Effort-related effects of chronic administration of the DA D-2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline

Rationale Long-acting antipsychotics such as haloperidol decanoate are becoming more commonly used. Long-acting depot formulations have several advantages, but secondary negative effects of prolonged delivery, including motivational dysfunctions, could have debilitating effects. Assessing the behavioral changes that emerge during chronic antipsychotic administration in rats could provide insight regarding the development of motivational dysfunctions and drug tolerance.Objectives Acute administration of dopamine D2 antagonists such as haloperidol induce motivational deficits in rats, as marked by a shift towards a low-effort bias during effort-based choice tasks. In the present studies, programmable subcutaneous infusion pumps provided continuous and controlled drug delivery of haloperidol. Animals were assessed using a fixed ratio (FR) 5 lever pressing schedule and the FR5/chow feeding test of effort-based choice. The adenosine A(2A) antagonist istradefylline was studied for its ability to reverse the effects of chronic haloperidol.Results Continuous chronic infusions of haloperidol produced significant reductions in FR5 performance and a shift from lever pressing to chow intake in rats tested on FR5/chow feeding choice, with no evidence of tolerance over the 4-week infusion period. Behavior returned to baseline during the vehicle-infusion washout period. Istradefylline significantly reversed the effects of haloperidol, increasing lever pressing and decreasing chow intake in haloperidol-treated rats.Conclusions These studies provide an important behavioral characterization of the effects of chronically infused haloperidol, and demonstrate that A2A antagonism reverses the effects of chronic haloperidol. This research could contribute to the understanding and treatment of motivational dysfunctions seen in schizophrenia, Parkinson's disease, and other disorders involving dopamine.