Research Article

5-HT_2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats

Ashley Furr^a1, M. Danet Lapiz-Bluhm^a2 and David A. Morilak^a1 c1

^a1 Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA

^a2 Department of Family and Community Health Systems, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA

Abstract

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-HT_2A receptors (5-HT_2ARs) 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-HT_2AR 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_2ARs in the OFC. In the next experiment, rats were exposed to 5 wk CIC 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_2ARs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.

(Received June 09 2011)

(Reviewed July 28 2011)

(Revised August 31 2011)

(Accepted September 07 2011)

(Online publication October 19 2011)

Key Words:

• Antidepressant;
• chronic stress;
• orbitofrontal cortex;
• reversal learning;
• 5-HT_2AR subtype

Correspondence:

^c1 Address for correspondence: Dr D. A. Morilak, Department of Pharmacology, MC 7764, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Tel.: 1-210-567-4174 Fax: 1-210-567-4300 Email: morilak@uthscsa.edu