The Gender-Biased Effects of Intranasal MPTP Administration on Anhedonic- and Depressive-Like Behaviors in C57BL/6 Mice: the Role of Neurotrophic Factors

Depression is a highly prevalent and debilitating non-motor symptom observed during the early stages of Parkinson’s disease (PD). Although PD prevalence is higher in men, the depressive symptoms in PD are more common in women. Therefore, the aim of this study was to investigate the development of anhedonic- and depressive-like behaviors in male and female mice and the potential mechanisms related to depressive symptoms in an experimental model of PD. Young adult male and female C57BL/6 mice (3 months old) received a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were submitted to a battery of behavioral tasks (sucrose consumption, splash test, tail suspension, forced swimming and open field tests) to assess their emotional and motor profiles. Considering the role of sexual hormones in emotional behaviors, the same protocol of i.n. MPTP administration and the splash, tail suspension, and open field tests were conducted in ovariectomized (OVX) and aged C57BL/6 female (20 months old) mice. We also investigated the immunocontent of neurotrophins (BDNF, GDNF, and VEGF) in the hippocampus and prefrontal cortex by western blot. I.n.  MPTP administration induced more pronounced anhedonic- and selective depressive-like behaviors in female adult mice, also observed in OVX and aged female mice, with the absence of motor impairments. Furthermore, MPTP induced a more pronounced depletion of neurotrophins in the prefrontal cortex and hippocampus in female than male mice. This study provides new evidence of increased susceptibility of female mice to anhedonic- and depressive-like behaviors following i.n. MPTP administration. The observed gender-related effects of MPTP on emotional parameters seem to be linked to increased depletion of neurotrophins (particularly BDNF and GDNF) in the hippocampus and prefrontal cortex of female mice.