Francois Jennifer, Grimm Oliver, Schwarz Adam J, Schweiger Janina, Haller Leila, Risterucci Celine, Böhringer Andreas, Zang Zhenxiang, Tost Heike, Gilmour Gary, Meyer-Lindenberg Andreas
Department of In Vivo Pharmacology, Eli Lilly and Company, Windlesham, UK.
Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
Neuropsychopharmacology. 2016 Apr;41(5):1386-94. doi: 10.1038/npp.2015.291. Epub 2015 Sep 21.
Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.
越来越多的证据表明，在几种精神疾病的发病机制中，区域神经对奖励预期的反应起到了作用，比如精神分裂症，在患者及高危人群中观察到腹侧纹状体对积极奖励的反应减弱。对清醒且有行为活动的大鼠腹侧纹状体进行的体内氧安培测量显示，与奖励相关的组织氧变化与人类功能磁共振成像（fMRI）中观察到的血氧水平依赖（BOLD）信号变化密切平行，这表明针对该机制的跨物种研究方法在精神药理学中可能是可行的。本研究利用人类的fMRI和大鼠的体内氧安培测量，探讨了急性、亚麻醉剂量的氯胺酮（一种在临床前和临床精神药理学研究中广泛使用的药理学模型）对两种动物在执行奖励预期任务期间腹侧纹状体活动的调节作用。在一项针对人类受试者的交叉安慰剂和氯胺酮研究之后进行的感兴趣区域分析中，在执行金钱激励延迟任务期间，与安慰剂相比，氯胺酮给药后观察到奖励预期期间腹侧纹状体反应减弱。在大鼠中，相对于赋形剂，氯胺酮激发后，对预测奖励发放的条件刺激的反应中，腹侧纹状体信号出现了类似的减弱。本研究首次在两种动物中提供了数据，证明急性氯胺酮对与奖励相关的腹侧纹状体（O2）和fMRI信号有减弱作用。这些发现可能有助于更深入地从机制上理解氯胺酮作为精神病模型的潜在作用，表明针对奖励信号的跨物种药理学实验是可行的，并提示这种表型是开发新型化合物、评估疾病状态和治疗效果的一种有前景的转化生物标志物。
