The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission

Danielle O. Sambo, Min Lin, Anthony Owens, Joseph J. Lebowitz, Ben Richardson, Darin A. Jagnarine, Madhur Shetty, Meghan Rodriquez, Taiwo Alonge, Mishaal Ali, Jonathan Katz, Long Yan, Marcelo Febo, L. Keith Henry, Adriaan W. Bruijnzeel, Lynette Daws, Habibeh Khoshbouei

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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 (σ1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and support the σ1R as a putative target for the treatment of methamphetamine addiction.

Original languageEnglish (US)
Article number2228
JournalNature communications
Issue number1
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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