Serotonin modulates sensitivity to reward and negative feedback in a probabilistic reversal learning task in rats

Abstract

Depressed patients show cognitive deficits that may depend on an abnormal reaction to positive and negative feedback. The precise neurochemical mechanisms responsible for such cognitive abnormalities have not yet been clearly characterized, although serotoninergic dysfunction is frequently associated with depression. In three experiments described here, we investigated the effects of different manipulations of central serotonin (5-hydroxytryptamine, 5-HT) levels in rats performing a probabilistic reversal learning task that measures response to feedback. Increasing or decreasing 5-HT tone differentially affected behavioral indices of cognitive flexibility (reversals completed), reward sensitivity (win-stay), and reaction to negative feedback (lose-shift). A single low dose of the selective serotonin reuptake inhibitor citalopram (1 mg/kg) resulted in fewer reversals completed and increased lose-shift behavior. By contrast, a single higher dose of citalopram (10 mg/kg) exerted the opposite effect on both measures. Repeated (5 mg/kg, daily, 7 days) and subchronic (10 mg/kg, b.i.d., 5 days) administration of citalopram increased the number of reversals completed by the animals and increased the frequency of win-stay behavior, whereas global 5-HT depletion had the opposite effect on both indices. These results show that boosting 5-HT neurotransmission decreases negative feedback sensitivity and increases reward (positive feedback) sensitivity, whereas reducing it has the opposite effect. However, these effects depend on the nature of the manipulation used: acute manipulations of the 5-HT system modulate negative feedback sensitivity, whereas long-lasting treatments specifically affect reward sensitivity. These results parallel some of the findings in humans on effects of 5-HT manipulations and are relevant to hypotheses of altered response to feedback in depression.

Figure 1

Effects of acute citalopram administration: (a) the lowest dose (1 mg/kg) decreased the number of reversals achieved by the animals, whereas 10 mg/kg increased it. (b) Citalopram administration did not influence performance during the acquisition phase, but increased lose-shift behavior at 1 mg/kg and decreased it at 10 mg/kg during reversal 1 (c) (^*p<0.05 compared with vehicle-treated animals).

Figure 2

Effects of repeated citalopram administration. Citalopram (5 mg/kg) increased win-stay (b), but had no effect on lose-shift (c) and on the number of reversals completed (a). Citalopram (10 mg/kg, b.i.d.) increased the number of reversals completed by the animals without any effect on lose-shift/win-stay behavior (^*p<0.05, Cit vs Veh; BL, baseline).

Figure 3

Effects of a single dose of citalopram (3 mg/kg) in both subchronic citalopram (Cit)- and vehicle (Veh)-treated animals. This acute challenge increased both reversals completed (a) and win-stay behavior (b), but only in the Cit group (^*p<0.05, Cit vs Veh).

Figure 4

Effects of global serotonin (5-HT) depletion: (a) 5-HT-depleted animals showed an enhanced tendency to shift after being rewarded (ie, decreased win-stay). (b) Lesioned animals showed a faster increase in lose-shift behavior compared with control animals, but the effect disappeared over sessions. (c) Lesioned rats completed fewer reversals than sham-operated rats. A significant effect of session indicates that both groups improved their performance over time.