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

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• 作者：Bin Qiu^a ; Richard L. Bell^b ; Yong Cao^a ; ^e ; Lingling Zhang^a ; Robert B. Stewart^d ; Tamara Graves^c ; Lawrence Lumeng^c ; Weidong Yong^a ; ^{wyong@cnilas.org" class="auth_mail" title="E-mail the corresponding author} ; Tiebing Liang^c ; ^{tliang@iu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Knockout rat ; Alcohol drinking behavior ; NPY and receptors ; CRH and receptors ; Melanocortin and receptors ; BDNF
• 刊名：Journal of Genetics and Genomics
• 出版年：2016
• 出版时间：20 July 2016
• 年：2016
• 卷：43
• 期：7
• 页码：421-430
• 全文大小：1535 K

文摘

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.