Vulnerability to cognitive, neurotoxic and neuroinflammatory effects of toxins that induce Parkinson's disease after administration of amphetamine-related drugs in mice

Clinical observations report a higher propensity to develop Parkinson’s disease (PD) in amphetamine users. 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine-related drug which may have neuroinflammatory and neurotoxic effects. The present study was aimed at evaluating in mice whether administration of MDMA during adolescence might influence neurotoxicity towards dopaminergic neurons and neuroinflammatory effects of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin known to induce PD in humans, in motor, limbic and cortical areas, and consequently affects cognitive performance. Mice received MDMA (10 mg/kg, twice a day/a week) for 9 weeks, followed by MPTP (20 mg/kg × 4 administrations), starting 2 weeks after MDMA discontinuation. Activation of astroglia and microglia by GFAP and CD11b immunohistochemistry in motor areas, as substantia nigra compacta (SNc) and striatum, limbic and cortical areas, as hippocampus and medial prefrontal cortex (mPFC), was assessed. Degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry in SNc and striatum was also evaluated. Neurochemical evaluations were paired with assessment of cognitive performance by means of the novel object recognition (NOR) and spontaneous alternation in a Y-maze tests. MPTP administration to MDMA-pretreated mice elicited a stronger increase in CD11b and GFAP levels in motor, limbic and cortical areas, and a stronger decrease of TH-positive neurons and fibers in motor areas, compared with either substance administered alone. Furthermore, NOR performance in the same group was lower, compared with mice that received either substance alone. Results demonstrate that MDMA administration during adolescence influence negatively MPTP effects on motor, limbic and cortical areas and result in cognitive impairment.