Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats

Abstract

Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

Fig. 1.

Schematic diagram and timeline for the procedures in experiment 1.

Fig. 2.

Schematic diagram and timeline for the procedures in experiment 2.

Fig. 3.

Effects of sub-chronic and acute vortioxetine treatment on reversal learning that had been compromised by serotonin depletion with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). PCPA treatment significantly impaired reversal learning compared to saline pre-treated rats (*p < 0.01). Vortioxetine (10 mg/kg, i.p.) given once per day over 3 d, 30 min prior to habituation, training and testing on the attentional set-shifting test, significantly attenuated the reversal learning impairment in PCPA pre-treated rats compared to PCPA-pretreated rats given sub-chronic vehicle injections (+p < 0.001). A single acute injection of vortioxetine (10 mg/kg, i.p.) immediately before testing also significantly attenuated the PCPA-induced reversal learning impairment compared to vehicle treatment after PCPA (+p < 0.02). Data are shown as mean ± s.e.m (n = 7–8/group).

Fig. 4.

Effects of chronic dietary vortioxetine treatment, administered concurrently with chronic intermittent cold (CIC) stress, on reversal learning. CIC stress significantly impaired reversal learning (*p < 0.01, compared to vehicle-treated controls; mean ± s.e.m; n = 7–8 per group). Chronic treatment with both the low (30 mg/kg/day) and high dose (90 mg/kg d⁻¹) of vortioxetine administered in the diet concurrently with CIC stress alleviated the stress-induced deficit in reversal learning (+p < 0.01 and p < 0.05, respectively, compared to vehicle-treated CIC-stressed rats; mean ± s.e.m; n = 8–11 per group).

Fig. 5.

Body weight change over the course of chronic treatment with vortioxetine in the diet or control diet, including the 2 wk period of chronic intermittent cold (CIC) stress and the 10 d period of food restriction preceding behavioral testing (bars). The respective diets were maintained for one additional day after testing to obtain brain tissue for receptor occupancy analyses. Animals exposed to CIC stress showed less weight gain than unstressed controls (open symbols compared to filled symbols), and this difference reached statistical significance during the period of food restriction, during which all groups lost weight (significance at specific time points is not indicated for the sake of clarity). These effects were equivalent across the different dietary treatments, for which there were no main effects or interactions. Data shown as mean ± s.e.m (n = 8–11 per group).