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

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 (?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.

SUBMITTER: Sambo DO

PROVIDER: S-EPMC5738444 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Sambo Danielle O DO Lin Min M Owens Anthony A Lebowitz Joseph J JJ Richardson Ben B Jagnarine Darin A DA Shetty Madhur M Rodriquez Meghan M Alonge Taiwo T Ali Mishaal M Katz Jonathan J Yan Long L Febo Marcelo M Henry L Keith LK Bruijnzeel Adriaan W AW Daws Lynette L Khoshbouei Habibeh H

Nature communications 20171220 1

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 (σ<sub>1</sub>R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ<sub>1</sub>R regulation o ...[more]

PMID: 29263318

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Project description:This study reveals a novel receptor mechanism for methamphetamine action in dopamine transporter (DAT) regulation. Trace amine-associated receptor 1 (TAAR1) is expressed in brain dopaminergic nuclei and is activated by methamphetamine in vitro. Here, we show that methamphetamine interaction with TAAR1 inhibits [(3)H]dopamine uptake, enhances or induces [(3)H]dopamine efflux, and triggers DAT internalization. In time course assays in which methamphetamine and [(3)H]dopamine were concurrently loaded into cells or synaptosomes or in pretreatment assays in which methamphetamine was washed away before [(3)H]dopamine loading, methamphetamine caused a distinct inhibition in [(3)H]dopamine uptake in TAAR1 + DAT-cotransfected cells and in wild-type mouse and rhesus monkey striatal synaptosomes. This distinct uptake inhibition was not observed in DAT-only transfected cells or in TAAR1 knockout mouse striatal synaptosomes. In [(3)H]dopamine efflux assays using the same cell and synaptosome preparations, methamphetamine enhanced [(3)H]dopamine efflux at a high loading concentration of [(3)H]dopamine (1 muM) or induced [(3)H]dopamine efflux at a low loading concentration of [(3)H]dopamine (10 nM) in a TAAR1-dependent manner. In DAT biotinylation assays using the same cell and synaptosome preparations, we observed that 1 muM methamphetamine induced DAT internalization in a TAAR1-dependent manner. All these TAAR1-mediated effects of methamphetamine were blocked by the protein kinase inhibitors H89 [N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline] and/or 2-{8-[(dimethylamino) methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methylindol-3-yl)maleimide (Ro32-0432), suggesting that methamphetamine interaction with TAAR1 triggers cellular phosphorylation cascades and leads to the observed effects of methamphetamine on DAT. These findings demonstrate a mediatory role of TAAR1 in methamphetamine action in DAT regulation and implicate this receptor as a potential target of therapeutics drugs for methamphetamine addiction.

Dataset Information

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

Publications

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

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