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The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice

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Abstract

Rationale

Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY’s effects on rodent anxiety and depression-related behaviors.

Objectives

To further elucidate the role of Y1R in (1) NPY’s anxiolytic-like effects and (2) fluoxetine’s antidepressant-like and neurogenesis-inducing effects.

Methods

Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R −/− were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.

Results

Y1R −/− exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R −/− mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R −/− mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.

Conclusions

These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.

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Acknowledgements

We thank Dr. Patrik Ernfors at the Karolinska Institute for providing the mutant mice for breeding, Dr. Judith Davis and Monique Melige for assistance with breeding, and Michael Feyder and Jaynann Juhasz for technical assistance. Research supported by the Intramural Research Programs of the National Institute of Alcoholism and Alcohol Abuse Research Program, National Institute of Mental Health (NH002784, NH02177), the NIH/Karolinska Graduate Partnership Program and the Swedish Medical Research Council.

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Correspondence to Rose-Marie Karlsson.

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Karlsson, RM., Choe, J.S., Cameron, H.A. et al. The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice. Psychopharmacology 195, 547–557 (2008). https://doi.org/10.1007/s00213-007-0945-2

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