Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys.
Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys.
复制标题
氯胺酮治疗对可卡因诱导的未麻醉恒河猴功能连接恢复和破坏的影响。
DOI：
10.1007/s00213-019-05204-4
复制
发表时间：
2019
影响因子：
3.4
通讯作者：
Howell,LeonardL
中科院分区：
文献类型：
--
作者：
Maltbie,EricA;Gopinath,KaundinyaS;Howell,LeonardL
理性物质使用障碍的特征是失去对基于奖励的决策的执行控制，额纹状体连接的中断与这一过程有关。亚麻醉氯胺酮最近被证明可以加强drug-naïve受试者的额纹状体连接。目的研究氯胺酮治疗对雌性恒河猴功能连接（FC）和可卡因寻求行为的破坏作用。方法对3只雌性恒河猴进行非麻醉MRI扫描训练。每人接受三次drug-naïve/戒断药理学MRI扫描，同时急性注射生理盐水、可卡因（0.3 mg/kg静脉注射）和可卡因（0.3 mg/kg静脉注射）。氯胺酮治疗48小时后（低剂量=0.345 mg/kg丸+ 0.256 mg/kg/h 1小时；静脉注射），并在每日可卡因自我给药2个月后进行第四次生理盐水注射扫描。另一组5只恒河猴（4只雌性），均有广泛的可卡因暴露史，在氯胺酮（或载具）治疗后48小时进行恢复测试。低剂量和高剂量分别为0.69 mg/kg + 0.512 mg/kg/h，持续1 h。结果氯胺酮治疗可减弱可卡因对drug-naïve/戒断受试者整体和额纹状体FC的影响。每天自我服用可卡因两个月导致全球和额纹状体FC的长期破坏。低剂量氯胺酮治疗后，恢复期间的可卡因寻求行为减少，但没有大剂量氯胺酮治疗。结论这些发现说明了可卡因对功能连接的破坏性作用，并为氯胺酮治疗兴奋剂使用障碍的潜在疗效提供了证据。
RationaleSubstance use disorders are characterized by a loss of executive control over reward-based decision-making, and disruption of fronto-striatal connectivity has been implicated in this process. Sub-anesthetic ketamine has recently been shown to bolster fronto-striatal connectivity in drug-naïve subjects.ObjectivesThe influence of ketamine treatment was examined on the disruptive effects of cocaine on functional connectivity (FC) and on cocaine-seeking behavior in female rhesus monkeys.MethodsThree female rhesus were trained for unanesthetized MRI scanning. Each received three drug-naïve/abstinent pharmacological MRI scans with acute injections of saline, cocaine (0.3 mg/kg i.v.), and cocaine (0.3 mg/kg i.v.) 48-h after a ketamine treatment (low dose =0.345 mg/kg bolus + 0.256 mg/kg/h for 1 h; i.v.), and a fourth scan with saline injection following 2 months of daily cocaine self-administration. A separate cohort of five rhesus (4 female), all with extensive histories of cocaine exposure, underwent reinstatement testing 48 h after ketamine (or vehicle) treatment. Two sub-anesthetic doses were tested:low doseandhigh dose= 0.69 mg/kg + 0.512 mg/kg/h for 1 h.ResultsKetamine treatment attenuated the effects of cocaine on both global and fronto-striatal FC in drug-naïve/abstinent subjects. Two months of daily cocaine self-administration led to prolonged disruption of both global and fronto-striatal FC. Cocaine-seeking behavior during reinstatement was reduced following ketamine treatment at thelow dose, but nothigh dose.ConclusionThese findings illustrate the disruptive effects of cocaine on functional connectivity and provide evidence for the potential efficacy of ketamine as a treatment for stimulant use disorder.