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.
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Acknowledgements
This research was supported by a Wellcome Trust program grant (076274/z/04/z) and completed within the Cambridge University Behavioral and Clinical Neuroscience Institute, supported by a joint award from the Medical Research Council (MRC) and Wellcome Trust. AB was supported by an MRC studentship. We thank Dr Belin for help with data analysis.
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TWR is a consultant for Cambridge Cognition, Pfizer, Eli Lilly, GlaxoSmithKline, Pangenics, Allon Therapeutics, and Roche. He is also in receipt of grants from Pfizer and GlaxoSmithKline and is an editor of Springer-Verlag (Psychopharmacology). AB, DET, DC, ACM, AA-M, and JWD have nothing to disclose.
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Bari, A., Theobald, D., Caprioli, D. et al. Serotonin Modulates Sensitivity to Reward and Negative Feedback in a Probabilistic Reversal Learning Task in Rats. Neuropsychopharmacol 35, 1290–1301 (2010). https://doi.org/10.1038/npp.2009.233
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DOI: https://doi.org/10.1038/npp.2009.233
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