Alcohol Reward Is Increased after Roux-en-Y Gastric Bypass in Dietary Obese Rats with Differential Effects following Ghrelin Antagonism

Hajnal, A.; Zharikov, Alevtina; Polston, James E.; Fields, Maxine; Tomasko, Jonathan M.; Rogers, Ann M.; Volkow, Nora D.; Thanos, Panayotis K.

doi:10.1371/journal.pone.0049121

Cited by 73 publications

(67 citation statements)

References 71 publications

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“…Ghrelin itself shows reinforcement properties akin to drugs of abuse by causing increases in locomotion, release of dopamine in the accumbens, and induction of conditioned place preference (Jerlhag, 2008). In the current study, although in agreement with previous works showing DLys reduces ethanol intake (Kaur and Ryabinin, 2010; Hajnal et al, 2012), the effect was only seen 4-hours post-injection on the first day. In a previous study from our lab, it was shown that following a 4-hour 2-bottle ethanol access, mice treated with DLys show decreased drinking and associated lower blood ethanol contents (BEC).…”

Section: Discussionsupporting

confidence: 93%

“…Kaur and Ryabinin (2010) found DLys reduces ethanol intake and preference, while also blocking ethanol-induced c-Fos expression in the Edinger-Westphal nucleus, a region affiliated with ethanol sensitivity and intake. DLys has also been shown to block ethanol reward seeking in rats (Hajnal et al, 2012). JMV2959 is a small molecule-type specific antagonist of ghrelin receptors (Moulin et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Gómez

Ryabinin

2014

Alcoholism Clin & Exp Res

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Gómez

Ryabinin

2014

Alcoholism Clin & Exp Res

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“…In a follow up study directly investigating changes in alcohol reward (Hajnal et al ., 2012), high fat diet-induced obese rats underwent RYGB or sham operation and were tested 4 months after surgery on a progressive ratio schedule of reinforcement operant task for 2, 4, and 8% EtOH. Compared to sham-operated controls, RYGB rats made significantly more efforts to earn access to alcohol reward, and also consumed more when it was available.…”

Section: Bariatric Surgery As a Risk For Audmentioning

confidence: 99%

The gut in the brain: the effects of bariatric surgery on alcohol consumption

2016

Self Cite

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Obesity represents a major medical and public health problem worldwide. Efforts have been made to develop novel treatments, and among them bariatric surgery is used as an effective treatment to achieve significant, long-term weight loss and alleviate medical problems related to obesity. Alcohol use disorder (AUD) is also a leading cause of morbidity and mortality worldwide. Recent clinical studies have revealed a concern for bariatric surgery patients developing an increased risk for alcohol consumption, raising concerns about development of AUD. A better understanding of the relationship between bariatric surgery and potential later development of AUD is important, given the critical need of identifying patients at high risk for AUD. This paper reviews current clinical and basic science research and discusses potential underlying mechanisms. Special emphasis in this review is given to recent work suggesting that, alterations in alcohol metabolism/pharmacokinetics resulting from bariatric surgery are unlikely to be the primary or at least the only explanation for increased alcohol use and development of AUD, as changes in brain reward processing are also likely to play an important role. Additional studies are needed to clarify the potential role and mechanisms of how bariatric surgery may increase alcohol use and lead to AUD development.

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“…Because of the possibility of functional recovery following genetic deletion of the receptor, Experiment 2 investigated the role of ghrelin in glucose conditioning by using the ghrelin receptor antagonist (D-Lys3)-GHRP-6. This antagonist is reported to decrease food intake, high-fat diet preference, alcohol intake, body weight, and lever pressing for food in rodents [2,17,18,19,21,24,25]. Here we determined if treating WT mice with (D-Lys3)-GHRP-6 during training sessions with CS+/GLU and CS−/S+S solutions altered their acquisition of a CS+ flavor preference.…”

Section: Experiments 2 Flavor Conditioning By Oral Glucose In Micementioning

confidence: 99%

Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice

Sclafani

Touzani

Ackroff

2015

Physiology & Behavior

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The oral and post-oral actions of sugar and fat stimulate intake and condition flavor preferences in rodents through a process referred to as appetition. Ghrelin is implicated in food reward processing, and this study investigated its involvement in nutrient conditioning in mice. In Exp. 1 ghrelin receptor-null (GHSR-null) and C57BL/6 wildtype (WT) mice learned to prefer a flavor (CS+) mixed into 8% glucose over another flavor (CS−) mixed into a "sweeter" but non-nutritive 0.1% sucralose + saccharin (S+S) solution. In Exp. 2 treating WT mice with a ghrelin receptor antagonist [(D-Lys3)-GHRP-6] during flavor training did not prevent them from learning to prefer the CS+glucose over the CS−S+S flavor. GHSR-null and WT mice were trained in Exp. 3 to drink a CS+ paired with intragastric (IG) infusion of 16% glucose and a CS− paired with IG water. Both groups drank more CS+ than CS− in training and preferred the CS+ to CS− in a choice test. The same (Exp. 4) and new (Exp. 5) GHSR-null and WT mice learned to prefer a CS+ flavor paired with IG fat (Intralipid) over a CS− flavor paired with IG water. GHSR-null and WT mice also learned to prefer a CS+ flavor added to 8% fructose over a CS− added to water. Together, these results indicate that ghrelin receptor signaling is not required for flavor preferences conditioned by the oral or post-oral actions of sugar and fat. This contrasts with other findings implicating ghrelin signaling in food reward processing and food-conditioned place preferences.

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Alcohol Reward Is Increased after Roux-en-Y Gastric Bypass in Dietary Obese Rats with Differential Effects following Ghrelin Antagonism

Cited by 73 publications

References 71 publications

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

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

The gut in the brain: the effects of bariatric surgery on alcohol consumption

Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice

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Alcohol Reward Is Increased after Roux-en-Y Gastric Bypass in Dietary Obese Rats with Differential Effects following Ghrelin Antagonism

Cited by 73 publications

References 71 publications

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

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

The gut in the brain: the effects of bariatric surgery on alcohol consumption

Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice

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

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