Requirement of central ghrelin signaling for alcohol reward

Abstract

The stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice. By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol. Our data suggest that central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders.appetite ͉ ethanol ͉ GHS-R1A ͉ mesolimbic dopamine system ͉ reinforcing

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

“…The findings that IP injections of ghrelin does not alter alcohol intake in alcohol‐naïve rats (Lyons et al., 2008), that ghrelin is produced centrally (Cowley et al., 2003; Lu et al., 2002; Mondal et al., 2005), and that NOX‐B11‐2 does not alter alcohol reinforcement collectively suggest that centrally, rather than peripherally, produced ghrelin is of importance for alcohol intake and alcohol reward in rodents. Supportively, local administration of ghrelin into the reward nodes ventral tegmental area or laterodorsal tegmental area increases alcohol consumption in mice (Jerlhag et al., 2009). Another tentative explanation may be that the preprandial increase of ghrelin (for review, see Egecioglu et al., 2011), which is blocked by administration of NOX‐B11‐2, is too low to regulate brain‐mediated behaviors such as alcohol intake in rats.…”

“…We have extensive experience with NMRI mice, and they are considered to be a good model for general use and are extensively used in behavioral studies used in psychopharmacology research (Jerlhag et al., 2009). All mice were group‐housed and maintained at a 12/12 hour light/dark cycle.…”

“…A dose of 1.75 g/kg was used since it induces a locomotor stimulation, accumbal dopamine release, and conditioned place preference in NMRI mice (Jerlhag et al., 2006b, 2009; Larsson et al., 2004). For the intermittent access 20% alcohol 2‐bottle‐choice drinking paradigm alcohol was diluted in tap water to a final concentration of 20% v/v.…”

“…To evaluate the effects of NOX‐B11‐2 on the rewarding effects of alcohol, conditioned place preference tests were performed in mice as previously described (Jerlhag et al., 2009). In brief, a 2‐chambered conditioned place preference apparatus (45 lux) and distinct visual and tactile cues was used.…”

“…Initially, it was shown that ghrelin activates cholinergic‐dopaminergic reward link (Abizaid et al., 2006; Jerlhag et al., 2006a, 2007). This was corroborated by the finding showing that the rewarding properties of alcohol, as measured by locomotor stimulation, accumbal dopamine release, and conditioned place preference are attenuated in mice with suppressed GHS‐R1A and ghrelin signaling (Jerlhag et al., 2009, 2011) and that GHS‐R1A antagonists reduced the intake and the motivation to consume alcohol in rodents (Jerlhag et al., 2009; Kaur and Ryabinin, 2010; Landgren et al., 2012). Supportively, human genetic findings show that a single‐nucleotide polymorphism in the GHS‐R1A gene is associated with high alcohol consumption in humans (Landgren et al., 2008).…”