Recently, a link was also proposed between the NPS system and alcohol withdrawal (Ruggeri et al., 2010). The data in this study suggest that elevated expression of NPSR following a history of alcohol dependence may represent a neuroadaptive mechanism that attempts to compensate for the increased anxiety of the animal strains used. This neuroadaptation may set the scene for a dynamic in which increased NPS neurotransmission, initially induced as a compensatory mechanism to counteract withdrawal anxiety, persists and promotes relapse during later stages of abstinence. It is also known that protracted abstinence is associated with increased HPA axis activity and higher peripheral corticosteroid levels (Rasmussen et al., 2000; Zorrilla et al., 2001). NPS given into the paraventricular nucleus increases adrenocorticotropic hormone release and augments plasma glucocorticoid levels (Smith et al., 2006), which may contribute to hormonal dysregulation occurring during the post-dependent state, further contributing to relapse behaviour (Sinha et al., 2011).
