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.

• Keywords
• addiction, cannabinoids, ghrelin signaling, growth hormone secretagogue receptor type A (GHS-R1A), nicotine/tobacco, opioids, preclinical and clinical research, review, stimulants,
• MeSH
• Biomarkers MeSH
• Genetic Predisposition to Disease MeSH
• Ghrelin metabolism   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Disease Susceptibility MeSH
• Nicotine adverse effects   MeSH
• Substance-Related Disorders etiology   metabolism   MeSH
• Reinforcement, Psychology MeSH
• Receptors, Ghrelin metabolism   MeSH
• Signal Transduction * MeSH
• Central Nervous System Stimulants adverse effects   MeSH
• Tobacco Use adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• Ghrelin MeSH
• GHRL protein, human MeSH Browser
• Ghsr1a protein, human MeSH Browser
• Nicotine MeSH
• Receptors, Ghrelin MeSH
• Central Nervous System Stimulants MeSH

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

• Keywords
• WIN55,212-2, addiction, behavioral stimulation, conditioned place preference, ghrelin antagonism, intravenous self-administration, synthetic cannabinoid, tetrahydrocannabinol (THC),
• MeSH
• Self Administration MeSH
• Behavior, Animal drug effects   MeSH
• Glycine analogs & derivatives   pharmacology   MeSH
• Administration, Intravenous MeSH
• Cannabinoids administration & dosage   pharmacology   MeSH
• Rats MeSH
• Conditioning, Operant drug effects   MeSH
• Conditioning, Psychological drug effects   MeSH
• Reinforcement, Psychology MeSH
• Rats, Wistar MeSH
• Receptors, Ghrelin antagonists & inhibitors   MeSH
• Triazoles pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ghsr1a protein, rat MeSH Browser
• Glycine MeSH
• Cannabinoids MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Receptors, Ghrelin MeSH
• Triazoles MeSH

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.

• Keywords
• 2-arachidonoylglycerol/2-AG, GABA, addiction, anandamide/AEA, dopamine, dopamine metabolism, endocannabinoids, ghrelin/GHS-R1A, nucleus accumbens shell microdialysis, synthetic cannabinoid WIN55,212-2,
• MeSH
• Benzoxazines administration & dosage   MeSH
• Dopamine metabolism   MeSH
• Endocannabinoids metabolism   MeSH
• gamma-Aminobutyric Acid metabolism   MeSH
• Ghrelin metabolism   MeSH
• Glycerides metabolism   MeSH
• Glycine administration & dosage   analogs & derivatives   MeSH
• Arachidonic Acids metabolism   MeSH
• Morpholines administration & dosage   MeSH
• Naphthalenes administration & dosage   MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Polyunsaturated Alkamides metabolism   MeSH
• Rats, Wistar MeSH
• Drug Evaluation, Preclinical MeSH
• Triazoles administration & dosage   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone MeSH Browser
• anandamide MeSH Browser
• Benzoxazines MeSH
• Dopamine MeSH
• Endocannabinoids MeSH
• gamma-Aminobutyric Acid MeSH
• Ghrelin MeSH
• Glycerides MeSH
• glyceryl 2-arachidonate MeSH Browser
• Glycine MeSH
• Arachidonic Acids MeSH
• Morpholines MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Naphthalenes MeSH
• Polyunsaturated Alkamides MeSH
• Triazoles MeSH

Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment.

• Keywords
• addiction, conditioned place preference, ghrelin antagonism, intravenous self-administration, methamphetamine, rat,
• MeSH
• Analysis of Variance MeSH
• Self Administration MeSH
• Time Factors MeSH
• Glycine administration & dosage   analogs & derivatives   pharmacology   MeSH
• Administration, Intravenous MeSH
• Methamphetamine administration & dosage   pharmacology   MeSH
• Conditioning, Psychological drug effects   MeSH
• Rats, Wistar MeSH
• Spatial Behavior drug effects   MeSH
• Receptors, Ghrelin antagonists & inhibitors   metabolism   MeSH
• Central Nervous System Stimulants administration & dosage   pharmacology   MeSH
• Body Weight drug effects   MeSH
• Triazoles administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Glycine MeSH
• Methamphetamine MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Receptors, Ghrelin MeSH
• Central Nervous System Stimulants MeSH
• Triazoles MeSH

The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and γ-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N-arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a µ-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl-induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl-evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour.

• Keywords
• 2-arachidonoylglycerol, GABA, anandamide, endocannabinoids, fentanyl, ghrelin, microdialysis, neural reward system, nucleus accumbens shell, ventral tegmental area,
• MeSH
• Behavior, Animal MeSH
• Endocannabinoids metabolism   MeSH
• Extracellular Space metabolism   MeSH
• Fentanyl pharmacology   MeSH
• gamma-Aminobutyric Acid metabolism   MeSH
• Ghrelin pharmacology   MeSH
• Glycine analogs & derivatives   pharmacology   MeSH
• Rats MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Receptors, Ghrelin metabolism   MeSH
• Ventral Tegmental Area drug effects   metabolism   MeSH
• Triazoles pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endocannabinoids MeSH
• Fentanyl MeSH
• gamma-Aminobutyric Acid MeSH
• Ghrelin MeSH
• Glycine MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Receptors, Ghrelin MeSH
• Triazoles MeSH

RATIONALE AND OBJECTIVES: In addition to dopamine, endocannabinoids are thought to participate in neural reward mechanisms of opioids. Number of recent studies suggests crucial involvement of ghrelin in some addictive drugs effects. Our previous results showed that ghrelin participates in morphine-induced changes in the mesolimbic dopaminergic system associated with reward processing. The goal of the present study was to test whether the growth hormone secretagogue receptor (GHS-R1A) antagonist JMV2959 was able to influence morphine-induced effects on anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) in the nucleus accumbens shell (NACSh). METHODS: We used in vivo microdialysis to determine changes in levels of AEA and 2-AG in the NACSh in rats following (i) an acute morphine dose (5, 10 mg/kg s.c.) with and without JMV2959 pretreatment (3, 6 mg/kg i.p.) or (ii) a morphine challenge dose (5 mg/kg s.c.) with and without JMV2959 (3, 6 mg/kg i.p.) pretreatment, administered during abstinence following repeated doses of morphine (5 days, 10-40 mg/kg). Co-administration of ghrelin (40 ug/kg i.p.) was used to verify the ghrelin mechanisms involvement. RESULTS: Pretreatment with JMV2959 significantly and dose-dependently reversed morphine-induced anandamide increases in the NACSh in both the acute and longer-term models, resulting in a significant AEA decrease. JMV2959 significantly intensified acute morphine-induced decreases in accumbens 2-AG levels and attenuated morphine challenge-induced 2-AG decreases. JMV2959 pretreatment significantly reduced concurrent morphine challenge-induced behavioral sensitization. JMV2959 pretreatment effects were abolished by co-administration of ghrelin. CONCLUSIONS: Our results indicate significant involvement of ghrelin signaling in morphine-induced endocannabinoid changes in the NACSh.

• Keywords
• 2-Arachidonoylglycerol, Acute, Anandamide, Challenge during abstinence, Endocannabinoids, Ghrelin, Microdialysis, Morphine, Neural reward system, Nucleus accumbens shell, Stereotyped behavior,
• MeSH
• Endocannabinoids metabolism   physiology   MeSH
• Extracellular Space drug effects   metabolism   MeSH
• Ghrelin physiology   MeSH
• Glycerides metabolism   MeSH
• Glycine analogs & derivatives   pharmacology   MeSH
• Rats MeSH
• Arachidonic Acids metabolism   MeSH
• Morphine pharmacology   MeSH
• Narcotics pharmacology   MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Polyunsaturated Alkamides metabolism   MeSH
• Rats, Wistar MeSH
• Receptors, Ghrelin antagonists & inhibitors   MeSH
• Receptors, Somatotropin antagonists & inhibitors   MeSH
• Stereotyped Behavior drug effects   MeSH
• Triazoles pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• anandamide MeSH Browser
• Endocannabinoids MeSH
• Ghrelin MeSH
• Glycerides MeSH
• glyceryl 2-arachidonate MeSH Browser
• Glycine MeSH
• Arachidonic Acids MeSH
• Morphine MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Narcotics MeSH
• Polyunsaturated Alkamides MeSH
• Receptors, Ghrelin MeSH
• Receptors, Somatotropin MeSH
• Triazoles MeSH