Andrey E. Ryabinin, Juan Gomez
Oregon Health and Science University, Portland, Oregon, USA
There is increased recognition that systems endogenously involved in regulation of food consumption contribute to regulation of alcohol drinking. Among these systems, the ghrelin peptide deserves a special attention, as it is the only peptide that promotes, rather than inhibits, appetite. Indeed, several laboratories have shown that alcohol dependence in humans is associated with changes in plasma ghrelin levels, that exogenous administration of ghrelin in rodents promotes alcohol consumption and reward, whereas administration of ghrelin antagonists inhibits it. This makes ghrelin antagonists promising as potential treatments against excessive alcohol use. To investigate this potential, we and our collaborators have tested the ability of two ghrelin antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, to inhibit alcohol consumption in several rodent models of alcohol dependence. These models included vapor inhalation – induced dependence in mice and rats, and intragastric infusions – induced dependence in mice. The antagonist were differentially effective in these models and showed preferential effects towards alcohol consumption, compared to food. However, the effects were temporary (lasted only first 4 hours), and repeated administration of these compounds resulted in rapid tolerance to their effects. Our more recent experiments shed light on how effectiveness of ghrelin antagonists can be improved. Specifically, we tested whether the inhibitory effects of ghrelin antagonists on alcohol drinking and tolerance to their effects are mediated by centrally- or peripherally- located ghrelin receptors. Adult male C57BL/6J mice were cannulated for intracebroventricular injections, and then exposed to a 2-bottle choice drinking procedure. DLys was injected prior to the dark phase of circadian cycle in one of two doses. Both doses were effective in decreasing alcohol intake. Moreover, and in contrast to effects of peripheral administration, we observed that repeated central administration of this drug increased its efficacy over time and this efficacy was maintained over 24 hours. These data indicate that central ghrelin receptors mediate inhibitory effects of DLys of alcohol consumption, whereas peripheral receptors are involved in tolerance. We hypothesize that targeting central sites of ghrelin antagonists would result in a successful treatment of alcohol dependence.
Supported by NIH grants U01 AA016647 and T32 AA007468.