5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats.
5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats.
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DOI：
10.1017/s1461145711001441
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Morilak DA
中科院分区：
文献类型：
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作者：
Furr A;Lapiz-Bluhm MD;Morilak DA
慢性压力是抑郁症的危险因素，慢性压力会诱发与前额皮质功能障碍相关的认知障碍，这也是抑郁症的主要组成部分。我们之前已经证明，5周的慢性间歇性寒冷（CIC）应激会导致大鼠出现逆转性学习缺陷，这与眶额皮质（OFC）中的血清素能传递减少有关，而通过选择性血清素再摄取抑制剂（SSRI）的长期治疗可以恢复这种传递。然而，长期 SSRI 治疗产生有益认知作用的机制目前尚不清楚。因此，本研究的目的是调查 OFC 中 5-HT2A 受体对逆转学习的潜在调节影响，以及它们对长期 SSRI 治疗的有益认知作用的潜在贡献。双侧显微注射选择性 5-HT2A 受体拮抗剂 MDL 100,907 至 OFC（0.02-2.0 nmole）对逆转学习任务产生剂量依赖性有害影响，表明 5-HT2A 受体对 OFC 具有促进作用。在下一个实验中，大鼠受到为期 5 周的 CIC 应激，这会损害逆转学习，并在慢性应激的最后 3 周内长期使用 SSRI、西酞普兰（20 毫克/公斤/天）进行治疗。慢性 CIT 治疗改善了 CIC 应激大鼠的逆转学习，而双侧显微注射 MDL 100,907（0.20 nmole，之前实验的最佳剂量）到 OFC 中再次对逆转学习产生不利影响，与西酞普兰的有益作用相反。我们得出结论，OFC 中的 5-HT2A 受体促进逆转学习，并可能有助于长期 SSRI 治疗的有益认知效果。
Chronic stress is a risk factor for depression, and chronic stress can induce cognitive impairments associated with prefrontal cortical dysfunction, which are also major components of depression. We have previously shown that 5-weeks of chronic intermittent cold (CIC) stress induced a reversal learning deficit in rats, associated with reduced serotonergic transmission in the orbitofrontal cortex (OFC), that was restored by chronic treatment with a selective serotonin reuptake inhibitor (SSRI). However, the mechanisms underlying the beneficial cognitive effects of chronic SSRI treatment are currently unknown. Thus, the purpose of the present study was to investigate the potential modulatory influence specifically of 5-HT2A-receptors in the OFC on reversal learning, and their potential contribution to the beneficial cognitive effects of chronic SSRI treatment. Bilateral microinjections of the selective 5-HT2A-receptor antagonist, MDL 100,907 into OFC (0.02–2.0 nmoles) had a dose-dependent detrimental effect on a reversal learning task, suggesting a facilitatory influence of 5-HT2A-receptors in the OFC. In the next experiment, rats were exposed to 5-weeks of CIC stress, which compromised reversal learning, and treated chronically with the SSRI, citalopram (20 mg/kg/day) during the final 3 weeks of chronic stress. Chronic CIT treatment improved reversal learning in the CIC-stressed rats, and bilateral microinjection of MDL 100,907 (0.20 nmoles, the optimal dose from the preceding experiment) into OFC once again had a detrimental effect on reversal learning, opposing the beneficial effect of citalopram. We conclude that 5-HT2A-receptors in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.