Barlow Rebecca L, Alsiö Johan, Jupp Bianca, Rabinovich Rebecca, Shrestha Saurav, Roberts Angela C, Robbins Trevor W, Dalley Jeffrey W
Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
1] Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK [2] Department of Neuroscience, University of Uppsala, Uppsala, Sweden.
Neuropsychopharmacology. 2015 Jun;40(7):1619-30. doi: 10.1038/npp.2014.335. Epub 2015 Jan 8.
Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.
眶额皮质（OFC）功能障碍会损害个体根据不断变化的刺激-奖励（S-R）偶联灵活调整行为的能力。改变OFC和背内侧纹状体（DMS）中5-羟色胺（5-HT）和多巴胺（DA）传递的干预措施也会导致灵活性受损。然而，尚不清楚类似的机制是否是行为灵活性自然变化的基础。在本研究中，我们使用空间辨别连续反转程序来研究大鼠行为灵活性的个体间差异。我们发现，全身给予5-HT再摄取抑制剂西酞普兰以及低剂量的DA再摄取抑制剂GBR12909后，该任务的灵活性得到改善。在重复的S-R反转过程中，持续性反应分布处于上五分位数的大鼠，其OFC中5-HT代谢物5-羟吲哚乙酸的水平显著降低。此外，与低五分位数组的大鼠相比，中、高五分位数大鼠OFC中的5-HT2A受体结合显著减少。这些扰动伴随着外侧OFC中单胺氧化酶-A（MAO-A）和MAO-B表达的增加，以及高度持续性大鼠背缝核中MAO-A、MAO-B和色氨酸羟化酶表达的减少。我们没有发现低持续性和高持续性大鼠在DMS中DA和5-HT功能标记物或腹侧被盖区MAO表达上存在显著差异的证据。这些发现表明，OFC中5-羟色胺能张力降低可能是一种内表型，易导致行为不灵活和其他形式的强迫行为。
