Ghrelin Receptor (GHS-R1A) Antagonism Suppresses Both Alcohol Consumption and the Alcohol Deprivation Effect in Rats following Long-Term Voluntary Alcohol Consumption
نویسندگان
چکیده
Alcohol dependence is a heterogeneous disorder where several signalling systems play important roles. Recent studies implicate that the gut-brain hormone ghrelin, an orexigenic peptide, is a potential mediator of alcohol related behaviours. Ghrelin increases whereas a ghrelin receptor (GHS-R1A) antagonist decreases alcohol consumption as well as operant self-administration of alcohol in rodents that have consumed alcohol for twelve weeks. In the present study we aimed at investigating the effect of acute and repeated treatment with the GHS-R1A antagonist JMV2959 on alcohol intake in a group of rats following voluntarily alcohol consumption for two, five and eight months. After approximately ten months of voluntary alcohol consumption the expression of the GHS-R1A gene (Ghsr) as well as the degree of methylation of a CpG island found in Ghsr was examined in reward related brain areas. In a separate group of rats, we examined the effect of the JMV2959 on alcohol relapse using the alcohol deprivation paradigm. Acute JMV2959 treatment was found to decrease alcohol intake and the effect was more pronounced after five, compared to two months of alcohol exposure. In addition, repeated JMV2959 treatment decreased alcohol intake without inducing tolerance or rebound increase in alcohol intake after the treatment. The GHS-R1A antagonist prevented the alcohol deprivation effect in rats. There was a significant down-regulation of the Ghsr expression in the ventral tegmental area (VTA) in high- compared to low-alcohol consuming rats after approximately ten months of voluntary alcohol consumption. Further analysis revealed a negative correlation between Ghsr expression in the VTA and alcohol intake. No differences in methylation degree were found between high- compared to low-alcohol consuming rats. These findings support previous studies showing that the ghrelin signalling system may constitute a potential target for development of novel treatment strategies for alcohol dependence.
منابع مشابه
The Ghrelin Signalling System Is Involved in the Consumption of Sweets
The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alc...
متن کاملRequirement of central ghrelin signaling for alcohol reward.
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...
متن کاملSub-chronic Ghrelin Receptor Blockade Attenuates Alcohol- and Amphetamine-Induced Locomotor Stimulation in Mice.
AIMS Ghrelin initially emerged as a gut-brain hormone controlling food intake, meal initiation and appetite mainly via hypothalamic circuits in both rodents and humans. The findings that ghrelin receptors (GHS-R1A) are expressed in reward-related areas, including the nucleus accumbens (NAc) and ventral tegmental area (VTA), suggest that ghrelin is a novel reward regulator. Indeed, ghrelin signa...
متن کاملAccess to the Published Version May Require Subscription. Published with Permission From: Springer-verlag Ghrelin Receptor Antagonism Attenuates Cocaine-and Amphetamine-induced Locomotor Stimulation, Accumbal Dopamine Release and Conditioned Place Preference
This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Ghrelin receptor antagonism attenuates cocaine-and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Abstract Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signalling system, involv...
متن کاملGlutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system
Recently, we demonstrated that the central ghrelin signalling system, involving the ghrelin receptor (GHS-R1A), is important for alcohol reinforcement. Ghrelin targets a key mesolimbic circuit involved in natural as well as drug-induced reinforcement, that includes a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present study was to determine...
متن کامل