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 and Habibeh Khoshbouei ()
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Danielle O. Sambo: University of Florida
Min Lin: University of Florida
Anthony Owens: University of Texas Health Science Center at San Antonio
Joseph J. Lebowitz: University of Florida
Ben Richardson: University of Florida
Darin A. Jagnarine: University of Florida
Madhur Shetty: University of North Dakota
Meghan Rodriquez: University of North Dakota
Taiwo Alonge: University of Florida
Mishaal Ali: University of Florida
Jonathan Katz: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health
Long Yan: Max Plank Institute for Neuroscience Jupiter
Marcelo Febo: University of Florida
L. Keith Henry: University of North Dakota
Adriaan W. Bruijnzeel: University of Florida
Lynette Daws: University of Texas Health Science Center at San Antonio
Habibeh Khoshbouei: University of Florida

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: 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 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.

Date: 2017
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DOI: 10.1038/s41467-017-02087-x

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