Anhedonia is characterized by impaired reward processing and blunted mesocorticolimbic dopamine (DA) system functioning (Borsini et al., 2020, Berridge and Kringelbach, 2008, Pizzagalli, 2014). This ascending DA tract passes through reward learning (-meso), cognitive control (-cortico), and emotional (-limbic) hubs of the brain (Berridge and Robinson, 2003), and impairments in motivation and the anticipation of rewards are associated with alterations in striatal DA tone, DA release, and DA signaling (Pizzagalli, 2014, Russo and Nestler, 2013, Schultz, 2019, Der-Avakian and Markou, 2012). Associations between anhedonia and mesocorticolimbic DA system functioning have primarily been investigated in major depressive disorder (MDD) (Peciña et al., 2017, Pizzagalli et al., 2019). While anhedonia is a core symptom of MDD, it is also a transdiagnostic symptom that is pervasive across numerous neuropsychiatric disorders (Husain and Roiser, 2018). A putative neural mechanism of anhedonia is striatal hypoactivation, and anhedonia severity negatively correlates with ventral striatal activity during the anticipation of rewards in depressed populations (Stringaris et al., 2015, Stringaris et al., 2015, Arrondo et al., 2015). Anhedonia severity is also associated with altered intrinsic functional connectivity between striatal regions and areas of the prefrontal cortex (PFC) in adolescents (Gabbay et al., 2013) and adults (Liu et al., 2021, Felger et al., 2015). In a non-clinical adult sample, reduced nucleus accumbens response to reward was uniquely related to anhedonia severity, and not depressive or anxious symptoms (Wacker et al., 2009). Together these findings demonstrate distinct patterns of mesocorticolimbic DA system activation and connectivity associated with anhedonia.

Simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging using [11C]raclopride, a radioligand that allows for the quantification of DA D2/D3 receptor binding, has demonstrated that functional magnetic resonance imaging (fMRI) activation and functional connectivity in mesolimbic brain regions during reward anticipation correlate with ventral striatal DA release in MDD (Hamilton et al., 2018) and non-clinical (Schott et al., 2008) samples. Anhedonia is associated with altered DA functioning, including decreased striatal DA transporter availability in MDD (Pizzagalli et al., 2019) and increased striatal DA D2/D3 receptor availability in MDD (Peciña et al., 2017), although no association between anhedonia and DA release capacity in MDD has been reported (Schneier et al., 2018). This inconsistency may be explained, in part, by the diagnostic heterogeneity of MDD as opposed to sampling an anhedonic phenotype.

Additionally, alterations in DA signaling, and mesocorticolimbic DA system functioning more broadly, are linked to stress (Pizzagalli, 2014, Der-Avakian and Markou, 2012, Stanton et al., 2018, Kumar et al., 2015). Considerable animal research on this topic supports the idea that chronic, uncontrollable, and unpredictable stressors impact DA signaling (Cabib and Puglisi-Allegra, 2012) thereby contributing to the emergence of anhedonic-like behaviors, such as reduced sucrose preference or intake (Antoniuk et al., 2019) and learned helplessness (Willner et al., 1992, Riga et al., 2015, Krishnan et al., 2007). Within human samples, stress is also associated with neural and behavioral deficits in reward processing, including reduced goal-directed behavior, blunted incentive motivation, impaired reward learning, and alterations in striatal activation and connectivity during anticipation and receipt of rewards (Pizzagalli, 2014, Hollon et al., 2015, Soares et al., 2012, Hanson et al., 2021). However, no research has examined associations between self-reported stress, anhedonia, and striatal dopamine functioning in a transdiagnostic anhedonic sample.

In the present study, we used simultaneous PET-MR imaging with the D2/D3 dopamine receptor antagonist [11C]raclopride in a transdiagnostic sample of adults with clinically impairing anhedonia to investigate relationships between anhedonia, striatal DA release, and mesocorticolimbic network functioning during reward processing. We hypothesized that the transdiagnostic anhedonia group would be characterized by decreased striatal task-related DA release to rewards, indexed by the non-displaceable binding potential (ΔBPND) of [11C]raclopride, relative to a control group. We also hypothesized that striatal DA functioning would predict anhedonia severity. Next, we predicted that the anhedonia group would show decreased mesocorticolimbic network activation and connectivity during reward processing using fMRI. Finally, an exploratory aim was to examine associations between self-reported stress, anhedonia, and mesocorticolimbic DA system functioning. This aim was exploratory given that participants were not recruited based on stress exposure. We hypothesized that greater self-reported stress would be inversely associated with striatal DA release and mesocorticolimbic network fMRI activation and connectivity during reward processing.