Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
J Neurosci. 2010 Jan 20;30(3):930-8. doi: 10.1523/JNEUROSCI.4312-09.2010.
We have recently demonstrated that systemic administration of 5-HT(2C) and 5-HT(2A) receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT(2C) and 5-HT(2A) receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT(2C) and 5-HT(2A) receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT(2C) and 5-HT(2A) receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT(2C) receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 microg) and perseverative errors to criterion (0.3 and 1.0 microg) compared with controls. However, the highest dose (1.0 microg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT(2C) receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT(2C) receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.
我们最近的研究表明，5-HT（2C）和 5-HT（2A）受体拮抗剂的全身给药分别显著增强和损害空间反转学习。在这项研究中，进一步研究了 5-HT（2C）和 5-HT（2A）受体亚型在介导这些相反作用方面的神经解剖特异性。通过靶向选择性 5-HT（2C）和 5-HT（2A）受体拮抗剂（分别为 SB 242084 和 M100907）在一些与认知灵活性相关的脑区，即眶额皮层（OFC）、内侧前额叶皮层（mPFC）和伏隔核（NAc）中，研究了 5-HT（2C）和 5-HT（2A）受体的作用。OFC 内的 5-HT（2C）受体拮抗作用产生了类似于全身给药的剂量依赖性效应，即通过减少试验次数（所有剂量：0.1、0.3 和 1.0μg）和达到标准的坚持错误（0.3 和 1.0μg），从而改善空间反转学习与对照组相比。然而，最高剂量（1.0μg）表现出非选择性作用，因为它也影响反转阶段之前的保留和减少学习错误。脑内注射 SB 242084 到 mPFC 或 NAc 对任何行为测量均无显著影响。同样，在 OFC、mPFC 或 NAc 内注射 M100907 也未观察到显着差异。这些数据表明，在 5-HT（2C）受体拮抗后观察到的反转学习表现改善是在 OFC 内介导的。这些数据也涉及到在 OFC 内进行 5-HT（2C）受体拮抗是否有助于阐明强迫症的生物学基础，从而为治疗应用提供了潜力。
