Effects of the monoamine stabilizer (−)-OSU6162 on locomotor and sensorimotor responses predictive of antipsychotic activity

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 391; no. 7; pp. 761 - 768
• Main Authors: da Silveira, Vívian T., Röpke, Jivago, Matosinhos, Ana L., Issy, Ana C., Del Bel, Elaine A., de Oliveira, Antônio C., Moreira, Fabrício A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-07-2018; Springer Nature B.V
• Subjects: Animals; Antipsychotic Agents - pharmacology; Antipsychotics; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Catalepsy; Cocaine; Cocaine - pharmacology; Dizocilpine; Dopamine; Dopamine receptors; Dopamine transporter; Dopamine Uptake Inhibitors - pharmacology; Drug abuse; Drug dosages; Excitatory Amino Acid Antagonists - pharmacology; Extrapyramidal system; Glutamatergic transmission; Hyperactivity; Ketamine; Ketamine - pharmacology; Liability; Locomotion; Locomotion - drug effects; Male; Mental disorders; Mice; N-Methyl-D-aspartic acid; Neurological diseases; Neurosciences; Original Article; Pharmacology/Toxicology; Piperidines - pharmacology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Reflex, Startle - drug effects; Schizophrenia; Schizophrenia - drug therapy; Sensorimotor system; Side effects; Startle response; Schizophrenia; Antipsychotics; Animal models; Dopamine; Glutamate
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-018-1500-x

The monoamine stabilizer (3S)-3-[3-(methenesulfonyl)phenyl]-1-propylpiperidine hidrochloride [(−)-OSU6162] is a promising compound for the treatment of neurological and psychiatric disorders, such as schizophrenia. Here, we tested the hypothesis that (−)-OSU6162 prevents hyperlocomotion and sensorimotor deficits in prepulse inhibition of the startle response (PPI) induced by psychomimetic drugs. Male Swiss mice received injections of (−)-OSU6162 (1, 3, 10, or 30 mg/kg), and their motor responses were investigated in the open field and in the catalepsy tests, which predicts liability to induce sedation and extrapyramidal side effects, respectively. Next, in independent experiments, this compound was evaluated for its efficacy to prevent hyperlocomotion induced by cocaine (10 mg/kg; dopamine transporter inhibitor) or ketamine (60 mg/kg; glutamate NMDA channel blocker) in the open field. Finally, we tested if (−)-OSU6162 prevents PPI disruption induced by MK-801 (0.5 mg/kg; glutamate NMDA channel blocker). (−)-OSU6162 induced neither locomotion impairment nor catalepsy. This compound prevented cocaine-induced hyperlocomotion at the doses of 10 and 30 mg/kg and ketamine-induced hyperlocomotion at the doses of 1 and 3 mg/kg. In the sensorimotor test, (−)-OSU6162 failed to reverse MK-801-induced PPI deficits. The dopamine stabilizer (−)-OSU6162 prevents the hyperactivity induced by dopaminergic and anti-glutamatergic drugs at doses that preserve motor functions, although it failed in the PPI test. Its therapeutic potential for specific symptoms of schizophrenia warrants further investigation in both preclinical and clinical studies.