背景:逆向学习需要联想学习和执行功能来抑制非适应性反应。在例如精神分裂症和强迫症中观察到逆转学习缺陷,并且涉及包括眶额皮质(OFC)的神经回路。血清素能功能与人类和实验动物的视觉逆转学习密切相关,但对涉及哪些受体亚型知之甚少。
目的:本研究的目的是测试全身和OFC内5-HT2C受体拮抗作用对大鼠视觉逆转学习的影响,并评估新型触摸屏范式中这些影响的潜在心理机制。
方法:在实验1-2中,我们使用了一种新的3-刺激任务来研究通过SB242084(0.1、0.5和1.0mg/kg腹膜内注射)交叉位点的5-HT2C受体拮抗作用。实验3评估了SB242084在2选择逆转学习中的作用。在实验4中,我们验证了一种新颖的触摸屏系列视觉逆转任务,该任务适用于通过巴氯芬/麝香酚诱导的OFC灭活进行的神经药理学微输注。在实验5中,我们测试了OFC内SB242084(1.0或3.0μg/侧)对该任务性能的影响。
结果:在实验1-3中,SB242084减少了早期错误,但将晚期错误增加到标准。在实验5中,OFC内部SB242084减少了早期错误,而不增加验证为OFC依赖的反转范例中的后期错误(实验4)。
结论:OFC内5-HT2C受体拮抗作用降低了大鼠新型触摸屏逆转学习范式的坚持。系统性5-HT2C受体拮抗作用还损害了后期学习-观察到的交叉位点的强大作用,并可能与冲动有关。这些结论是根据逆转学习的神经机制及其与精神疾病的相关性进行讨论的。
BACKGROUND: Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved.
OBJECTIVE: The objectives of the
study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms.
METHODS: In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 μg/side) on performance in this task.
RESULTS: In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4).
CONCLUSIONS: Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.