Antagonism of the adenosine A_2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model

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• 作者：Carina J. Bleickardt ; Tatiana M. Kazdoba ; Nicholas T. Jones ; John C. Hunter ; Robert A. Hodgson
• 关键词：Akathisia ; Non-human primate ; A2A antagonist ; PDE10A inhibitor ; EPS ; SCH 412348
• 刊名：Pharmacology Biochemistry and Behavior
• 出版年：March, 2014
• 年：2014
• 卷：118
• 期：Complete
• 页码：36-45
• 全文大小：537 K

文摘

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 m>Cebus apellam> 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 A_2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A_2A 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 A_2A receptor antagonists for the treatment of antipsychotic-induced movement disorders.