New Study in The FASEB Journal: Methamphetamine Impairs Dopamine Uptake by Targeting a Protein Modification
Tuesday, November 25, 2025Dopamine brings on a surge of pleasure, but too much dopamine in a synapse can ultimately lead to mood disorders and addiction. A recent preclinical study published in The FASEB Journal suggests that methamphetamine boosts dopamine levels by reversibly reducing the amount of a modification on the dopamine transporter. Loss of the modification decreases the transporter’s ability to remove the neurotransmitter from synapses. The findings shed new light on how the transporter works and could help researchers develop new treatments for addiction and neurological disorders, such as depression and schizophrenia.
The neurotransmitter dopamine is involved in many processes, such as movement, reward, motivation, learning, and memory. When triggered, special neurons in the brain release dopamine into the gaps between neurons, called synapses, making a person experience happiness and euphoria. Low levels, however, can make a person feel depressed. Because inappropriate amounts can lead to psychological disorders or addiction, levels of the neurotransmitter are regulated by dopamine transporters (DATs) that remove excess dopamine from synapses. Protein modifications can modulate DAT activity. Palmitoylation enhances DAT reuptake of dopamine, whereas phosphorylation by the enzyme protein kinase C decreases reuptake.
Methamphetamine can slow reuptake by stimulating phosphorylation, but Roxanne Vaughan, James Foster, and colleagues at the University of North Dakota wanted to see whether the drug also affects DAT palmitoylation.
In a rat model and in in vitro experiments, methamphetamine rapidly reduced DAT palmitoylation and DAT transporter activity. Palmitoylation returned to normal levels much more quickly than transporter activity, which suggests that additional processes are involved in keeping DAT activity suppressed after palmitoylation recovers. The methamphetamine effects were specific—cocaine did not impact palmitoylation. In vitro experiments revealed that protein kinase C was necessary for the reduction in palmitoylation. Additional experiments with DAT mutated at a position where half of the palmitoylation typically occurs reduced palmitoylation to about half of wild-type levels, and the mutant took up even less dopamine in methamphetamine-treated cells.
“By revealing that methamphetamine suppresses dopamine transporter palmitoylation, this study identifies a previously unknown mechanism through which the drug alters dopamine signaling,” says Vaughan. “Understanding this process could guide the development of treatments aimed at stabilizing or restoring transporter regulation, potentially reducing the long-term dopamine imbalances and neurochemical damage linked to methamphetamine addiction.”
Funding: University of North Dakota and National Institute of General Medical Sciences
Read the full article, “Transient suppression of dopamine transporter palmitoylation by methamphetamine: Implications for transport regulation,” published in The FASEB Journal.