Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • Taken together our results demonstrate

    2019-10-17

    Taken together, our results demonstrate that the changes of striatal dopamine release and locomotor activity observed following chronic nicotine treatment and consequent acute withdrawal are mediated by CRF1, but not CRF2. Previous studies have already indicated that blocking CRF1 would prevent some of the affective symptoms (the dysphoria and the reward deficit) (Bruijnzeel et al., 2009, Bruijnzeel et al., 2012, George et al., 2007, Marcinkiewcz et al., 2009), whereas blocking CRF2 would reverse some of the somatic symptoms (the excessive food intake and the increased body weight) of nicotine withdrawal syndrome in rats (Kamdi et al., 2009). A recent study have also indicated that administration of selective CRF2 agonists could ameliorate the anxiety- and depression-like state developed during acute nicotine withdrawal in mice (Bagosi et al., 2016). The present study completes the previous ones, suggesting that both the rewarding, positive reinforcing effects of nicotine promoted by enhanced striatal dopamine release and the aversive, negative effects of nicotine withdrawal mediated partly by deficient striatal dopamine release could be attenuated by administration of selective CRF1 antagonists. As such, antalarmin may normalize the striatal dopamine release by blocking CRF1 receptors that regulate dopamine neuron firing at the level of the substantia nigra and the ventral tegmental area (Van Pett et al., 2000). Alternatively, antalarmin may inhibit CRF1 receptors located in the dorsal and ventral striatum, but also in the amygdala and hippocampus, from where it can modulate bidirectionally the striatal dopamine release via GABAergic and glutamatergic neurotransmission (Bagosi et al., 2006, Bagosi et al., 2008, Bagosi et al., 2015, Palotai et al., 2013a, Palotai et al., 2013b). The present study does not exclude the possibility that the ability of the selective antagonist of CRF1, but not CRF2, to abolish the behavioral and neurochemical effects of nicotine could simply be due to the differential distribution of CRF1 and CRF2 receptors in the substantia nigra and ventral tegmental area or the dorsal and ventral striatum. Moreover, previous studies demonstrated that CRF1 is expressed abundantly in all these ion channel regions, whereas CRF2 is limited centrally to the hypothalamus, amydgala, and hippocampus (Van Pett et al., 2000). However, a recent study reported an increased expression of CRF2 in the dorsal striatum after the development of nicotine-induced sensitization in rats (Carboni et al., 2018). In this order of thoughts, both CRF1 and CRF2 must be considered potential targets in the therapy of nicotine addiction.
    Experimental procedures
    Acknowledgements
    Introduction The colonic epithelium forms a barrier through cell-cell interactions, involving dynamic structures such as tight junctions (TJ) and cadherin-based adherens junctions (AJ). These intercellular junctions are subjected to modulation during epithelial tissue remodeling, wound repair, inflammation and tumorigenic transformation (for review [1]). In the latter case, epithelial cells acquire a mesenchymal phenotype characterized by alterations in cell-cell contacts, cell-matrix interactions and cytoskeletal structures. Epidemiology works support the adverse influence of stress in the development and/or aggravation of gastrointestinal disorders such as inflammatory bowel disease (IBD) and colon cancer [2], [3], [4], [5], [6]. Colitis associated cancer (CAC) is a subtype of colon cancer that is preceded by clinically detectable IBD. Development of malignancies is more frequent in ulcerative colitis (UC) patients where the epithelial alterations are more pronounced; suggesting that disturbance of junction associated molecules is likely to be involved in carcinogenesis from IBD patients. Stress effects are mediated through the secretion of specific stress neuromediators, such as corticotrophin releasing factor (CRF) or its analogs, urocortins (Ucn) 2 and 3 [7]. These peptides act through the corticotrophin releasing factor receptors 1 and 2 (CRF1/CRF2), two class II G protein coupled receptor (GPRC) [8]. Ligands and receptors regulated by stress and inflammation in the GI tract are expressed and secreted by many normal and cancer cells [9], [10]. Animal models and in vitro experiments have shown that acute or chronic stress impairs the intestinal barrier by various mechanisms involving cytokines or kinases mediated regulation of cell junctions (for review [11]). Using two colorectal cancer (CRC) cell lines, we have previously demonstrated that CRF2 signals through Src/Erk pathway to induce cell-cell junction alterations followed by endocytosis of E-cadherin and shuttling of p120ctn into the nucleus [12]. This signaling pathway also leads to the remodeling of cell-ECM adhesion complexes by the phosphorylation of focal adhesion kinase (FAK), which stimulates migration and invasion.