A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats

Edvardsson, Christian E.; Vestlund, Jesper; Jerlhag, Elisabet

doi:10.1016/j.ejphar.2021.174039

Cited by 36 publications

(30 citation statements)

References 67 publications

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“…A recent microdialysis study in rats explored in detail the mesoaccumbal ghrelin—dopamine interactions participating in the stimulants’ reinforcing effects [ 178 ]. Previously, it was suggested that not only the dopamine release in the NAC shell, but the concomitant dopamine release in the VTA and NAC shell might represent a common underlying characteristic induced by various reinforcing stimuli, including natural rewards such as food/water [ 179 ], drugs of abuse [ 12 , 180 , 181 ] and the orexigenic peptide ghrelin (included due to later results) [ 178 ]. When acyl-ghrelin was infused into the third ventricle (i.c.v.…”

Section: Ghrelin/ghs-r1as and Stimulantsmentioning

confidence: 99%

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

Sustkova-Fiserova

Charalambous

Khryakova

et al. 2022

IJMS

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Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

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Section: Ghrelin/ghs-r1as and Stimulantsmentioning

confidence: 99%

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

Sustkova-Fiserova

Charalambous

Khryakova

et al. 2022

IJMS

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“…These results are complemented by an abundance of in vivo studies showing that ghrelin administered either peripherally or centrally, into the intracerebroventricular space (i.c.v. ), induces the dopaminergic reward pathway and dopamine release in NAc in rodents (Abizaid et al, 2006 ; Jerlhag, 2008 ; Quarta et al, 2009 ; Jerlhag et al, 2011a ; Edvardsson et al, 2021 ). Furthermore, ghrelin appears to act on several levels of this pathway, as local injections in the VTA or LDTg independently stimulates dopamine release in NAc (Jerlhag et al, 2007 ).…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

“…As such, peripheral treatment of JMV2959, i.c.v. administration of the GHSR-1A antagonist BIM28163, or genetic suppression utilizing GHSR-1A knockout mice, attenuates the acute phase of alcohol as measured by locomotor stimulation, the reward of alcohol in the CPP test and dopamine overflow in NAc (Jerlhag et al, 2009 ; Suchankova et al, 2016a ; Edvardsson et al, 2021 ). Interestingly, in GHSR knockout mice, alcohol appears to be unable to induce the above-mentioned behaviors (Jerlhag et al, 2011b ; Bahi et al, 2013 ), suggesting that the GHSR-1A might not only play a key role but may even be required for alcohol to elicit its rewarding properties.…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

“…In contrast, the antagonist JMV2959 attenuates nicotine-induced dopamine release in NAc, locomotor sensitization and stimulation as well as attenuates reward in the CPP test in rodents (Jerlhag and Engel, 2011 ; Wellman et al, 2011 , 2013 ; Palotai et al, 2013 ). Similarly, systemic or central administration of ghrelin potentiates the effects of central stimulants (e.g., amphetamine and cocaine) on locomotor stimulation and CPP (Wellman et al, 2005 ; Davis et al, 2007 ; Jang et al, 2013 ; Schuette et al, 2013 ; Dunn et al, 2019 ), whereas GHSR-1A antagonists attenuate these behavioral responses in rodents (Jerlhag et al, 2010 ; Abizaid et al, 2011 ; Clifford et al, 2012 ; Suchankova et al, 2016a ; Havlickova et al, 2018 ; Wenthur et al, 2019 ; Edvardsson et al, 2021 ). Further, the acute rewarding effect of opiates and its relationship with the GHSR-1A is evident as JMV2959 inhibits the dopaminergic release in NAc and CPP caused by morphine or fentanyl (Engel et al, 2015 ; Sustkova-Fiserova et al, 2016 , 2020 ; Jerabek et al, 2017 ).…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

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An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

2021

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There is a substantial need for new pharmacological treatments of addiction, and appetite-regulatory peptides are implied as possible candidates. Appetite regulation is complex and involves anorexigenic hormones such as glucagon-like peptide-1 (GLP-1) and amylin, and orexigenic peptides like ghrelin and all are well-known for their effects on feeding behaviors. This overview will summarize more recent physiological aspects of these peptides, demonstrating that they modulate various aspects of addiction processes. Findings from preclinical, genetic, and experimental clinical studies exploring the association between appetite-regulatory peptides and the acute or chronic effects of addictive drugs will be introduced. Short or long-acting GLP-1 receptor agonists independently attenuate the acute rewarding properties of addictive drugs or reduce the chronic aspects of drugs. Genetic variation of the GLP-1 system is associated with alcohol use disorder. Also, the amylin pathway modulates the acute and chronic behavioral responses to addictive drugs. Ghrelin has been shown to activate reward-related behaviors. Moreover, ghrelin enhances, whereas pharmacological or genetic suppression of the ghrelin receptor attenuates the responses to various addictive drugs. Genetic studies and experimental clinical studies further support the associations between ghrelin and addiction processes. Further studies should explore the mechanisms modulating the ability of appetite-regulatory peptides to reduce addiction, and the effects of combination therapies or different diets on substance use are warranted. In summary, these studies provide evidence that appetite-regulatory peptides modulate reward and addiction processes, and deserve to be investigated as potential treatment target for addiction.

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“…It has been argued that ghrelin is centrally produced, however, these results are still controversial as other studies have not been able to confirm but rather contradict these findings ( 26 , 27 ). Generally, it has been suggested that ghrelin has an excitatory effect on DAergic neurons in the VTA, which leads to DA release in the NAc in the presence of food and blockage of the GhrR signaling has been shown to inhibit this DA release ( 28 , 29 ) ( Figure 1 ). Potentially, other pathways of the DAergic system are influenced by GhrR signaling, however with the current knowledge this is rather a suggestion ( 7 ).…”

Section: Energy Balancementioning

confidence: 99%

Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa

2021

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Anorexia Nervosa (AN) is a complex disease that impairs the metabolic, mental and physiological health of affected individuals in a severe and sometimes lethal way. Many of the common symptoms in AN patients, such as reduced food intake, anxiety, impaired gut motility or overexercising are connected to both the orexigenic gut hormone ghrelin and the dopaminergic system. Targeting the ghrelin receptor (GhrR) to treat AN seems a promising possibility in current research. However, GhrR signaling is highly complex. First, the GhrR can activate four known intracellular pathways Gαq, Gαi/o, Gα12/13 and the recruitment of β-arrestin. Biased signaling provides the possibility to activate or inhibit only one or a subset of the intracellular pathways of a pleiotropic receptor. This allows specific targeting of physiological functions without adverse effects. Currently little is known on how biased signaling could specifically modulate GhrR effects. Second, GhrR signaling has been shown to be interconnected with the dopaminergic system, particularly in the context of AN symptoms. This review highlights that a biased agonist for the GhrR may be a promising target for the treatment of AN, however extensive and systematic translational studies are still needed and the connection to the dopaminergic system has to be taken into account.

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A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats

Cited by 36 publications

References 67 publications

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa

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