Dopamine D1 receptors mediate methamphetamine-induced dopaminergic damage: involvement of autophagy regulation via the AMPK/FOXO3A pathway

Rationale Clinical studies have revealed that methamphetamine abuse increases risk for developing Parkinson’s diseases. It is thus important to elucidate the mechanisms by which methamphetamine damages dopaminergic neurons. Objectives The present study was designed to elucidate the role of the dopamine D1 receptor in methamphetamine-mediated dopaminergic neuronal damage and its underlying mechanisms. Methods Mice were treated for 4 days with vehicle, methamphetamine, or the D1 agonist SKF38393 and then assessed for locomotion and performance in the pole and rotarod tests. Cellular indices of autophagy, LC3, P62, and Beclin-1, tyrosine hydroxylase, and the AMPK/FOXO3A pathway were analyzed in striatal tissue from treated mice, in PC12 cells, and in D1 receptor mutant mice. Results Repeated treatment with a relatively high dose of methamphetamine for 4 days induced both loss of dopaminergic neurons and activation of autophagy in the striatum as evidenced by increased expression of LC3 and P62. However, such treatment did not induce either loss of dopaminergic neurons or activation of autophagy in D1 receptor knockout mice. D1 receptor-mediated activation of autophagy was also confirmed in vitro using dopaminergic neuronal PC12 cells. Further studies demonstrated that the AMPK/FOXO3A signaling pathway is responsible for D1 receptor-mediated activation of autophagy. Conclusions The present data indicate a novel mechanism for methamphetamine-induced dopaminergic neuronal damage and reveal an important role for D1 receptors in the neurotoxicity of this drug.