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Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades

Published online by Cambridge University Press:  20 March 2019

Vitor Silva Pereira*
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark School of Medicine of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil
Angélica C.D. Romano Suavinha
Affiliation:
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil
Gregers Wegener
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark
Sâmia R.L. Joca
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark
*
Author for correspondence: Sâmia R.L. Joca, School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of Sao Paulo (USP), Sao Paulo, Brazil. E-mail: samia@usp.br

Abstract

Objectives

NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.

Methods

Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.

Results

We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.

Conclusion

Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

Type
Original Article
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

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