Multimodal Investigations of Reward Circuitry and Anhedonia in Adolescent Depression

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While inflammation has been implicated in the manifestation of psychiatric symptoms, the role of immune attenuation via sympathetic modulation in psychopathology remains unclear. Here, this study aimed to assess β2-agonist clenbuterol (CBL) as a promising agent to model adrenergic-induced immune response following ex vivo immune activation with lipopolysaccharide (LPS). Relationships between CBL-modulated cytokine levels and symptom measures were then explored. Adolescents were evaluated with semi-structure interviews and self-reported depression, anxiety, and anhedonia levels. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, with supernatants being subjected to Luminex multiplex assay for 41 cytokines. Cytokine levels between conditions were compared using Bonferroni-corrected nonparametric tests. Exploratory factor analysis reduced 41 cytokines into fewer factors in each experimental condition, and their relationships with psychiatric symptoms were examined with Spearman correlations controlling for age, sex, and BMI. Data from 130 participants (15.25 ± 2.16 years old, 59% female) were analyzed. 10 cytokines were significantly affected by CBL treatment compared to LPS alone. LPS+CBL factor 3 significantly correlated with both anticipatory (rho = -0.39, p = 7.4 × 10-5) and consummatory anhedonia (rho = -0.36, p = 3.3 × 10-4), and these correlations remained significant when controlling additionally for depression. There were no significant associations between immune factors with depression or anxiety severity. Findings support our hypothesis that clenbuterol attenuates inflammatory effects thought to underlie psychiatric conditions in youth. Using a data-driven analytic method, distinctive relationships between CBL-affected cytokines and dimensional anhedonia were reported, further elucidating the role of β2-agonism in adolescent affective symptomatology.

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