title: Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model.
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.
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Carina J
authors.initials: CJ
authors.lastname: Bleickardt
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Kazdoba
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Jones
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: Robert.Hodgson@merck.com.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hodgson
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D017109:Akathisia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D000068180:Aripiprazole; D001522:Behavior, Animal / Q000187:drug effects; D002428:Cebus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D011720:Pyrazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D015363:Quinolones / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D014230:Triazoles / Q000494:pharmacology
chemical_list: C534887:(7-(2-(4-difluorophenyl)-1-piperazinyl)ethyl)-2-(2-furanyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D058917:Adenosine A2 Receptor Antagonists; D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D015363:Quinolones; D014230:Triazoles; D000068180:Aripiprazole; D006220:Haloperidol
keywords: A(2A) antagonist; Akathisia; EPS; Non-human primate; PDE10A inhibitor; SCH 412348