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S-ketamine reduces marble burying behaviour: Involvement of ventromedial orbitofrontal cortex and AMPA receptors

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  • Cristina Luz Tosta, Pharmaceutical Sciences Graduate Program, Health Sciences Centre, Federal University of Espírito Santo, Vitória, ES, Brazil.
  • ,
  • Gabriela Pandini Silote
  • Maria Paula Fracalossi, Department of Pharmaceutical Sciences, Health Science Centre, Federal University of Espirito Santo, Vitoria, ES, 29043-900, Brazil.
  • ,
  • Ariandra Guerini Sartim, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil; Department of Clinical Medicine - Translational Neuropsychiatry Unit, Aarhus University, Denmark. Electronic address: samia@usp.br.
  • ,
  • Roberto Andreatini, Department of Pharmacology, Biological Sciences Centre, Federal University of Paraná, Brazil.
  • ,
  • Sâmia Regiane Lourenço Joca
  • Vanessa Beijamini, Pharmaceutical Sciences Graduate Program, Health Sciences Centre, Federal University of Espírito Santo, Vitória, ES, Brazil; Department of Pharmaceutical Sciences, Health Science Centre, Federal University of Espírito Santo, Vitória, ES, Brazil. Electronic address: vanessa.harres@ufes.br.

Previous clinical and pre-clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long-lasting antidepressant effect, but its anti-compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5-HT) release and attenuation of nitric oxide (NO) synthesis. It is not known if these mechanisms are involved in ketamine-induced anti-compulsive effect. Therefore, we firstly investigated the effect of S-ketamine in the marble-burying test (MBT), a model for screening of drugs with potential to treat OCD. Then, we evaluated whether ketamine effects in the MBT would involve the vmOFC, be dependent on AMPA receptors, facilitation of serotonergic neurotransmission and inhibition of nitrergic pathway. Our results showed that single systemic (10 mg/kg) and intra-vmOFC (10 nmol/side) administration of S-ketamine reduces marble burying behaviour (MBB) without affecting spontaneous locomotors activity. Pre-treatment with NBQX (3 mg/kg; AMPA receptor antagonist) blocked the reduction of MBB induced by S-ketamine. However, pre-treatment with p-CPA (150 mg/kg/day; a 5-HT synthesis inhibitor), WAY100635 (3 mg/kg; a 5-HT1A receptor antagonist), or L-arginine (500 mg/kg; a nitric oxide precursor) did not counteract S-ketamine effect in the MBT. In contrast, associating sub-effective doses of L-NAME (10 mg/kg; NOS inhibitor) and S-ketamine (3 mg/kg) decreased MBB. In conclusion, the reduction of MBB by S-ketamine strengthens its possible anti-compulsive effect. The vmOFC is involved in this S-ketamine effect, which is dependent on the activation of AMPA receptors.

Original languageEnglish
JournalNeuropharmacology
Volume144
Pages (from-to)233-243
Number of pages11
ISSN0028-3908
DOIs
Publication statusPublished - Jan 2019

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