Department of Neuroscience, University of Florida, Gainesville, FL, 32611, USA.
Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Nat Commun. 2017 Dec 20;8(1):2228. doi: 10.1038/s41467-017-02087-x.
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.
多巴胺神经递质的传递受到精神兴奋剂苯丙胺的高度调节，苯丙胺是多巴胺转运体（DAT）的底物。通过与 DAT 的相互作用，苯丙胺增加大脑中细胞外多巴胺的水平，导致其具有奖励和成瘾的特性。苯丙胺还与 sigma-1 受体（σR）相互作用，sigma-1 受体是一种细胞器间信号调节剂。我们使用互补策略，确定了 σR 调节多巴胺神经递质传递对苯丙胺反应的新机制。我们发现，σR 的激活可防止苯丙胺诱导的、由 DAT 介导的多巴胺神经元放电活动的增加。在体外和体内安培测量显示，σR 的激活可降低苯丙胺刺激的多巴胺外排，而不影响基础多巴胺神经递质传递。这些发现与以下发现一致：σR 的激活可降低苯丙胺诱导的运动、动机行为和增强大脑奖励功能。值得注意的是，我们揭示了 σR 与 DAT 在质膜上或附近相互作用，并降低了苯丙胺诱导的 Ca 信号，提供了潜在的机制。广义而言，这些数据为 σR 调节多巴胺神经递质传递提供了证据，并支持 σR 作为治疗苯丙胺成瘾的潜在靶点。
