Abstract
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.
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Acknowledgements
The authors received funding from Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG): Processes APQ-02064-15 (FAM) and APQ-02044-15 (ACPO) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq): Processes 406122/2016-4 (FAM) and 424588/2016-1 (ACPO). FAM and ACPO are recipients of research fellowships (level 2) from CNPq.
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All procedures used in this study followed the ethical principles of animal experimentation adopted by the Ethic Committee on Animal Use of Federal University of Minas Gerais (CEUA–UFMG), and institutionally approved under protocol number 227/2013.
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Antônio C. Pinheiro de Oliveira and Fabrício A. Moreira shared senior authorship
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da Silveira, V.T., Röpke, J., Matosinhos, A.L. et al. Effects of the monoamine stabilizer (−)-OSU6162 on locomotor and sensorimotor responses predictive of antipsychotic activity. Naunyn-Schmiedeberg's Arch Pharmacol 391, 761–768 (2018). https://doi.org/10.1007/s00210-018-1500-x
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DOI: https://doi.org/10.1007/s00210-018-1500-x