Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Collo, Ginetta; Bono, Federica; Cavalleri, Laura; Plebani, Laura; Mitola, Stefania; Pich, Emilio Merlo; Millan, Mark J.; Zoli, Michèle; Maskos, Uwe; Spano, PierFranco; Missale, Cristina

doi:10.1124/mol.113.084863

Cited by 61 publications

(96 citation statements)

References 59 publications

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“…We found that ANA-12 reversed ethanol intake both in the two-bottle choice and DID paradigms and strongly decreased the expression of D 3 R in the striatum of WT-treated mice. Recently, D 3 R on VTA-SN dopaminergic neurons were found to mediate neuroplasticity effects of several addictive drugs (Collo et al , 2012; Collo et al , 2013). Therefore, our conclusion about the engagement of striatal RACK1, BDNF, and D 3 R in mediating ethanol consumption may be only a part of a more complex mechanism, whose elucidation may require an assessment of the effects of ethanol intake in the VTA-SN dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Leggio

Camillieri

Platania

et al. 2014

Neuropsychopharmacol

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Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.

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Section: Discussionmentioning

confidence: 99%

Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Leggio

Camillieri

Platania

et al. 2014

Neuropsychopharmacol

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“…In utero exposure of embryos to nicotine results in an increase in the soma size of DA neurons of newborn mice. This effect is mediated by dopamine D 3 receptors and recruitment of ERK/Akt/ mTORC1 signaling (53). In mouse lines with a deletion of the mTORC2 component Rictor in the entire CNS or in Purkinje cells, neurons are smaller and exhibit an abnormal morphology (283).…”

Section: Neurogenesis Brain Cell Differentiation and Morphogenesismentioning

confidence: 99%

mTOR in Brain Physiology and Pathologies

Bockaert

Marin

2015

Physiological Reviews

300

223

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TOR (target of rapamycin) and its mammalian ortholog mTOR have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin extracted from a bacterium of the Easter Island (Rapa Nui) soil. mTOR is a serine/threonine kinase found in two functionally distinct complexes, mTORC1 and mTORC2, which are differentially regulated by a great number of nutrients such as glucose and amino acids, energy (oxygen and ATP/AMP content), growth factors, hormones, and neurotransmitters. mTOR controls many basic cellular functions such as protein synthesis, energy metabolism, cell size, lipid metabolism, autophagy, mitochondria, and lysosome biogenesis. In addition, mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development, synaptic plasticity, memory storage, and cognition. Thus it is not surprising that deregulation of mTOR signaling is associated with many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy, cognitive impairment, and brain tumors, whereas stimulation of mTORC1 (direct or indirect) can be beneficial for other pathologies such as depression or axonal growth and regeneration.

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“…Studies of cancer pathogenesis have shown that the activation of the ERK1/2 and PI3K/PKB signaling pathways plays an important role in the process of ECM deposition of turmor cells. Inhibitors such as PD98059 and LY294002 can promote apoptosis, reduce their biological activities and inhibit the conversion of cellular phenotype by inhibiting the deposition of ECM in malignant mesothelioma cells 6,22,23 . Another study found that the increased expression of fibronectin protein in rat mesangial cells was related to glomerular fibrosis and sclerosis…”

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confidence: 99%

Roles of the ERK1/2 and PI3K/PKB signaling pathways in regulating the expression of extracellular matrix genes in rat pulmonary artery smooth muscle cells

Jia

et al. 2017

Acta Cir. Bras.

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Roles of the ERK1/2 and PI3K/PKB signaling pathways in regulating the expression of extracellular matrix genes in rat pulmonary artery smooth muscle cells The pulmonary artery was then extracted, the fibrous tunica externa dissected and the runica intima stripped. The myogenous tissues of the vascular middle layer of the artery were then cut into 1 mm³ tissue blocks, and seeded into the culture flasks with the density as 1cm -2 . After 2 h wall-adherent cultivation at 37°C and 5% CO 2 , M199 medium containing 10% fetal bovine serum (FBS) was added. A week later, cells had grown outwards from the tissue blocks; when the growth covered 70% of the area of the base of the vessel, the culture was passaged. The 3rd-generation cells were taken for slice culturing and an immunohistochemical method was performed to detect the expression of cellular α-SMA and to confirm the purity of the PASMCs.The PASMCs were then divided into five groups and cultured in M199 medium containing different additional components, and for 48 h and 72 h. The control group was cultivated in M199 medium with 10% FBS. Indeed, in this study, the control group is negative control. The CTGF group with 10% FBS + 50 ng/ml CTGF (PeproTech, USA), the CP group with 10% FBS + 50 ng/ml CTGF + 20 μmol/L PD98059 (Sigma, USA), the CL group with 10% FBS + 50 ng/ml CTGF + 10 μmol/L LY294002 (Sigma, USA) and the CPL group with 10% FBS + 50 ng/ml CTGF + 20 μmol/L PD98059 + 10 μmol/L LY294002. RT-PCRFor the RT-PCR, the cDNA sequences of rat collagen III, fibronectin and β-actin were downloaded from NCBI gene database, then the Primer Premier 5 software was used to design appropriate PCR primers. The primer sequences were in the Table 1.

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Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Cited by 61 publications

References 59 publications

Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

mTOR in Brain Physiology and Pathologies

Roles of the ERK1/2 and PI3K/PKB signaling pathways in regulating the expression of extracellular matrix genes in rat pulmonary artery smooth muscle cells

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