Neurotoxicology of dopamine: Victim or assailant?

Since the identification of dopamine as a neurotransmitter in the mid-20th century, investigators have examined the regulation of dopamine homeostasis at a basic biological level and in human disorders. Genetic animal models that manipulate the expression of proteins involved in dopamine homeostasis have provided key insight into the consequences of dysregulated dopamine. As a result, we have come to understand the potential of dopamine to act as an endogenous neurotoxin through the generation of reactive oxygen species and reactive metabolites that can damage cellular macromolecules. Endogenous factors, such as genetic variation and subcellular processes, and exogenous factors, such as environmental exposures, have been identified as contributors to the dysregulation of dopamine homeostasis. Given the variety of dysregulating factors that impact dopamine homeostasis and the potential for dopamine itself to contribute to further cellular dysfunction, dopamine can be viewed as both the victim and an assailant of neurotoxicity. Parkinson's disease has emerged as the exemplar case study of dopamine dysregulation due to the genetic and environmental factors known to contribute to disease risk, and due to the evidence of dysregulated dopamine as a pathologic and pathogenic feature of the disease. This review, inspired by the talk, "Dopamine in Durham: location, location, location" presented by Dr. Miller for the Jacob Hooisma Memorial Lecture at the International Neurotoxicology Association meeting in 2023, offers a primer on dopamine toxicity covering endogenous and exogenous factors that disrupt dopamine homeostasis and the actions of dopamine as an endogenous neurotoxin.