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  • The objective of the present study was to investigate


    The objective of the present study was to investigate the role of the CRF system in the neuroadaptations associated with nicotine dependence. To this aim, the regulation of the gene expression of CRF and its receptors was assessed in now regions belonging to the reward pathway using a model of nicotine dependence based on nicotine sensitization (Carboni et al., 2016; Robinson and Berridge, 2008, 2003). We discovered that nicotine sensitization specifically altered the expression of CRF, CRF1, and CRF2 receptors in the DS, the hippocampus (Hip), and the PFCx. These findings suggest additional relevant roles for this system in the development of habituated behaviours in response to nicotine, in the reduced control of impulses, and in aberrant memory plasticity characterising addiction.
    Material and methods
    Discussion This study was performed to investigate the molecular correlates of addiction in a model based on the development of psychomotor sensitization which takes place after repeated nicotine administrations (Carboni et al., 2016; Vezina et al., 2007; Ziviani et al., 2011). The neuroplasticity responses fundamental to sensitization are considered central neural mechanisms underlying addictive behaviours (Hyman et al., 2006; Robinson and Berridge, 2003); thus, the gene expression alterations observed by applying this experimental procedure are expected to be involved in the molecular alterations sustaining the development of nicotine addiction. Indeed, the experimental design adopted here allowed the discrimination of three different effects: the treatment effect due to nicotine administration, which likely derives from acute activities that occur at each single administration and are not likely to play a role in the development of addiction, the overall time effect due to repeated manipulations of the animals, and the interaction effects related to the development of sensitization, which truly reflect the molecular signalling permanently altered in the brains of the sensitized animals. The alterations observed during the development of nicotine sensitization display differently in the various brain regions examined. In the VM, a CRF increase and CRF1R decrease after single nicotine administration was observed, while after repeated treatments these effects subsided. In a different species (mouse) and different administration protocol (chronic infusion), Grieder et al. (2014) observed increased CRF mRNA expression in the VTA after chronic nicotine exposure and withdrawal. In mice that were rendered dependent by nicotine administered in drinking water, it was demonstrated that CRF synthesis in the VTA is critical for the activation of the interpeduncular nucleus and habenula during withdrawal as well as for withdrawal-induced anxiety (Zhao-Shea et al., 2015). Both of these studies convincingly show that CRF increase in the VTA is related to increased anxiety in withdrawal. The results presented in this study suggest that a single nicotine administration causes an increase that undergoes tolerance after repeated exposure; however, it is possible that continuous nicotine administration may maintain high CRF levels in the VTA and that the discrepancies are due to the administration protocol. Providing partial support to the notion that the administration schedule is important in the CRF response, Cohen et al. (2015) observed that CRF1R–mediated anxiety in central amygdala specifically occurred in animals with long access to self-administration. In this study, a significant five-fold increase of CRF mRNA in the sensitized condition in the DS was observed. Moreover, the markedly increased expression of the CRF2R receptor suggests a major involvement of DS CRF transmission in sensitization processes. Indeed, although the time*treatment interaction in the 2-way ANOVA did not reach statistical significance, the presence of both time and treatment effects are linked with a significant CRF2R mRNA increase which was exclusively observed in the sub-chronic administration. It is conceivable that this receptor may also be differently regulated by sensitization, although the high variability did not allow more definite conclusions to be made. In contrast, CRF1R levels were reduced by nicotine administration in both acute and sub-chronic treatments independently of the development of sensitization. This finding implies that a relevant role in nicotine sensitization in the DS is played by CRF though CRF2 receptors, whereas CRF1R only plays a role in nicotine response. A significant negative correlation was observed between CRF2R mRNA levels in the DS and an index of locomotor sensitization in sub-chronically nicotine treated rats. This suggests that increased CRF transmission in the DS is an attempt to contrast the locomotor sensitizing effect of sub-chronic nicotine and tallies well now with the notion of the CRF system as an anti-reward, pro-stress system (Koob, 2010). Liu et al. recently demonstrated that striatal CRF1 receptors specifically mediate the enhancement of cocaine-induced locomotor sensitization induced by stress exposure, while CRF2 receptors were not involved in the enhancement (Liu et al., 2017). These results indicate that receptor subtypes are endowed with different specificity of response in modulating the sensitization behaviour with respect to its stress-induced enhancement, which is also reflected in the different binding affinities for the endogenous ligands.