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Pituitary adenylate cyclase-activating polypeptide induces a depressive-like phenotype in rats

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Abstract

Background

Major depressive disorder (MDD) is a chronic, life-threatening psychiatric condition characterized by depressed mood, psychomotor alterations, and a markedly diminished interest or pleasure in most activities known as anhedonia. Available pharmacotherapies have limited success and the need for new strategies is clear. Recent studies attribute a major role to the pituitary adenylate cyclase-activating polypeptide (PACAP) system in mediating the response to stress. PACAP knockout mice display profound alterations in depressive-like behaviors, and genetic association studies have demonstrated that genetic variants of the PACAP gene are associated with MDD. However, the effects of PACAP administration on depressive-like behaviors in rodents have not yet been systematically examined.

Objectives

The present study investigated the effects of central administration of PACAP in rats on depressive-like behaviors, using well-established animal models that represent some of the endophenotypes of depression.

Methods

We used intracranial self-stimulation (ICSS) to assess the brain reward function, saccharin preference test to assess anhedonia, social interaction to assess social withdrawal, and forced swim test (FST) to assess behavioral despair.

Results

PACAP raised the current threshold for ICSS, elevation blocked by the PACAP antagonist PACAP(6–38). PACAP reduced the preference for a sweet saccharin solution and reduced the time the rats spent interacting with a novel animal. Interestingly, PACAP administration did not affect immobility in the FST.

Conclusions

Our results demonstrate a role for the central PACAP/PAC1R system in the regulation of depressive-like behaviors and suggest that hyperactivity of the PACAP/PAC1R system may contribute to the pathophysiology of depression, particularly the associated anhedonic symptomatology and social dysfunction.

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Acknowledgments

We thank Stephen St. Cyr for technical assistance and Andrew Kim for editorial assistance. This publication was made possible by grants # MH093650, MH091945, DA030425, and GM008541 from the National Institute of Health, by the Peter McManus Charitable Trust, and the Peter Paul Career Development Professorship (P.C.).

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The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, 72 E. Concord St., R-612, Boston, MA, 02118, USA

      Mariel P. Seiglie, Karen L. Smith, Angelo Blasio, Pietro Cottone & Valentina Sabino

    2. Graduate Program in Neuroscience, Boston University School of Medicine, Boston, MA, USA

      Mariel P. Seiglie

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    1. Mariel P. Seiglie
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    Correspondence to Valentina Sabino.

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    Mariel P. Seiglie and Karen L. Smith contributed equally to this work.

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    Seiglie, M.P., Smith, K.L., Blasio, A. et al. Pituitary adenylate cyclase-activating polypeptide induces a depressive-like phenotype in rats. Psychopharmacology 232, 3821–3831 (2015). https://doi.org/10.1007/s00213-015-4045-4

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