The Effects of Ghrelin Antagonists [D‐Lys³]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice

Abstract

Background Alcohol use and abuse patterns have created a need for novel treatment models. Current research has turned its focus on reward pathways associated with intrinsic necessities, such as feeding. Theories suggest that drugs of abuse seize control of natural reward pathways and disregulate normal function, leading to chronic addiction. One such pathway involving the hunger stimulating peptide, ghrelin, is the focus of our study. Methods Male C57BL/6 mice were randomly assigned to groups and treated with vehicle or a ghrelin antagonist, either [D-Lys3]-GHRP-6 (DLys) or JMV2959. Three experiments tested ghrelin antagonism using different doses; Experiment 1 – 12mg/kg JMV2959; Experiment 2 – 15mg/kg DLys; Experiment 3 – 9mg/kg JMV2959. Using a two-bottle choice 24-hour access paradigm, data was collected for ethanol intake, preference, water intake, and food intake at 4- and 24-hours after injection. Results Experiment 1 showed that 12mg/kg of JMV2959 decreased ethanol, water, and food intake, without affecting preference. Experiment 2 showed that 15mg/kg of DLys decreased ethanol intake, preference, and water intake only on the first day of treatment. Experiment 3 showed that 9mg/kg of JMV2959 decreased only ethanol and food intake. No change was seen during deprivation and JMV2959 was still effective at reducing ethanol intake upon reintroduction. Despite the change in food intake, there were no differences in body weight throughout the experiments. It should be noted that the majority of significant effects were only found 4-hours post injection. Conclusion The results show that compounds that block ghrelin receptor activity are effective at decreasing ethanol intake. However, DLys was only effective at reducing intake and preference on the first day, suggesting a quick tolerance and selectivity for ethanol. JMV2959 consistently reduced ethanol intake, but at the higher dose also reduced all other consummatory behaviors. Thus, ghrelin antagonists provide a viable potential for treatment of alcohol abuse disorders, but further research is needed to determine an appropriate dose and administration paradigm.

Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence

“…In experiment 2, sterile water was used as the vehicle. All solutions were prepared fresh daily and different doses of drugs were used in mice and rats based on previously published experiments (Jerlhag et al, 2009; Kaur and Ryabinin, 2010; Gomez and Ryabinin, 2014). …”

“…For each testing period, a three-way repeated measures ANOVA was used with vapor and drug as between-subjects factors and day as the within-subjects factor. Planned comparisons assessed the drug and vapor effects on day 1, as previous work determined this day to show the most robust effects (Gomez and Ryabinin, 2014). To determine any drug differences on day 1, a one-way ANOVA was used with post-hoc LSD.…”

Evaluation of Pharmacological Modification of Growth Hormone Secretagogue Receptor in a Mouse Model of Non-Obese Type 2 Diabetes Mellitus

“…In consistent with that, a recent study showed that [D-Lys3]-GHRP-6 did not decrease stress-induced caloric intake, but paradoxically increased the intake of HFD (343). Moreover, the infusion of [D-Lys3]-GHRP-6 in a rat model did not have a significant impact on food intake and appetite (342).…”

“…In consistent with that, more recent studies did not find a significant impact of the infusion of ghrelin antagonist [D-Lys3]-GHRP-6 on food intake and appetite in a rat model (342).…”

“…Moreover, the possibility of quick tolerance to [D-Lys3]-GHRP-6 should not be excluded as [D-Lys3]-GHRP-6 decreased ethanol intake, preference, and water intake in mice only on the first day of treatment (342). Similarly, there have even been a number of reported GHS-R1a antagonists which exhibit orexigenic effects.…”