In this study we observed alterations in mRNA
In this study, we observed alterations in mRNA levels of CRF receptors in the PFCx and Hip during the development of sensitization. In particular, in the Hip both CRF receptors showed significantly increased CARIPORIDE when the sensitization condition was established. Similarly, CRF2 receptor increase was detected in the PFCx. These findings suggest an involvement of the CRF response in the maladaptive regulation of decision-making and in the drug-induced alterations of both working memory and declarative memory. Moreover, it is possible that the increased CRF receptor levels in the PFCx and Hip may promote increased responses to stress-induced CRF release, a condition known to trigger relapse. We speculate that the contribution to the addiction-related alterations in these regions may be due to CRF-mediated modulation of synaptic plasticity, as documented in other conditions (e.g., Bonci and Borgland, 2009; Fu et al., 2007; Guan et al., 2009; Krishnan et al., 2010).
In conclusion, the present study indicates that the modulation of the CRF system in the development of addiction may play additional functions with respect to its well-established role in increasing anxiety and developing a negative emotional state during the withdrawal phase. These effects are mainly mediated by the central nucleus of the amygdala, the nucleus accumbens shell, the bed nucleus of the stria terminalis, the habenula, and the interpeduncular nucleus (Baiamonte et al., 2014; Bruijnzeel et al., 2012, 2009; Cohen et al., 2015; George et al., 2007; Koob, 2010; Marcinkiewcz et al., 2009; Zhao-Shea et al., 2015). The alterations detected in this investigation suggest that the CRF system is involved in the development of habituated behaviours in response to nicotine in a way similar to the dynorphinergic system (Carboni et al., 2016). In addition, the alterations observed in the Hip and PFCx support the hypothesis that the CRF system contributes to the reduced control of impulses and the aberrant memory plasticity that provides relevance to drug-related cues, thus promoting relapse even after long abstinence.
Role of the funding source
Conflict of interest
Acknowledgements This study was supported by Grants by the University of Bologna (RFO 2014 to LC and PR) and by the University of Modena and Reggio Emilia (UNIMORE FAR2014 to MZ).
Corticotropin releasing factor (CRF), a 41-amino acid neuropeptide first isolated and characterized by Vale et al., is secreted from the paraventricular nucleus of the hypothalamus, and is the primary physiological regulator of the hypothalamic–pituitary–adrenal (HPA) axis mediating the autonomic, endocrine and behavioral responses to stress., , CRF exerts its action in the pituitary by binding to CRF receptors, resulting in the release of adrenocorticotropic hormone (ACTH), β-endorphin, and other proopiomelanocortin (POMC) derived peptides. Increased levels of ACTH initiate the synthesis and release of adrenal corticosteroid hormones (e.g., cortisol), enabling the body to respond to the stressor. The increased levels of corticosteroid hormones also provide negative feedback to suppress the synthesis of additional CRF and ACTH, thereby restoring homeostasis of the HPA axis. Two G-protein coupled CRF receptor subtypes have been identified and designated as CRF and CRF., These receptors are widely distributed throughout the central and peripheral nervous systems. It appears that the CRF receptor subtype plays a significant role in the stress-related response. The heterogeneous distribution patterns of CRF and CRF receptors suggest distinct functional roles for these receptor subtypes. Studies suggest that increased level of CRF mRNA in the hypothalamic paraventricular nucleus (PVN) due to various kinds of stress can be decreased by glucocorticoid treatment. However, the levels of CRF mRNA in PVN were not affected by glucocorticoid treatment. Studies have also indicated that hypersecretion of CRF in the central nervous system is associated with a variety of psychiatric and stress-related illnesses including anxiety, depression, and post-traumatic stress disorder, and that CRF receptor antagonists may be useful for the treatment of these conditions., ,