Abstract
Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.
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Acknowledgements
This research was supported by a grant from the National Science and Engineering Research Council to ANS (Grant No. 355923) and a salary award from the Fonds de la Recherche en Santé du Québec to ANS (Grant No. 16193). We are grateful to Dr Paul Fletcher for procedural advice on the operant responding for conditioned reward paradigm. We thank Drs Shelly Flagel and Terry E Robinson for advice on the Pavlovian conditioned approach paradigm as well as for critical reviews of earlier versions of this manuscript. We thank Dr Guy Rousseau for help with statistical analyses.
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Bédard, AM., Maheux, J., Lévesque, D. et al. Continuous, but not Intermittent, Antipsychotic Drug Delivery Intensifies the Pursuit of Reward Cues. Neuropsychopharmacol 36, 1248–1259 (2011). https://doi.org/10.1038/npp.2011.10
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DOI: https://doi.org/10.1038/npp.2011.10
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