Sigma‐1 Receptor Attenuates Methamphetamine Stimulation of Dopamine Transporter Activity

The dopamine (DA) transporter (DAT) is a presynaptic membrane protein implicated in multiple physiological and pathological conditions, including cognition, movement, and psychostimulant addiction. DAT functions to translocate DA across the plasmalemmal membrane and to modulate the excitability of dopaminergic neurons, making it a crucial regulator of DA homeostasis. DAT is the primary target for methamphetamine, a highly addictive psychostimulant. What is not often recognized, however, is that methamphetamine is both a substrate for DAT as well as a ligand for the sigma‐1 receptor, an intracellular chaperone protein.Although findings from multiple laboratories have confirmed that methamphetamine rapidly enters the neuron as a DAT substrate, the molecular actions of methamphetamine once it enters the dopaminergic neuron are less understood. Here, we identified the sigma‐1R as a novel protein partner of DAT at the surface membrane. We show that increasing concentrations of methamphetamine are associated with both increased concentrations of sigma‐1R protein levels and increased DAT/sigma‐1R interactions. Addition of a sigma‐1R agonist also increases DAT/sigma‐1R interactions. Increased DAT/sigma‐1R interactions prevent methamphetamine‐induced, DAT‐mediated increases in dopaminergic neuron firing rates. Interestingly, we found administration of a sigma‐1R agonist reduces methamphetamine‐induced inhibition of DA uptake and markedly decreases methamphetamine‐mediated DA efflux. These changes in DAT function occur without altering DAT trafficking. These data are the first to demonstrate reciprocally regulated sigma‐1R/DAT interactions and their impact on the regulation of DAT by methamphetamine.