Y1 receptors regulate aggressive behavior by modulating serotonin pathways

doi:10.1073/pnas.0404085101

Y1 receptors regulate aggressive behavior by modulating serotonin pathways

^*Neurobiology Program, Garvan Institute of Medical Research, Sydney NSW 2010, Australia; ^†Department of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; ^§Department of Pharmacology, Medical University Innsbruck, A-6020 Innsbruck, Austria; and ^‡Neuroscience Institute of Schizophrenia and Allied Disorders, Sydney NSW 2010, Australia

Edited by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, and approved July 16, 2004 (received for review June 8, 2004)

Abstract

Neuropeptide Y (NPY) is pivotal in the coordinated regulation of food intake, growth, and reproduction, ensuring that procreation and growth occur only when food is abundant and allowing for energy conservation when food is scant. Although emotional and behavioral responses from the higher brain are known to be involved in all of these functions, understanding of the coordinated regulation of emotion/behavior and physiological functions is lacking. Here, we show that the NPY system plays a central role in this process because ablation of the Y1 receptor gene leads to a strong increase in territorial aggressive behavior. After exposure to the resident-intruder test, expression of c-fos mRNA in Y1-knockout mice is significantly increased in the medial amygdala, consistent with the activation of centers known to be important in regulating aggressive behavior. Expression of the serotonin [5-hydroxytryptamine (5-HT)] synthesis enzyme tryptophan hydroxylase is significantly reduced in Y1-deficient mice. Importantly, treatment with a 5-HT-1A agonist, (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, abolished the aggressive behavior in Y1-knockout mice. These results suggest that NPY acting through Y1 receptors regulates the 5-HT system, thereby coordinately linking physiological survival mechanisms such as food intake with enabling territorial aggressive behavior.

Footnotes

↵ ¶ To whom correspondence should be addressed at: Neurobiology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia. E-mail: h.herzog{at}garvan.org.au.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CART, cocaine- and amphetamine-regulated transcript; 5-HT, 5-hydroxytryptamine (serotonin); GnRH, gonadotropin-releasing hormone; NPY, neuropeptide Y; 8-OH-DPAT, (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide; POMC, proopiomelanocortin; RI, resident-intruder; SA, spontaneous aggression; TPH, tryptophan hydroxylase.