Carli Mirjana, Baviera Marta, Invernizzi Roberto W, Balducci Claudia
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Neuropsychopharmacology. 2006 Apr;31(4):757-67. doi: 10.1038/sj.npp.1300893.
Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT(1A) receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.
血清素（5-羟色胺，5-HT）受体日益被认为是精神分裂症认知增强的主要靶点。多项证据表明，谷氨酸N-甲基-D-天冬氨酸（NMDA）受体在精神分裂症前额叶皮质以及注意力和执行功能相关障碍中具有病理生理作用。我们研究了内侧前额叶皮质（mPFC）中5-HT1A和5-HT2A与谷氨酸NMDA受体机制之间的相互作用如何影响注意力表现不同方面的控制。大鼠接受了五选择连续反应时（5-CSRT）任务训练，该任务可提供注意力功能指标（正确反应百分比）、执行控制指标（通过预期反应和持续性反应测量）以及速度指标。在向同一脑区注射8-羟基二丙胺基四氢萘（8-OH-DPAT，30和100 ng/侧）或M100907（100和300 ng/侧）5分钟后，将竞争性NMDA受体拮抗剂环丙哌嗪（CPP，50 ng/侧）直接注入mPFC。两种剂量的8-OH-DPAT或M100907均完全消除了CPP诱导的注意力功能损害。此外，M100907消除了CPP诱导的预期反应，但对持续性过度反应无影响，而8-OH-DPAT减少了持续性过度反应，但对CPP诱导的预期反应无影响。选择性5-HT(1A)受体拮抗剂WAY100635（30 ng/侧）拮抗了8-OH-DPAT（100 ng/侧）的作用。30 ng/侧的8-OH-DPAT缩短了对照组和注射CPP大鼠的正确反应潜伏期，并降低了注射CPP大鼠的遗漏百分比。数据表明，mPFC中的5-HT1A和5-HT2A受体对注意力功能发挥相反作用，并证明mPFC中的5-HT1A和5-HT2A受体对执行控制的不同方面（如冲动性和强迫性持续性）有可分离的贡献。
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