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Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline

Year: 2025

Type: article

Abstract: Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson's disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects. • Repeated METH binges cause tolerance to motor impairment. • Repeated binges induce tolerance to nigrostriatal toxicity. • Microglial activation recedes after the first binge, astroglial response persists. • Presynaptic DAT levels only partially recover but lag behind TH & VMAT2 recovery. • METH-induced DAT depletion explains behavioral recovery and reduced toxicity.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.106839

Authors: Noelia Granado, Liliana Mendieta, Yousef Tizabi, Mario Gustavo Murer, Rosario Moratalla