Cell type and sex specific insights into ventral striatum deep brain stimulation for cocaine relapse.
Cell type and sex specific insights into ventral striatum deep brain stimulation for cocaine relapse.
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细胞类型和性别对腹侧纹状体深部脑刺激可卡因复发的具体见解。
DOI：
10.1038/s41386-022-01513-z
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Moussawi,Khaled
中科院分区：
文献类型：
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作者：
Lehmann,CollinM;Moussawi,Khaled
复发仍然是兴奋剂使用障碍的一个主要问题。目前正在探索使用脑深部电刺激（DBS）等工具进行神经调节作为潜在的治疗方法[1]。自从二十多年前FDA批准DBS用于治疗帕金森病以来，DBS已成为治疗其他难治性神经精神疾病的有前途的方法[2]。DBS目前具有FDA的人道主义器械豁免地位，用于治疗强迫症，如难治性强迫症和图雷特综合征[2]。这表明DBS也可能成为治疗物质使用障碍（SUD）的有价值的工具[1]。临床前研究表明，腹侧纹状体的DBS抑制可卡因寻求的复发。然而，这种对药物寻求的影响的潜在生物学机制尚不清楚。经典DBS涉及高频电刺激，其是非特异性的，并且不仅可以影响电极附近的神经元细胞体，而且可以影响经过或终止于附近的来自远端部位的神经胶质细胞和轴突，这导致远端脑区域的顺向或逆向刺激。在腹侧纹状体中，DBS可能刺激主要的纹状体细胞类型-D1和D2中等多刺神经元（MSN）-以及GABA能和胆碱能中间神经元，以及终止于或穿过腹侧纹状体的各种轴突。目前尚不清楚腹侧纹状体DBS对药物寻求的影响是否由一种或多种细胞类型介导，这些细胞类型通常相互关联并共同调节最终的行为结果。现在DBS可以选择性地影响不同的神经元群体[3]，并且考虑到D1和D2 MSN在调节药物寻求行为中的不同作用，理解不同腹侧纹状体细胞类型，特别是D1和D2 MSN在DBS对药物寻求的影响中的作用非常重要。在这一期的《神经精神药理学》中，Swinford-Jackson等人使用高频细胞类型特异性光遗传学刺激（opto-DBS）作为DBS的替代品，以测试腹侧纹状体中D1和D2 MSN的DBS样高频刺激对雄性和雌性大鼠可卡因引发复发的影响[4]。作者在转基因D1-cre和D2-cre雄性和雌性大鼠中使用静脉内（IV）可卡因自我给药。将表达Cre依赖性通道视紫红质的腺病毒（AAV）双侧注入内侧腹侧纹状体（纹状体壳），允许选择性刺激D1与D2 MSN。训练大鼠在FR 1和FR 5强化时间表上自我施用IV可卡因，总共21个疗程，然后进行消退训练。杠杆按压熄灭后，大鼠进行两次可卡因预充恢复测试，在此期间，每只动物在1小时的时间段内接受opto-DBS（130 Hz，5 ms脉冲宽度，1 mW）或假刺激（连接贴片电缆，但不输送功率），在恢复期间平衡。鉴于D1与D2 MSN分别在增强与抑制药物相关行为中的作用，作者假设D1与D2 MSN的光DBS将增强与抑制可卡因引发的药物寻求恢复。然而，结果表明，D1 MSN的光-DBS不影响雄性或雌性大鼠的恢复，而D2 MSN的光-DBS仅抑制雄性大鼠的恢复-在雌性大鼠中没有观察到影响。Swinford-Jackson等人报告的结果为腹侧纹状体DBS对可卡因寻求的潜在作用机制提供了有价值但不完整的见解。光化学治疗的复发抑制作用
Relapse continues to be a major problem for stimulant use disorder. Neuromodulation with tools like deep brain stimulation (DBS) is currently being explored as a potential treatment [1]. Since it was FDA-approved for the treatment of Parkinson’s disease more than two decades ago, DBS has emerged as a promising approach for otherwise intractable neuropsychiatric illnesses [2]. DBS currently has a humanitarian device exemption status from the FDA for the treatment of compulsive disorders like refractory obsessive-compulsive disorder and Tourette’s syndrome [2]. This suggests that DBS may also become a valuable tool in treating substance use disorders (SUDs)[1]. Preclinical studies show that DBS of the ventral striatum inhibits relapse to cocaine seeking. However, the underlying biological mechanism of this effect on drug seeking is not clear. Classical DBS involves high-frequency electrical stimulation, which is nonspecific and can affect not only neuronal cell bodies near the electrode, but also glial cells and axons from distant sites passing by or terminating in the vicinity, which results in orthodromic or antidromic stimulation of distant brain areas. In the ventral striatum, DBS likely stimulates the major striatal cell types—D1 and D2 medium spiny neurons (MSNs)—as well as GABAergic and cholinergic interneurons, and various axons terminating in or passing through the ventral striatum. It is not clear whether ventral striatum DBS’effects on drug seeking are mediated by one or more cell types which are normally interconnected and together modulate the ultimate behavioral outcome. Now that DBS can be deployed to selectively affect different neuronal populations [3], and given the different roles of D1 and D2 MSNs in regulating drug-seeking behaviors, understanding the role of the different ventral striatum cell types, especially D1 and D2 MSNs, in DBS’s effects on drug seeking is of high importance. In this issue of Neuropsychopharmacology, Swinford-Jackson et al. use high-frequency cell-type-specific optogenetic stimulation (opto-DBS) as a surrogate for DBS to test the effects of DBS-like high-frequency stimulation of D1 and D2 MSNs in the ventral striatum on cocaine-primed relapse in male and female rats [4]. The authors used intravenous (IV) cocaine self-administration in transgenic D1-cre and D2-cre male and female rats. An adenovirus (AAV) expressing Cre-dependent channelrhodopsin was infused into the medial ventral striatum (accumbens shell) bilaterally allowing selective stimulation of D1 vs. D2 MSNs. Rats were trained to self-administer IV cocaine on FR1 and then FR5 reinforcement schedules for a total of 21 sessions, followed by extinction training. After lever pressing was extinguished, rats underwent two cocaine-primed reinstatement testing sessions during which each animal received either opto-DBS throughout the 1-h session (130Hz, 5ms pulse width, 1mW) or sham stimulation (patch cable attached, but no power delivered), counterbalanced between reinstatement sessions. Given the role of D1 vs. D2 MSNs in enhancing vs. inhibiting drug-related behaviors respectively, the authors hypothesized that opto-DBS of D1 vs. D2 MSNs would enhance vs. inhibit cocaine-primed reinstatement of drug seeking. However, the results show that opto-DBS of D1 MSNs did not affect reinstatement in either male or female rats, while opto-DBS of D2 MSNs inhibited reinstatement only in male rats—no effect was observed in female rats. The results reported by Swinford-Jackson et al. provide valuable yet incomplete insight into a potential mechanism of action of ventral striatum DBS on cocaine seeking. The relapse-inhibiting effect of opto …