Abstract
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.
Highlights
Alcohol dependence, a chronic, relapsing brain disorder, is one of our societies major public health problems [1] and the clinical efficacy of the available pharmaceutical agents is limited [2]
To evaluate the effects of long-term voluntary alcohol intake on the central ghrelin system, we examined the expression of the GHS-R1A gene, Ghsr, as well as a3, a4 and b2 nicotinic acetylcholine receptor subtype genes in reward related areas including the ventral tegmental area (VTA), N.Acc., prefrontal cortex (PFC), hippocampus and amygdala in rats after approximately ten months of voluntary alcohol consumption
No differences in methylation degree were found between these rats nor did we find a correlation between overall methylation degree and Ghsr expression in the VTA
Summary
A chronic, relapsing brain disorder, is one of our societies major public health problems [1] and the clinical efficacy of the available pharmaceutical agents is limited [2]. GHS-R1A are expressed throughout the mesocorticolimbic dopamine system [15,16] and it has recently been suggested that ghrelin may have a role in reinforcement as well as reward-seeking behaviour [7,10,17] This hypothesis is supported by preclinical studies showing that ghrelin activates the mesocorticolimbic dopamine system [18,19,20,21,22] and that central ghrelin signalling is involved in the regulation of the rewarding properties of addictive drugs including alcohol [7,23,24,25,26,27,28,29]. Glucagon-like peptide 1, leptin and galanin all reduce food, as well as alcohol consumption in rodents [30,31,32,33]
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