Abstract
We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and video-scored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia.
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Acknowledgements
This work was supported by the Lieber Center for Schizophrenia Research, National Institute of Mental Health Grant 5R01MH068073 (PDB), the National Institute of Mental Health, Silvio O Conte Center for Schizophrenia Research Grants MH66171 MH086404 (to EHS and ERK), National Institute of Mental Health Grant F32MH090750-01 (to RDW), the Lieber Institute for Brain Development (to RDW and ERK), and the Howard Hughes Medical Institute (to ERK). We are indebted to Tessa Hirschfeld-Stoler and Iram Haq for maintaining the transgenic mouse colony and to Billur Avtlar, Ari Pollock, Julia Kahn, and Nicole Rudy for assistance in the conduct of these experiments.
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Ward, R., Simpson, E., Richards, V. et al. Dissociation of Hedonic Reaction to Reward and Incentive Motivation in an Animal Model of the Negative Symptoms of Schizophrenia. Neuropsychopharmacol 37, 1699–1707 (2012). https://doi.org/10.1038/npp.2012.15
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DOI: https://doi.org/10.1038/npp.2012.15
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