Yuen Jason, Goyal Abhinav, Rusheen Aaron E, Kouzani Abbas Z, Berk Michael, Kim Jee Hyun, Tye Susannah J, Abulseoud Osama A, Oesterle Tyler S, Blaha Charles D, Bennet Kevin E, Lee Kendall H, Oh Yoonbae, Shin Hojin
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States.
IMPACT-The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
Front Pharmacol. 2023 Jun 20;14:1199655. doi: 10.3389/fphar.2023.1199655. eCollection 2023.
Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone. Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130 Hz, 0.2 ms, and 0.2 mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5 mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5 g/kg, i.p.). I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0 nM) compared to baseline (150.7 ± 15.5 nM) and saline administration (152.0 ± 16.1 nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, = 0.022, = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6 min vs. 67.9 ± 8.3 min; pre- vs. post-oxycodone; < 0.001). Continuous DBS targeted at the VTA ( = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7 min vs. 105.2 ± 4.1 min; pre- vs. post-oxycodone; = 0.072). Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction.
阿片类药物是美国过量用药死亡的主要原因，2020年导致近7万例死亡。深部脑刺激（DBS）是一种有前景的治疗物质使用障碍的新方法。在此，我们假设腹侧被盖区（VTA）深部脑刺激会调节羟考酮的多巴胺能效应和呼吸效应。采用多循环方波伏安法（M-CSWV）研究对含有丰富多巴胺能神经元的啮齿动物腹侧被盖区（VTA）进行深部脑刺激（130Hz、0.2ms和0.2mA）如何调节羟考酮静脉注射（2.5mg/kg）对伏隔核核心（NAcc）的多巴胺张力性细胞外水平以及对乌拉坦麻醉大鼠（腹腔注射1.5g/kg）呼吸频率的急性影响。与基线水平（150.7±15.5nM）和生理盐水注射组（152.0±16.1nM）相比，静脉注射羟考酮导致NAcc多巴胺张力性水平升高（296.9±37.0nM）（分别为296.9±37.0与150.7±15.5与152.0±16.1，F=0.022，df=5）。这种由羟考酮引起的NAcc多巴胺浓度的显著升高与呼吸频率的急剧降低相关（111.7±2.6次/分钟与67.9±8.3次/分钟；注射羟考酮前与注射后；P<0.001）。针对VTA的持续深部脑刺激（n=5）降低了基线多巴胺水平，将羟考酮引起的多巴胺水平升高减弱至（+39.0%对+95%），并减轻了呼吸抑制（121.5±6.7次/分钟与105.2±4.1次/分钟；注射羟考酮前与注射后；P=0.072）。在此我们证明VTA深部脑刺激可减轻羟考酮引起的NAcc多巴胺水平升高并逆转呼吸抑制。这些结果支持了使用神经调节技术治疗药物成瘾的可能性。
