1. Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model.
- Author
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Bleickardt CJ, Kazdoba TM, Jones NT, Hunter JC, and Hodgson RA
- Subjects
- Akathisia, Drug-Induced physiopathology, Akathisia, Drug-Induced psychology, Animals, Antipsychotic Agents administration & dosage, Antipsychotic Agents antagonists & inhibitors, Antipsychotic Agents toxicity, Aripiprazole, Behavior, Animal drug effects, Cebus, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Haloperidol administration & dosage, Haloperidol antagonists & inhibitors, Haloperidol toxicity, Humans, Male, Motor Activity drug effects, Phosphodiesterase Inhibitors administration & dosage, Phosphodiesterase Inhibitors toxicity, Piperazines administration & dosage, Piperazines antagonists & inhibitors, Piperazines toxicity, Pyrazoles administration & dosage, Pyrazoles antagonists & inhibitors, Pyrazoles toxicity, Pyrimidines pharmacology, Quinolines administration & dosage, Quinolines antagonists & inhibitors, Quinolines toxicity, Quinolones administration & dosage, Quinolones antagonists & inhibitors, Quinolones toxicity, Triazoles pharmacology, Adenosine A2 Receptor Antagonists pharmacology, Akathisia, Drug-Induced drug therapy
- Abstract
Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
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