The significant CRF increase in the DS
The significant CRF increase in the DS and the overall changes in the CRF system observed in the VM and DS during the development of sensitization suggest that this neuropeptide (and possibly urocortin) contributes to the specific molecular alterations occurring in the mesolimbic pathway that support the development of addiction. Available evidence implies a model in which the development of addiction is established through sequential neuroadaptations: as the initial impulsive drug assumption driven by reward and impulsive action turns chronic and compulsive, neuronal circuits are reprogrammed and adapted. The modifications involve circuits that process reward and motivation, conditioning and habituation, declarative memory and working memory, and the inhibitory control of impulsive behaviours (Hyman et al., 2006; Koob and Volkow, 2010). The activation of the mesolimbic dopamine system is a common response to the acute administration of addictive drugs (Everitt and Robbins, 2013; Hyman et al., 2006; Koob and Volkow, 2010), but it Angiotensin 1/2 (1-7) amide is not thought to be sufficient to determine the transition to addiction (Volkow and Morales, 2015). When the behavioural responses of cue-activated drug seeking and drug taking become established, there is a progressive transfer from outcome driven behaviours to behaviours driven by stimulus/response habits, which depend on the DS (Everitt and Robbins, 2013, 2005; Hyman et al., 2006). This shift from voluntary control on drug intake to automatic or habit-like drug seeking, governed by the DS, can contribute to the loss of control in drug intake and the high probability of relapsing into drug use that characterise addiction. The recruitment of the DS during the development of compulsive drug assumption is reflected in our data, which show a shift of the activation of the CRF system from the VM to the CPu region. Therefore, we can postulate that the CRF circuit, in addition to other neuropeptides (Carboni et al., 2016), may contribute to the control of DS circuits over drug intake behaviours. Other adaptations characterising the transition to compulsion-driven behaviours are the reduced control over impulse-driven and maladaptive behaviours and the establishment of drug-associated memories that determine linking of affective conditions or circumstances with drug taking (Koob and Volkow, 2016, 2010). The PFCx controls executive functions that include working memory and behavioural inhibition of inappropriate responses to environmental stimuli. In both human chronic drug users and rodent models, complex changes in PFCx have been documented which have been implicated in the impulsivity and compulsivity characterising addiction (Nestler, 2005; Volkow and Morales, 2015). Cortical regions develop hypersensitivity to drug-associated stimuli and impaired executive control over behaviour associated with reduced sensitivity to natural reward and deficits in working memory (Kalivas et al., 2005; Koob and Volkow, 2010; Nestler, 2005). The underperforming prefrontal system is thought to be responsible for the cortical hypofrontality observed in human drug users, and Epistasis is widely believed to be crucial in the addiction process (Kalivas et al., 2005; Koob and Volkow, 2010). In addition, chronic drug exposure causes maladaptive neuroadaptations in memory and conditioned learning. PFCx-dependent working memory is believed to contribute to assigning value to goals; thus, interference with its function may support the distorted drug-induced positive evaluation of the drug above natural reinforcement (Hyman et al., 2006; Volkow and Morales, 2015). Hip-dependent declarative memory is proposed to be involved in contextual conditioning, which is the processing of contextual and spatial cues to access and retrieve memories. This form of memory is implicated in establishing strong associations between context and drug that are believed to be involved in drug craving (Everitt and Robbins, 2005; Koob and Volkow, 2010).