Efeitos da exposição ao fentanil em camundongos machos e fêmeas : alterações comportamentais e moleculares durante a adolescência

Abstract

Introduction: Differences between the sexes play a crucial role in vulnerability to substance use disorders. However, there are still few studies that seek to investigate these effects during adolescence in preclinical models. The hypothesis of this study is that male and female mice respond differently to the effects of fentanyl administration and naloxone treatment, and that these differences manifest at both behavioral and neurobiological levels. Objective: To compare male and female behaviors in response to fentanyl administration and naloxone treatment. To investigate changes in the gene expression of Drd1, Drd2, Drd4, Drd5, and Oprm1, and modifications of epigenetic bases 5mC and 5hmC in genomic regions relevant to genes that show differences between sexes. Methodology: Adolescent C57BL/6J mice were exposed to fentanyl treatment with increasing doses over 7 days, behavioral tests were conducted for locomotor activity parameters, anxious-like behavior, and response to acute fentanyl withdrawal induced by naloxone. For molecular analyses, real-time quantitative PCR (qPCR) was used to evaluate gene expression and epigenetic base modifications. Results: After chronic fentanyl treatment, females showed higher locomotor activity than males. Females also exhibited a higher behavioral score of acute fentanyl withdrawal compared to male animals. Females had lower expression of the Drd4 gene in the striatum compared to males. When evaluating levels of epigenetic modifications in the Drd4 gene body in the striatum, lower levels of 5mC + 5hmC were observed in females compared to males. Negative correlations were identified between the levels of these epigenetic modifications in Drd4 and post-fentanyl treatment locomotor activity, as well as with acute withdrawal scores. Conclusion: Female mice showed greater sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene in the striatum.