title: Npy deletion in an alcohol non-preferring rat model elicits differential effects on alcohol consumption and body weight.
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 alcohol consumption. 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 in Npy(+/-) 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.
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.affiliation: Institute 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Psychology, Purdue School of Science, Indiana University-Purdue University of Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Stewart
authors.affiliation: Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Graves
authors.affiliation: Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lumeng
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China. Electronic address: wyong@cnilas.org.
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.affiliation: Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: tliang@iu.edu.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000235:genetics*; D002460:Cell Line; D004435:Eating / Q000235:genetics; D055786:Gene Knockout Techniques; D009478:Neuropeptide Y / Q000172:deficiency* / Q000235:genetics*; D051381:Rats
chemical_list: D009478:Neuropeptide Y
keywords: Alcohol drinking behavior; BDNF; CRH and receptors; Knockout rat; Melanocortin and receptors; NPY and receptors