Dopamine D1 Receptor Is Involved In The Modulation On Methamphatamine-mediated Autophagy And Dopaminergic Neurons Survival

Methamphetamine is a widely abused synthetic drug.Long-term abuse of methamphetamine can lead to a series of neurodegenerative diseases,such as Parkinson's disease,huntington's disease.Since methamphetamine causes neurotoxicity resulting in the death of dopaminergic neurons,elucidating its mechanism is important to prevent neurotoxicity.Many studies have shown that dopamine receptor may be an effective target of action.Compared with wild type mice,dopamine D1 receptor knockout mice can protect the dopaminergic neurons from methamphetamine induced neuronal death,but the role of dopamine D1 receptor in the neurotoxicity of methamphetamine is not very clear.This paper aims to explore the role and mechanism of dopamine D1 receptor in the death of dopaminergic neurons in the striatum caused by methamphetamine.In mice model,we found that methamphetamine treatment can obviously cause autophagic dopaminergic neurons death in the striatum,show the increased LC3B,P62 and tyrosine hydroxylase expression(TH)protein expression,the lack of dopamine D1 receptor will reduce the death of striatal dopaminergic neurons and inhibit the excessive autophagy of dopaminergic neurons.In vitro,PC 12 cell lines were used for single stimulation and repeated stimulation with dopamine D1 receptor agonist SKF38393,the results showed that LC3B,p62 and other protein levels were significantly upregulation,and treatment with the dopamine D1 receptor antagonist SCH23390 reduced the levels of autophagy related proteins.Mechanism studies have shown that dopamine D1 receptor regulated FOXO3A nuclear transcriptiona through AMPK/FOXO3 A signaling pathway.In conclusion,the results showed that the dopamine D1 receptor plays an important role in the methamphetamine induced dopaminergic neuronal death in the striatum,the inactivation of dopamine D1 receptor could significantly reduce methamphetamine inducing autophagic dopaminergic neurons death,and methamphetamine may through the D1R/AMPK/FOXO3A signaling pathways regulating the autophagy.