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.

• Klíčová slova
• addiction, cannabinoids, ghrelin signaling, growth hormone secretagogue receptor type A (GHS-R1A), nicotine/tobacco, opioids, preclinical and clinical research, review, stimulants,
• MeSH
• biologické markery MeSH
• genetická predispozice k nemoci MeSH
• ghrelin metabolismus   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• náchylnost k nemoci MeSH
• nikotin škodlivé účinky   MeSH
• poruchy spojené s užíváním psychoaktivních látek etiologie   metabolismus   MeSH
• posilování (psychologie) MeSH
• receptory ghrelinu metabolismus   MeSH
• signální transdukce * MeSH
• stimulanty centrálního nervového systému škodlivé účinky   MeSH
• užívání tabáku škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• ghrelin MeSH
• GHRL protein, human MeSH Prohlížeč
• Ghsr1a protein, human MeSH Prohlížeč
• nikotin MeSH
• receptory ghrelinu MeSH
• stimulanty centrálního nervového systému 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.

• Klíčová slova
• WIN55,212-2, addiction, behavioral stimulation, conditioned place preference, ghrelin antagonism, intravenous self-administration, synthetic cannabinoid, tetrahydrocannabinol (THC),
• MeSH
• autoaplikace MeSH
• chování zvířat účinky léků   MeSH
• glycin analogy a deriváty   farmakologie   MeSH
• intravenózní podání MeSH
• kanabinoidy aplikace a dávkování   farmakologie   MeSH
• krysa rodu Rattus MeSH
• operantní podmiňování účinky léků   MeSH
• podmiňování (psychologie) účinky léků   MeSH
• posilování (psychologie) MeSH
• potkani Wistar MeSH
• receptory ghrelinu antagonisté a inhibitory   MeSH
• triazoly farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Ghsr1a protein, rat MeSH Prohlížeč
• glycin MeSH
• kanabinoidy MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Prohlížeč
• receptory ghrelinu MeSH
• triazoly 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.

• Klíčová slova
• 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
• benzoxaziny aplikace a dávkování   MeSH
• dopamin metabolismus   MeSH
• endokanabinoidy metabolismus   MeSH
• GABA metabolismus   MeSH
• ghrelin metabolismus   MeSH
• glyceridy metabolismus   MeSH
• glycin aplikace a dávkování   analogy a deriváty   MeSH
• kyseliny arachidonové metabolismus   MeSH
• morfoliny aplikace a dávkování   MeSH
• naftaleny aplikace a dávkování   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• polynenasycené alkamidy metabolismus   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• triazoly aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone MeSH Prohlížeč
• anandamide MeSH Prohlížeč
• benzoxaziny MeSH
• dopamin MeSH
• endokanabinoidy MeSH
• GABA MeSH
• ghrelin MeSH
• glyceridy MeSH
• glyceryl 2-arachidonate MeSH Prohlížeč
• glycin MeSH
• kyseliny arachidonové MeSH
• morfoliny MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Prohlížeč
• naftaleny MeSH
• polynenasycené alkamidy MeSH
• triazoly 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.

• Klíčová slova
• addiction, conditioned place preference, ghrelin antagonism, intravenous self-administration, methamphetamine, rat,
• MeSH
• analýza rozptylu MeSH
• autoaplikace MeSH
• časové faktory MeSH
• glycin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• intravenózní podání MeSH
• methamfetamin aplikace a dávkování   farmakologie   MeSH
• podmiňování (psychologie) účinky léků   MeSH
• potkani Wistar MeSH
• prostorové chování účinky léků   MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• stimulanty centrálního nervového systému aplikace a dávkování   farmakologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• triazoly aplikace a dávkování   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glycin MeSH
• methamfetamin MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Prohlížeč
• receptory ghrelinu MeSH
• stimulanty centrálního nervového systému MeSH
• triazoly MeSH

RATIONALE AND OBJECTIVES: Ghrelin, an orexigenic (appetite stimulating) peptide activates binding sites in the ventral tegmental area (a structure linked with the neural reward system) allowing it to participate in reward-seeking behavior. An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine, and nicotine abuse. However, the role of ghrelin, in opioid effects, has rarely been examined. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit markers of morphine-induced activation of the neural reward system, namely morphine-induced increase of dopamine in the nucleus accumbens and behavioral changes in rats. METHODS: We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens shell in rats following morphine (MO, 5, 10 mg/kg s.c.) administration with and without ghrelin antagonist pretreatment (JMV2959, 3, 6 mg/kg i.p., 20 min before MO). Induced behavioral changes were simultaneously monitored. RESULTS: JMV2959 significantly and dose dependently reduced MO-induced dopamine release in the nucleus accumbens shell and affected concentration of by-products associated with dopamine metabolism: 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). JMV2959 pretreatment also significantly reduced MO-induced behavioral stimulation, especially stereotyped behavior. CONCLUSIONS: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

• MeSH
• chování zvířat účinky léků   MeSH
• dopamin analogy a deriváty   metabolismus   farmakologie   MeSH
• ghrelin metabolismus   MeSH
• glycin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina 3,4-dihydroxyfenyloctová metabolismus   MeSH
• kyselina homovanilová farmakologie   MeSH
• mikrodialýza MeSH
• morfin aplikace a dávkování   farmakologie   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• odměna MeSH
• opioidní analgetika aplikace a dávkování   farmakologie   MeSH
• potkani Wistar MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• stereotypní chování účinky léků   MeSH
• triazoly aplikace a dávkování   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-methoxytyramine MeSH Prohlížeč
• dopamin MeSH
• ghrelin MeSH
• glycin MeSH
• kyselina 3,4-dihydroxyfenyloctová MeSH
• kyselina homovanilová MeSH
• morfin MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Prohlížeč
• opioidní analgetika MeSH
• receptory ghrelinu MeSH
• triazoly MeSH