title: Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues.
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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bédard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Maheux
authors.forename: Daniel
authors.initials: D
authors.lastname: Lévesque
authors.forename: Anne-Noël
authors.initials: AN
authors.lastname: Samaha
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D004298:Dopamine