Clenbuterol attenuates immune reaction to lipopolysaccharide and its relationship to anhedonia in adolescents

Abstract

While inflammation has been implicated in psychopathology, relationships between immune-suppressing processes and psychiatric constructs remain elusive. This study sought to assess whether β₂-agonist clenbuterol (CBL) would attenuate immune activation in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. To capture a diverse range of immunologic and symptomatologic phenotypes, we included 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All participants had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, then analyzed for 41 cytokines, chemokines, and hematopoietic growth factors. Comparison analyses used Bonferroni-corrected nonparametric tests. Levels of nine immune biomarkers-including IL-1RA, IL-1β, IL-6, IP-10, MCP-1, MIP-1α, MIP-1β, TGF-α, and TNF-α-were significantly reduced by CBL treatment compared to LPS alone. Exploratory factor analysis reduced 41 analytes into 5 immune factors in each experimental condition, and their relationships with psychiatric symptoms were examined as a secondary aim. CBL + LPS Factor 4-comprising EGF, PDGF-AA, PDGF-AB/BB, sCD40L, and GRO-significantly correlated with anticipatory and consummatory anhedonia, even after controlling for depression severity. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected immune biomarkers and dimensional anhedonia were reported, further elucidating the role of β₂-agonism in adolescent affective symptomatology.

Keywords: Adolescence; Anhedonia; Chemokines; Clenbuterol; Cytokines; Hematopoietic Growth Factors; Immune Challenge; Lipopolysaccharide; RDoC.

Fig. 1.

Partial correlations controlling for age, sex, and body mass index (BMI) between (A) Control Factor 4 and Anticipatory Anhedonia; (B) LPS Factor 4 and Anticipatory Anhedonia; (C) LPS+CBL Factor 4 and Anticipatory Anhedonia; (D) LPS+CBL Factor 4 and Consummatory Anhedonia. All are significant at Bonferroni-corrected significant threshold $\mathit{\alpha }=\frac{0.05}{5\times 2\times 3}\approx 1.7\times {10}^{-3}$. Abbreviations: CBL: clenbuterol; HC: healthy control participants; LPS: lipopolysaccharide; Clinical: participants with psychiatric symptoms and/or diagnoses. TEPS-A: Temporal Experience of Pleasure Scale – Anticipatory; TEPS-C: Temporal Experience of Pleasure Scale – Consummatory.

Fig. 2.

Change in analyte correlations in the LPS + CBL condition relative to the LPS condition (LPS + CBL – LPS; lower half triangle), and their corresponding log-transformed p values (upper half triangle). With false discovery rate correction, significant differences were detected in the following pairs: (a) RANTES and PDGF-AA, (b) MIP-1β and IL-2, (c) MCP-1 and IL-6, (d) MCP-1 and IL-8, (e) MCP-1 and IP-10, (f) MIP-1α and MCP-1, (g) MIP-1β and MCP-1, (h) RANTES and TNF-α. Abbreviations: CBL: clenbuterol; LPS: lipopolysaccharide.