Epigenetic alterations in medial prefrontal cortex and testis after chronic caffeine and cocaine administration in mice

GONZALEZ BETINA; GONZALEZ CANDELA ROCÍO; MUÑIZ JAVIER; CADET JEAN LUD; GARCIA-RILL EDGAR; URBANO FRANCISCO; VITULLO ALFREDO DANIEL; BISAGNO VERÓNICA

Chicago

Congreso; SfN's 45rd Annual Meeting; 2015

Society of Neuroscience

There is growing evidence of epigenetic mechanisms contributing to the transgenerational transmission of stress, psychiatric disease and addiction vulnerability. Regarding paternal transmission, it has been proposed that environmental factors like chronic stress, nutritional status, toxins and drugs of abuse trigger epigenetic mechanisms in the testicular germ line that can lead to variations in offspring?s development and behavior. Chronic psychostimulant intake also causes epigenetic changes and toxic consequences not only in dopaminergic brain areas but in peripheral organs as well, including the testis. From that perspective, several groups have reported epigenetic alterations in the medial prefrontal cortex (mPFC) of cocaine-experienced sires that were present in the testicular germ line and were transmitted to the male offspring. Recreational use of cocaine (Coc) is often abused in combination with other psychostimulants like caffeine (Caf). Caf was reported to enhance cocaine-mediated effects in brain areas. In the present study, we measured epigenetic and functional markers in the mPFC and testis of adult mice treated with Coc (10 mg/kg), Caf (5 mg/kg), or the combination (Caf-Coc) (10 mg/kg Coc + 5 mg/kg Caf) compared to vehicle (Veh), in an intermittent binge protocol (3 i.p. injections, 1 h apart, one day on/off for 13 days. Mice were euthanized on day 14. Deacetylation by histone deacetylases (HDACs) at lysine residues are post-translational histone modifications that have been reported in various neuropsychiatric diseases including addiction. In our study, we found that Coc and Caf-Coc treatments caused a decrease of HDAC2 expression and a concomitant increase in histone 3 acetylation (H3ac) in both mPFC and testis. Morphometric analyses of the testis revealed reduced volume of the seminiferous tubules after Coc and Caf-Coc treatments, indicative of altered spermatogenic process. In addition, there was reduced mRNA expression of AMPA-type glutamate receptor subunit Gria1, adenosine receptor subunit Adora2a, scaffolding protein Psd95 and methyl CpG binding protein Mecp2 in the mPFC after Caf, Coc and Caf-Coc treatments. We are currently investigating whether these psychostimulants might differentially regulate gene expression in the testis.Our results further support that psychostimulant abuse can induce epigenetic marks in CNS and testis that could lead to impaired function with the possibility of affecting individuals from next generation.