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Npy deletion in an alcohol non-preferring rat model elicits differential effects on alcohol consumption and body weight

Qiu B1, Bell RL2, Cao Y3, Zhang L1, Stewart RB4, Graves T5, Lumeng L5, Yong W6, Liang T7.

Author information

1Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.

2Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

3Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China; Experimental Medicine Center, The First Affiliated Hospital of Sichuan Medical University, Luzhou 646000, China.

4Department of Psychology, Purdue School of Science, Indiana University-Purdue University of Indianapolis, Indianapolis, IN 46202, USA.

5Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

6Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China. Electronic address: wyong@cnilas.org.

7Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: tliang@iu.edu.

Abstract

Neuropeptide Y (NPY) is widely expressed in the central nervous system and influences many physiological processes. It is located within the rat quantitative trait locus (QTL) for alcohol preference on chromosome 4. Alcohol-nonpreferring (NP) rats consume very little alcohol, but have significantly higher NPY expression in the brain than alcohol-preferring (P) rats. We capitalized on this phenotypic difference by creating an Npy knockout (KO) rat using the inbred NP background to evaluate NPY effects on alcoholconsumption. Zinc finger nuclease (ZNF) technology was applied, resulting in a 26-bp deletion in the Npy gene. RT-PCR, Western blotting and immunohistochemistry confirmed the absence of Npy mRNA and protein in KO rats. Alcohol consumption was increased inNpy(+/-) but not Npy(-/-) rats, while Npy(-/-) rats displayed significantly lower body weight when compared to Npy(+/+) rats. In whole brain tissue, expression levels of Npy-related and other alcohol-associated genes, Npy1r, Npy2r, Npy5r, Agrp, Mc3r, Mc4r, Crh and Crh1r, were significantly greater in Npy(-/-) rats, whereas Pomc and Crhr2 expressions were highest in Npy(+/-) rats. These findings suggest that the NPY-system works in close coordination with the melanocortin (MC) and corticotropin-releasing hormone (CRH) systems to modulate alcohol intake and body weight.

全文下载:http://linkinghub.elsevier.com/retrieve/pii/S1673-8527(16)30046-7