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  • Nicotine is the main psychoactive component of tobacco


    Nicotine is the main psychoactive component of tobacco that causes addiction. Besides the regulation of the stress responses, CRF has been implicated in nicotine addiction based on several lines of evidence (Bruijnzeel and Gold, 2005, Sarnyai et al., 2001). First, acute administration of nicotine, like any other stressor, evokes a dose-dependent activation of the hypothalamic–pituitary–adrenal (HPA) axis that is initiated by hypothalamic CRF (Bruijnzeel and Gold, 2005, Sarnyai et al., 2001). Second, nicotine withdrawal syndrome resembles the behavioral stress response that is mediated by extrahypothalamic CRF (Bruijnzeel and Gold, 2005, Sarnyai et al., 2001). Third, exposure to stressors is one of the leading causes of nicotine relapse (Bruijnzeel and Gold, 2005, Sarnyai et al., 2001). Finally, both CRF receptors participate to the acute, chronic and withdrawal actions of nicotine (Bruijnzeel et al., 2009, Bruijnzeel, 2012, George et al., 2007, Kamdi et al., 2009, Marcinkiewcz et al., 2009). The actions of nicotine are mediated by nicotinic Otilonium Bromide synthesis receptors (nAchRs) that are considered ligand-gated ion channels composed of pentameric combinations of α and β subunits, since normally they respond to acetycholine and allow natrium or calcium ions to enter the cells (Benowitz, 2010). Based on their primary sites of expression, nAchRs are classified into two subtypes: muscle-type nicotinic receptors found in neuromuscular junctions and neuronal-type nicotinic receptors found on neuronal bodies and nerve terminals (Benowitz, 2010). The most abundant neuronal nAchRs are α4β2, α3β4 and α7 located both pre- and postsynaptically where they can influence the release of other neurotransmitters, such as dopamine, glutamate and GABA (Benowitz, 2010). Some of the psychoactive actions of nicotine are mediated by the nigrostriatal and mesolimbic pathways (Di Chiara, 2000, Di Chiara et al., 2004). The nigrostriatal pathway originates in the dopaminergic neurons located in the substantia nigra and terminates in the putamen and nucleus caudatus which together constitute the dorsal striatum (Di Chiara, 2000, Di Chiara et al., 2004). The mesolimbic pathway arises from the dopaminergic neurons situated in the ventral tegmental area and projects to the nucleus accumbens that represents the ventral striatum (Di Chiara, 2000, Di Chiara et al., 2004). Classically, the nigrostriatal pathway controls motor behavior, posture and learning of motor programs and habits, whereas the mesolimbic pathway contributes to motor behavior by mediation of reward, emotion and motivation (Everitt and Robbins, 2013). Nevertheless, manipulations of dopamine release in the dorsal and ventral striatum affect motor behavior in distinct, but parallel ways, which depend upon the nature of the cortical and limbic input to these brain structures (Everitt and Robbins, 2013). Acute administration of nicotine increases the release of striatal dopamine that is associated with a sensation of reward and locomotor hyperactivity in rats (Fung and Lau, 1986, Fung and Lau, 1989). Chronic administration of nicotine also increases the striatal dopamine release, although its impact on the locomotor activity depends upon the dose and schedule of administration (Fung and Lau, 1991, Fung and Lau, 1992). Usually, continuous infusion of nicotine several times a day may induce tolerance, while repetitive injection once a day may produce sensitization to the effects of nicotine (Di Chiara, 2000, Di Chiara et al., 2004). Nicotine also augments glutamate release, which stimulates the release of dopamine, and GABA release, which inhibits the release of dopamine. With long-term exposure to nicotine, some nAchRs become desensitized, but some do not (Benowitz, 2008, Benowitz, 2010). As a result, GABAergic inhibitory tone diminishes, while glutamatergic excitation continues, thereby increasing excitation of dopaminergic neurons and enhancing responsiveness to nicotine (Benowitz, 2008, Benowitz, 2010). Acute withdrawal following chronic administration of nicotine causes a nicotine withdrawal syndrome that starts promptly within few hours and peaks around 24 h following cessation of chronic nicotine administration (Fung et al., 1996). The nicotine withdrawal syndrome in rats consists of a somatic component, characterized by locomotor hypoactivity, increased appetite and weight gain and an affective component, represented by anxiety, depression and reward deficit (Kenny and Markou, 2001). Some of the affective symptoms, such as anxiety and depression, may persist during chronic nicotine withdrawal (Kenny and Markou, 2001). The basis of nicotine addiction is a combination of positive reinforcement, given by the rewarding, positive effects of nicotine, and negative reinforcement, maintained by the avoidance of the aversive, negative effects of nicotine withdrawal (Benowitz, 2010). The changes of the dorsal and ventral striatal dopamine release can be partly or entirely implicated in both forms of reinforcement, and reflected in the changes of the horizontal and vertical locomotor activity (Di Chiara, 2000, Di Chiara et al., 2004). Therefore, these behavioral and neurochemical parameters can be considered important measures of nicotine addiction (Fung et al., 1996).