br Role of ghrelin in reward

Role of ghrelin in reward and addiction In addition to its well-known effects on dan shen homeostasis regulation at the hypothalamic level [reviews in (Al Massadi et al., 2017, Muller et al., 2015)], ghrelin also has the ability to increase food motivation acting on hypothalamic and extra-hypothalamic areas implicated in motivational and incentive behavior, -VTA and NAc- (Naleid et al., 2005, Skibicka et al., 2011), in learning and memory -hippocampus and amygdala- (Alvarez-Crespo et al., 2012, Diano et al., 2006, Kanoski et al., 2013, Palotai et al., 2013), and in control/decision making -prefrontal cortex- (Kroemer et al., 2015, Parent et al., 2015). Ghrelin modulates the reward system (Egecioglu et al., 2010, Perello et al., 2010). It enhances the time mice spend in a place previously associated with highly palatable food and this effect is abrogated in GHSR1a-null mice (Egecioglu et al., 2010, Perello et al., 2010, Skibicka et al., 2011, Skibicka et al., 2012a). This effect varies, however, depending of the route and the doses used and if the conditioning sessions are done in the presence or absence of food (Schele et al., 2017). For example, peripheral injection of a high dose of ghrelin in the absence of food causes conditioned place aversion (CPA, Lockie et al., 2015). In contrast, with a low dose or if the conditioning sessions are made in the presence of food, ghrelin induces conditioned place preference (CPP, Jerlhag, 2008, Lockie et al., 2015). In like manner, central administration of ghrelin in the presence of food induces CPA (Schele et al., 2017). Intracerebroventricular (i.c.v.) or peripheral ghrelin injections increase the intake of highly palatable food (Denis et al., 2015, Perello et al., 2010). Ghrelin injection into the VTA enhances cue-induced reinstatement of operant responses for palatable food pellets (St-Onge et al., 2016), while injection into the ventral hippocampus also enhances cue-potentiated feeding in food-sated animals (Kanoski et al., 2013). Conversely, genetic or pharmacological inhibition of ghrelin signaling abrogates the potentiated feeding after presentation of a conditioned stimulus (Walker et al., 2012). Brain imaging in rats showed that intravenous ghrelin administration activates brain areas that control homeostatic feeding and components of the mesolimbic reward circuitry including the prefrontal cortex, NAc, and septum (Sarvari et al., 2014). In human subjects exposed to palatable food pictures, ghrelin activates reward-related areas including amygdala, ventral striatum, anterior insula, orbitofrontal cortex and hippocampus (Goldstone et al., 2014, Malik et al., 2008). Ghrelin also activates the olfactory area of the piriform cortex, and increases olfactory sensitivity (Malik et al., 2008, Tong et al., 2011). During presentation of food pictures, circulating ghrelin levels are positively correlated with the brain response to these pictures (Kroemer et al., 2013). Interestingly, brain activation in response to food pictures differs depending on the genotype at an “obesity-risk” locus associated with dysregulated circulating ghrelin levels (Karra et al., 2013). Other findings suggest that appetitive and food seeking behaviors may be driven by negative emotions. For example, starvation-sensitive agouti-related peptide (AgRP) neurons, which are activated by ghrelin (see below), provide a negative-valence teaching signal (Betley et al., 2015). Importantly, although ghrelin induces food seeking behavior in rodents and humans, it was shown in most studies that this peptide causes CPA in rodents (Lockie et al., 2015, Schele et al., 2017). Thus, by itself ghrelin appears to be aversive rather than rewarding whereas it increases the motivation to seek and consume food. Along these lines, it was proposed that ghrelin mediates eating behaviors associated with stress or depression since chronic stress-increased intake and CPP for high fat food were prevented in mice devoid of GHSR1a in catecholaminergic neurons (Chuang et al., 2011).