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 human 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 (Tnf) 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.

Molecular tools to elucidate factors regulating alcohol use

“…Liu et al, 2011) or GABA A α 4 or GABA A δ levels in the medial NAc shell (Nie, Rewal, Gill, Ron, & Janak, 2011;Rewal et al, 2012;Rewal et al, 2009) all reduced alcohol intake. RNAi knockdown of mu opioid receptor expression in the VTA also reduced drinking, whereas inhibition of a midbrain trophic factor called midkine elevated alcohol intake (H. Chen, He, & Lasek, 2017;Lasek, Janak, He, Whistler, & Heberlein, 2007). Together these data highlight multiple receptors involved in promoting alcohol drinking and trophic factors working to limit alcohol consumption whose behavioral functions were confirmed by virus-mediated RNAi.…”

Genetic variations in chromodomain helicase DNA-binding protein 5, gene-environment interactions and risk of sporadic Alzheimer’s disease in Chinese population

“…In our study, drinking status with CHD5 rs11121295 variant presented a promising association with Alzheimer's disease risk compared with non-drinking carrying that genotype, which indicated that this variant might act in response to drinking, and true associations might be detected by alcoholic stimulation. It has been shown that alcohol could modulate the effect of various cytokines, receptors or neuroimmune signaling in brain, such as midkine (MDK) [ 24 ], PPARgamma receptor [ 25 ], and HMGB1, miRNA and TLR receptors [ 26 ]. Therefore, we speculated, alcohol intake might trigger proinflammatory events through their induction of oxidative stress and extensive inflammation.…”

Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder

“…Interestingly, Mdk knockout mice also exhibited altered behavioral responses to ethanol, demonstrating ethanol CPP at low doses of ethanol that do not normally induce CPP, increased sensitivity to ethanol-induced ataxia, and increased ethanol intake in both moderate (2-bottle choice) and binge drinking (drinking in the dark) tests [108,109]. Local knockdown of Mdk in the mouse VTA also increased binge-like drinking [108].…”