Psychostimulant-induced testicular toxicity in mice: evidence of cocaine and caffeine effects on the local dopaminergic system

C. GONZALEZ; B. GONZALEZ; M. E. MATZKIN; J.A. MUÑIZ; J. L. CADET; E. GARCIA-RILL; F. J. URBANO; V. BISAGNO

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2015

1932-6203

Severalorgan systems can be affected by psychostimulant toxicity. However, there isnot sufficient evidence about the impact of psychostimulant intake ontesticular physiology and catecholaminergic systems. The aim of the presentstudy was to further explore potential toxic consequences of chronic exposureto cocaine, caffeine, and their combination on testicular physiology. Mice wereinjected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine(3×10mg/kg), or combined administration. Mice treated with cocaine alone orcombined with caffeine showed reduced volume of the seminiferous tubule associatedto a reduction in the number of spermatogonia. Cocaine-only and combinedtreatments induced increased lipid peroxidation evaluated by TBARS assay anddecreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocainecombination potentiated the cocaine-induced germ cell loss, and inducedpro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNAlevels. We analyzed markers of dopaminergic function in the testis and detectedthe presence of tyrosine hydroxylase (TH) in the cytoplasm ofandrogen-producing Leydig cells, but also in meiotic germs cells withinseminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato andD2R-eGFP mice, we report for the first time the presence of dopamine receptors(DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presenceof DRD1 was also detected in the spermatogonia nearest the basal lamina of theseminiferous tubules, which did not show TH staining. We observed that psychostimulantsinduced downregulation of DRs mRNA expression and upregulation of TH proteinexpression in the testis. These findings suggest a potential role of the localdopaminergic system in psychostimulant-induced testicular pathology.