期刊
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
卷 15, 期 9, 页码 1295-1305出版社
OXFORD UNIV PRESS
DOI: 10.1017/S1461145711001441
关键词
Antidepressant; chronic stress; orbitofrontal cortex; reversal learning; 5-HT2AR subtype
资金
- National Institute of Mental Health [MH083669, MH072672]
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 wk 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 this study was to investigate the potential modulatory influence specifically of 5-HT2A receptors (5-HT(2A)Rs) 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-HT2AR antagonist, MDL 100,907 into OFC (0.02-2.0 nmol) had a dose-dependent detrimental effect on a reversal-learning task, suggesting a facilitatory influence of 5-HT(2A)Rs in the OFC. In the next experiment, rats were exposed to 5 wk DC stress, which compromised reversal learning, and treated chronically with the SSRI, citalopram (20 mg/kg.d) during the final 3 wk of chronic stress. Chronic citalopram treatment improved reversal learning in the CIC-stressed rats, and bilateral microinjection of MDL 100,907 (0.20 nmol, 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-HT(2A)Rs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.
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