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NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine

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Abstract

Rationale

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests.

Objectives

The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice.

Methods

Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests.

Results

Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine.

Conclusions

NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.

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Acknowledgments

This work was supported by funds from the Brazilian National Council Research (CNPq; Grant No. PVE 401289/2014-1, No. 302302/2015-8, and No. 401837/2016-5 to ECG). VADH was recipient of PhD scholarship from Capes Foundation. LA held a PDJ fellowship from the Brazilian National Research Council.

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Authors and Affiliations

  1. Behavioral Pharmacology Laboratory, Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, sn, Campus Universitário, Lagoa Nova, Natal, 59072-970, Brazil

    Victor A. D. Holanda, Wilton B. Santos, Laila Asth & Elaine C. Gavioli

  2. Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

    Remo Guerrini

  3. Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy

    Girolamo Calo’ & Chiara Ruzza

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  1. Victor A. D. Holanda
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  2. Wilton B. Santos
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  5. Girolamo Calo’
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  7. Elaine C. Gavioli
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Correspondence to Elaine C. Gavioli.

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Holanda, V.A.D., Santos, W.B., Asth, L. et al. NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine. Psychopharmacology 235, 3093–3102 (2018). https://doi.org/10.1007/s00213-018-5004-7

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