The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission.

Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (σR), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σR regulation of dopamine neurotransmission in response to methamphetamine. We found that σR activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σR activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σR activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σR interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca signaling, providing potential mechanisms. Broadly, these data provide evidence for σR regulation of dopamine neurotransmission and support the σR as a putative target for the treatment of methamphetamine addiction.