1] Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA [2] The Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology. 2013 Oct;38(11):2179-87. doi: 10.1038/npp.2013.115. Epub 2013 May 9.
Neuroimaging studies in humans have demonstrated that inflammatory cytokines target basal ganglia function and presynaptic dopamine (DA), leading to symptoms of depression. Cytokine-treated nonhuman primates also exhibit evidence of altered DA metabolism in association with depressive-like behaviors. To further examine cytokine effects on striatal DA function, eight rhesus monkeys (four male, four female) were administered interferon (IFN)-α (20 MIU/m(2) s.c.) or saline for 4 weeks. In vivo microdialysis was used to investigate IFN-α effects on DA release in the striatum. In addition, positron emission tomography (PET) with [(11)C]raclopride was used to examine IFN-α-induced changes in DA2 receptor (D2R) binding potential before and after intravenous amphetamine administration. DA transporter binding was measured by PET using [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane. Anhedonia-like behavior (sucrose consumption) was assessed during saline and IFN-α administration. In vivo microdialysis demonstrated decreased release of DA after 4 weeks of IFN-α administration compared with saline. PET neuroimaging also revealed decreased DA release after 4 weeks of IFN-α as evidenced by reduced displacement of [(11)C]raclopride following amphetamine administration. In addition, 4 weeks of IFN-α was associated with decreased D2R binding but no change in the DA transporter. Sucrose consumption was reduced during IFN-α administration and was correlated with decreased DA release at 4 weeks as measured by in vivo microdialysis. Taken together, these findings indicate that chronic peripheral IFN-α exposure reduces striatal DA release in association with anhedonia-like behavior in nonhuman primates. Future studies examining the mechanisms of cytokine effects on DA release and potential therapeutic strategies to reverse these changes are warranted.
神经影像学研究表明，炎症细胞因子作用于基底神经节功能和多巴胺（DA）的突触前，导致抑郁症状。细胞因子处理的非人类灵长类动物也表现出与抑郁样行为相关的 DA 代谢改变的证据。为了进一步研究细胞因子对纹状体 DA 功能的影响，8 只恒河猴（4 只雄性，4 只雌性）接受皮下注射干扰素（IFN）-α（20 MIU/m2）或生理盐水 4 周。采用在体微透析法研究 IFN-α对纹状体 DA 释放的影响。此外，正电子发射断层扫描（PET）与[11C]raclopride 联合使用，在静脉注射安非他命前后检查 IFN-α诱导的 DA2 受体（D2R）结合潜能的变化。通过使用[18F]2β- carbomethoxy-3β-（4-氯苯基）-8-（2-氟乙基）-nortropane 的 PET 测量 DA 转运体结合。通过在生理盐水和 IFN-α给药期间评估快感缺失样行为（蔗糖消耗）来评估。与生理盐水相比，4 周 IFN-α 给药后 DA 的释放减少。PET 神经影像学还显示，4 周 IFN-α 后 DA 的释放减少，这表现为安非他命给药后[11C]raclopride 的置换减少。此外，4 周 IFN-α与 D2R 结合减少有关，但 DA 转运体没有变化。在 IFN-α给药期间，蔗糖消耗减少，与 4 周时通过在体微透析测量的 DA 释放减少相关。总之，这些发现表明，慢性外周 IFN-α 暴露会减少非人类灵长类动物纹状体 DA 的释放，并与快感缺失样行为相关。需要进一步研究细胞因子对 DA 释放的作用机制以及潜在的治疗策略来逆转这些变化。
