title: Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression.
abstract: Midkine (MDK) is a cytokine and neurotrophic factor that is more highly expressed in the brains of alcoholics and in mice predisposed to drink large amounts of ethanol, suggesting that MDK may regulate ethanol consumption. Here we measured ethanol consumption in male and female Mdk knockout (-/-) mice using the two-bottle choice and the drinking in the dark (DID) tests. We found that Mdk -/- mice consumed significantly more ethanol than wild-type controls in both tests. To determine if MDK acts in the ventral tegmental area (VTA) to regulate ethanol consumption, we delivered lentivirus expressing a Mdk shRNA into the VTA of male C57BL/6J mice to locally knockdown Mdk and performed the DID test. Mice expressing a Mdk shRNA in the VTA consumed more ethanol than mice expressing a control non-targeting shRNA, demonstrating that the VTA is one site in the brain through which MDK acts to regulate ethanol consumption. Since MDK also controls the expression of inflammatory cytokines in other organs, we examined gene expression of interleukin-1 beta (Il1b), tumor necrosis factor alpha (Tnfα) and the chemokine (C-C motif) ligand 2 (Ccl2) in the VTA of Mdk -/- mice and in mice expressing Mdk shRNA in the VTA. Expression of Ccl2 was elevated in the VTA of Mdk -/- mice and in mice expressing Mdk shRNA in the VTA. These results demonstrate that MDK functions in the VTA to limit ethanol consumption and levels of CCL2, a chemokine known to increase ethanol consumption.
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: A W
authors.identifier: 0000-0002-7099-2442
authors.initials: AW
authors.lastname: Lasek
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000078792:Midkine; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism* / Q000502:physiology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; C582105:Mdk protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000078792:Midkine
keywords: Addiction; Ccl2; Il1b; Mdk; alcohol; chemokine; cytokine; dopamine; innate immune; ventral tegmental area