Nicotine dependence drives the habit of smoking which causes

Nicotine dependence drives the habit of smoking, which causes a heavy load of disease and death, as smoking is one of the largest contributors to preventable morbidity and mortality (GBD 2015 Risk Factors Collaborators, 2016; World Health Organization(WHO), 2017). Inhaled nicotine reaches the brain, where it binds and activates nicotinic L002 receptors (Hurst et al., 2013; Zoli et al., 2015) in several brain regions, including the mesocorticolimbic regions involved in the reward system (Picciotto and Kenny, 2013). Nicotine stimulates dopamine release from neurons originating in the ventral tegmental area (VTA) and terminating in the nucleus accumbens and prefrontal cortex (PFCx). Repeated nicotine exposure causes long-lasting adaptations of dopaminergic transmission that mediate the motivation to maintain nicotine self-administration despite the known harmful effects. The long-term effects of nicotine that support compulsive use require the activation, desensitization, and up-regulation of the nicotinic receptor to mediate alterations in the activity of the neuronal circuitry of the mesocorticolimbic system (De Biasi and Dani, 2011; Pistillo et al., 2015). The changes in synaptic function are based on the regulation of transcriptional and epigenetic modulations that sustain the onset of addiction (Pistillo et al., 2015). Among the systems which mediate the neurobiological adaptations supporting addiction, a role has been proposed for the corticotropin releasing factor (CRF) system (Koob, 2010; Zorrilla et al., 2014). CRF (also known as CRH) is a 41-amino acid neuropeptide that has a role in coordinating the endocrine, autonomic, and behavioural response to stress through the regulation of the hypothalamic-pituitary-adrenal stress system (Bale and Vale, 2004). In addition to the stress-response regulation related to its hypothalamic expression, a wider set of functions were discovered in association with CRF expression in numerous brain areas which demonstrate its relevance in anxiety, depression, and addiction (Bale and Vale, 2004; Hauger et al., 2006; Zorrilla et al., 2014). The CRF family includes three additional members called urocortin 1, urocortin 2 and urocortin 3, which show a more confined expression ocurring mainly in hypothalamic and brainstem structures (Hauger et al., 2006). CRF released from synaptic vesicles plays a neuromodulatory role that varies depending on whether the neuropeptide and its receptor are expressed on glutamatergic or GABAergic neurons, which leads to different responses in distinct brain regions (Henckens et al., 2016). CRF binds to two G-protein-coupled receptors, CRF1R and CRF2R, with a 4- to 20-fold higher affinity towards CRF1R, thus activating signal transduction pathways including cyclic AMP–protein kinase A, mitogen-activated protein kinases, and other pathways. These signals result in modulating the transcription of downstream target genes, synaptic transmission, and plasticity, thus mediating short- and long-term effects (Hauger et al., 2006; Henckens et al., 2016). Within the conceptual three-stage framework for addiction, comprising of binge/intoxication, reward, and withdrawal (Koob and Volkow, 2016, 2010), a role for the CRF system has been mainly proposed in the withdrawal phase in association with negative affect, dysphoria, and anxiety feelings (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). However, a significant role in the reward component cannot be ruled out (Brielmaier et al., 2012; Lemos et al., 2012; Peciña et al., 2006).