5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats

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-HT2A receptors (5-HT2ARs) 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-HT2ARs 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-HT2ARs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.

Figure 1

Representative photomicrograph of a Cresyl Violet-stained coronal section, corresponding to plate 7 in the atlas of Paxinos and Watson (1998), showing the tracks of the guide cannulae implanted bilaterally above the OFC (arrowheads). Microinjection sites were 1 mm beyond the tip of the cannulae, in the OFC (asterisks). Abbreviations: Cg, cingulate cortex; Fr, frontal cortex; OFC, orbital frontal cortex; Pir, piriform cortex. Scale bar = 1 mm.

Figure 2

Acute bilateral microinjections of the selective 5-HT_2A-receptor antagonist, MDL 100,907, into the OFC immediately prior to testing on the reversal stage of the attentional set-shifting test impaired reversal learning compared to vehicle microinjections in control rats. Significant reversal deficits were observed in rats given MDL 100,907 at 0.10, 0.20, 1.00 and 2.00 nmoles/0.50 μl/side (*p<0.05 compared to the vehicle-injected control group by Newman-Keuls post hoc comparisons; mean ± S.E.M., n=7–12/group).

Figure 3

Effects of acute bilateral microinjections of MDL 100,907 into the OFC on reversal learning in CIC-stressed rats treated chronically with citalopram (CIT). CIC stress compromised reversal learning (main effect, p < 0.01), and chronic CIT treatment improved reversal learning in CIC-stressed rats but not in controls (+p<0.01, effect of CIT compared to the corresponding vehicle-treated group). The effect of CIT was reversed by microinjections of MDL 100,907 into OFC, which increased trials to criterion on the reversal task in all treatment conditions (*p<0.05, compared to corresponding HBC-vehicle control groups) (mean ± S.E.M., n=7–11/group).