Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct;240(10):2173-2185.
doi: 10.1007/s00213-023-06439-y. Epub 2023 Aug 24.

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline

Renee A Rotolo  1   2 , Alev Ecevitoglu #  1 , Rose E Presby  1   3 , Hanna Lindgren  4 , Cedric Mombereau  5 , Cyrene Nicholas  1 , Alana Moore  1 , Gayle A Edelstein  1 , Merce Correa  5 , John D Salamone  6
Affiliations

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline

Renee A Rotolo et al. Psychopharmacology (Berl). 2023 Oct.

Abstract

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 A2A 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.

Keywords: Avolition; Dopamine; Motivation; Negative; Schizophrenia; Symptoms.

PubMed Disclaimer

References

    1. Abe C, Tashiro T, Tanaka K, Ogihara R, Morita H (2009) A novel type of implantable and programmable infusion pump for small laboratory animals. J Pharmacol Toxicol Methods 59(1):7–12. https://doi.org/10.1016/j.vascn.2008.09.002 - DOI - PubMed
    1. Abe K, Fujita M, Yoshikawa H (2016) Effectiveness of Istradefylline for Fatigue and Quality of Life in Parkinson’s Disease Patients’ and of Their Caregivers’. Adv Parkinson’s Dis 5:24–28 - DOI
    1. Aberman JE, Salamone JD (1999) Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience 92(2):545–552. https://doi.org/10.1016/s0306-4522(99)00004-4 - DOI - PubMed
    1. Artaloytia JF, Arango C, Lahti A et al (2006) Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am J Psychiatry 163(3):488–493. https://doi.org/10.1176/appi.ajp.163.3.488 - DOI - PubMed
    1. Bailey MR, Chun E, Schipani E, Balsam PD, Simpson EH (2020) Dissociating the effects of dopamine D2 receptors on effort-based versus value-based decision making using a novel behavioral approach. Behav Neurosci 134(2):101–118. https://doi.org/10.1037/bne0000361 - DOI - PubMed - PMC

LinkOut - more resources