The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Academic Article uri icon

abstract

  • 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┬ábrain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (?1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for ?1R regulation of dopamine neurotransmission in response to methamphetamine. We found that ?1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that ?1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, ?1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the ?1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for ?1R regulation of dopamine neurotransmission and support the ?1R as a putative target for the treatment of methamphetamine addiction.

publication date

  • December 20, 2017