Physical fitness and exercise as modulators of the endocannabinoid system in adults with mild-to-moderate depression the sonrie study

The endocannabinoid system (ES) is a lipid-based signaling network involved in multiple physiological processes including mood regulation, stress response, and neuroplasticity. The primary and most well studied endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These components, along with associated analogues interact with CB1 and CB2 receptors. CB1 receptors are abundant in the central nervous system and implicated in cognitive, emotional, and motor functions, whereas CB2 receptors are mainly associated with immune regulation. Depression is a complex, heterogeneous disorder with multifactorial etiology, ranging from genetic vulnerabilities to environmental stressors. Diagnostic criteria include persistent mood alterations and cognitive-somatic symptoms, with considerable variability across individuals. Pathophysiological hypotheses highlight disruptions in neuroendocrine and plasticity-related mechanisms, including ES dysregulation. Preclinical and clinical studies suggest that ES signaling pathway impairment, particularly CB1 receptor dysfunction and altered endocannabinoid tone contribute to depressive symptoms. Notably, AEA and 2-AG appear to exert complementary, stress-buffering roles. Physical exercise has emerged as a promising non-pharmacological strategy to the depression treatment. Acute exercise, especially at moderate-to-high intensities, appear to elevate AEA and 2-AG. However, the effects of chronic exercise on ES are inconsistent. Importantly, while exercise-induced changes in eCBs ligands are documented, the relationship between physical fitness (e.g., cardiorespiratory and muscular fitness) and eCBs remains unclear. Given that fitness reflects sustained physiological adaptations, it may independently modulate ES activity, offering a novel perspective in understanding and treating depressive disorders. Thus, the main aim of the present Doctoral Thesis is to clarify the extent to which physical exercise behavior and the physical-fitness adaptations it elicits modulate circulating endocannabinoid biomarkers in adults with depressive disorders, and to determine whether an internet-delivered psycho-physical program can leverage this pathway to improve fitness and biological profiles. The results in Study I confirmed that moderate-intensity aerobic and high-load resistance exercise reliably increases AEA, with less consistent effects on 2-AG, while supramaximal intensities may attenuate the eCB response. Chronic exercise appears to normalize eCB dysregulation in stressrelated conditions. Study II we found that higher fitness levels were inversely associated with baseline plasma eCBs and their analogues. Study III showed that a structured psycho-physical intervention enhanced cardiorespiratory fitness and induced directional changes in ES, with partial retention of benefits during followup. These findings demonstrate that physical exercise behavior and fitness modulate the ES in individuals with depression and support the role of eCBs as promising biomarkers of psychophysiological health. Moreover, internetdelivered interventions represent a feasible, non-pharmacological strategy to target ES dysfunction in depression.

Author dc:creator

• Ruiz Muñoz, Manuel

Advisors dc:contributor.advisor

• Rosety Rodríguez, Miguel Ángel
• España Romero, Vanesa

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 Internacional

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10498/39607

OAI identifier oai:identifier

oai:rodin.uca.es:10498/39607