Restoration of MPTP-induced dopamine and tyrosine hydroxylase depletion in the mouse brain through ethanol and nicotine

Abstract

Abstract Here, we investigate whether ethanol (EtOH) and nicotine (Nic) alone or in co-exposure can restore the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine (DA), DA metabolites, and tyrosine hydroxylase (TH) in the striatum and hippocampus of C57BL/6N mice. MPTP-treated mice were treated intraperitoneally with saline (control), EtOH (1.0–3.0 g/kg), Nic (0.5–2.0 mg/kg), or a combination of EtOH and Nic. Brain samples were collected 1 h after treatment. DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were measured by HPLC-ECD, while TH expression and Ser31 phosphorylation were quantified by Western blot. EtOH (2.0 and 3.0 g/kg) alone reversed the effects of MPTP treatment in both studied brain regions, as evidenced by an increase in DA, DOPAC, and HVA contents, TH expression, and its phosphorylation at Ser31 compared to the MPTP group, indicating restorative effects on DA neurons in the MPTP model. Likewise, Nic (1.0 and 2.0 mg/kg) alone reversed MPTP treatment effects, with treated mice showing increased DA, DOPAC, and HVA contents, TH expression, and Ser31 phosphorylation compared to MPTP mice. Co-administration of EtOH (2.0 g/kg) and Nic (1.0 mg/kg) further increased DA, DOPAC and HVA tissue contents, TH expression, and Ser31, indicating an additive effect. These results show that moderate to high doses of EtOH and Nic induce similar increases in brain DA and TH via TH phosphorylation activation in MPTP model mice. EtOH and Nic showed an additive effect in combination, suggesting that their co-application could be a potent therapeutic strategy for treating PD.