Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs

Vicente-Rodríguez, Marta; Pérez-Garcı́a, Carmen; Haro, María Carla Piazzon de; Ramos, M. Teresa; Herradón, Gonzalo

doi:10.1016/j.bbr.2014.08.023

Cited by 13 publications

(24 citation statements)

References 37 publications

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“…The effects of Mdk deletion on ethanol consumption are not due to alterations in taste sensitivity, as evidenced by normal quinine and saccharin preference in Mdk −/− mice compared with Mdk +/+ mice. Prior to this study, Mdk −/− mice were tested for the rewarding properties of ethanol and found to be more sensitive to ethanol reward in the conditioned place preference test (Vicente-Rodriguez et al , 2014). It is possible that Mdk gene knockout mice consume more ethanol because they find ethanol more rewarding than mice with normal levels of Mdk .…”

Section: Discussionmentioning

confidence: 99%

“…MDK protein levels are also higher in the prefrontal cortex of alcoholics, suggesting that expression of this gene is not only responsive to ethanol, but may also contribute to excessive alcohol drinking in humans (Flatscher-Bader et al , 2005, Flatscher-Bader & Wilce, 2006, Flatscher-Bader & Wilce, 2008). Recently, Vicente-Rodriguez et al demonstrated that Mdk knockout (−/−) mice, in contrast to wild type mice, develop ethanol conditioned place preference at a low dose of ethanol (1 g/kg), indicating that MDK may act to limit the rewarding properties of ethanol (Vicente-Rodriguez et al , 2014). Mdk −/− mice also demonstrate a delayed recovery of ethanol-induced ataxia on the rotarod (Vicente-Rodriguez et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Vicente-Rodriguez et al demonstrated that Mdk knockout (−/−) mice, in contrast to wild type mice, develop ethanol conditioned place preference at a low dose of ethanol (1 g/kg), indicating that MDK may act to limit the rewarding properties of ethanol (Vicente-Rodriguez et al , 2014). Mdk −/− mice also demonstrate a delayed recovery of ethanol-induced ataxia on the rotarod (Vicente-Rodriguez et al , 2014). …”

Section: Introductionmentioning

confidence: 99%

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Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

Lasek

2017

Genes Brain and Behavior

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

Lasek

2017

Genes Brain and Behavior

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“…The acceptor vector contained the regulatory regions responsible for tissue-specific expression of Thy-1 gene, which drives neuron-specific expression of transgenes [25, 26]. PTN-specific overexpression in different brain areas, including an ~3–4-fold upregulation in the prefrontal cortex (PFC) and a 20% increase of PTN protein levels in striatum, was established by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridization, and by western blot [23, 27, 28]. …”

Section: Methodsmentioning

confidence: 99%

Pleiotrophin regulates microglia-mediated neuroinflammation

Fernández-Calle

Vicente-Rodríguez

Gramage

et al. 2017

J Neuroinflammation

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BackgroundPleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved.MethodsIn immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO).ResultsWe found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS.ConclusionsOur findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.

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“…The acceptor vector used was pTSC-a2 and contained the regulatory regions responsible for tissue specific expression of Thy-1 gene, which drives neuron-specific expression of transgenes (Aigner et al, 1995;Caroni, 1997). PTN specific overexpression in different brain areas, including a 20% increase of PTN protein levels in striatum, was established by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), in situ hybridization, and by Western blot (Ferrer-Alcón et al, 2012;Vicente-Rodriguez et al, 2015;2014b).…”

Section: Animalsmentioning

confidence: 99%

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation

Vicente-Rodríguez

Gonzalez

Gramage

et al. 2016

European Neuropsychopharmacology

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Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs

Cited by 13 publications

References 37 publications

Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

Pleiotrophin regulates microglia-mediated neuroinflammation

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation

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