are caused by such pre-existing baseline differences, or that the sample size was not sufficient to detect these effects in a between-subject design. We also note that the doses for amisulpride and naltrexone might not have been pharmacologically equivalent. In fact, while 50 mg naltrexone produces 95% μ-opioid receptor occupancy (Weerts et al., 2008), 400 mg amisulpride leads to a lower dopamine receptor occupancy of 85% (Lako et al., 2013), which might be a further reason for why naltrexone showed stronger effects on behavior and brain activation than amisulpride. Lastly, while high doses of amisulpride (≥400 mg) reduce postsynaptic dopaminergic signaling, lower doses of amisulpride increase dopaminergic activity via presynaptic mechanisms (Schoemaker et al., 1997), but higher doses may also increase signaling at D1 receptors and thereby counteract the inhibitory effects on D2 neurotransmission. As the effective dose of amisulpride might differ between participants (Sescousse et al., 2016), one might argue that presynaptic and postsynaptic effects of dopamine might have canceled out across participants, leading to the observed null effect of amisulpride on behavior on the group level. However, contrary to this view, we observed no significant amisulpride effects even when controlling for body weight as proxy for effective dose, and we note that in previous studies we had observed effects of 400 mg amisulpirde on behavior (Burke et al., 2018; Soutschek et al., 2017) and multivariate neural data (Kahnt et al., 2015). It seems thus unlikely that the null effects of amisulpride on the rating task can be explained solely by the chosen dosage.

Taken together, our findings deepen our understanding of the neurochemical mechanisms mediating the impact of wanting of rewards on behavior. Opioid receptors are involved in the modulation of the strength of inhibitory prefrontal input to the striatum encoding the behavioral relevance of the wanting dimension of rewards. These insights into the interactions between neuroanatomical and neurochemical brain mechanisms implementing wanting-driven approach behavior advance our understanding of the mechanisms underlying pharmacological treatments of substance use disorders.

The behavioral data that support the findings of this study are available on Open Science Framework https://osf.io/6cevt/.

1. 1. Soutschek A

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   ID 6cevt. Wanting_liking_pharma_fmri.

   https://osf.io/6cevt/

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Author details

1. Alexander Soutschek

   Department of Psychology, Ludwig Maximilian University, Munich, Germany

   Contribution

   Formal analysis, Writing - original draft

   For correspondence

   alexander.soutschek@psy.lmu.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8438-7721

2. Susanna C Weber

   Zurich Center for Neuroeconomics, Department of Economics, University of Zurich, Zürich, Switzerland

   Contribution

   Conceptualization, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Thorsten Kahnt

   Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States

   Contribution

   Conceptualization, Writing - review and editing

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-3575-2670

4. Boris B Quednow

   1. Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
   2. Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zürich, Switzerland

   Contribution

   Conceptualization, Writing - review and editing

   Competing interests

   No competing interests declared

5. Philippe N Tobler

   1. Zurich Center for Neuroeconomics, Department of Economics, University of Zurich, Zürich, Switzerland
   2. Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zürich, Switzerland

   Contribution

   Conceptualization, Funding acquisition, Supervision, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4915-9448

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