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

Abstract

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.

Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence

“…Interestingly, our results show that impairing ghrelin signaling through GHSR knockout does not affect the long-term outcome of the THC treatment. Since ghrelin and THC often act synergistically in many pathways [37], the results on GHRS KO mice further corroborate the lack of significant long-term alterations of anxiety-like behavior induced by THC in our experimental setting.…”

“…GHSR and the cannabinoid CB1R are expressed within overlapping brain regions that are crucial for feeding (hypothalamus), reward and motivation (Ventral tegmental area/VTA, nucleus accubens/NAC). Both systems mutually interact to a significant extent in the regulation of homeostatic as well as hedonic food intake [34][35][36][37]. Further, systemic pretreatment with the CB1R antagonist rimonabant significantly reduced intracerebroventricular ghrelin-induced NAC dopamine release and hyperlocomotion in mice [38].…”

Are Signals Regulating Energy Homeostasis Related to Neuropsychological and Clinical Features of Gambling Disorder? A Case–Control Study

“…Despite its stimulating appetite role, ghrelin has been described as a hedonic neural reinforcer for natural (e.g., food) and non-natural rewards (e.g., drugs) by its interaction with dopamine signaling in the mesolimbic circuit and other neuroendocrine pathways (e.g., linked to stress, appetite, and metabolic processing) [ 12 ]. Ghrelin has been extensively studied in different addictive-related disorders, such as binge eating disorder (BED) and obesity [ 13 , 14 ], as well as in SUDs [ 15 ], especially involving alcohol [ 16 , 17 ].…”

Shared Mechanisms of GABAergic and Opioidergic Transmission Regulate Corticolimbic Reward Systems and Cognitive Aspects of Motivational Behaviors

“…This modulation is regulated by GABAergic neurons with or without the expression of opioid GPCRs, which results in changes in dopaminergic inputs to the NAc [224]. Another study focusing on the reinforcement in food intake manifested that ghrelin/GHS-R1A signaling may be involved in the reinforcing effect of opioid GPCRs in addiction [225]. The excitability of MORs in the NAc is associated with dopamine efflux owing to the suppression of the release of GABA from the VTA interneurons following a tonic inhibition in the mesocorticolimbic dopaminergic neurons [226].…”