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

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: 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
• Behavior, Animal drug effects   MeSH
• Dopamine analogs & derivatives   metabolism   pharmacology   MeSH
• Ghrelin metabolism   MeSH
• Glycine administration & dosage   analogs & derivatives   pharmacology   MeSH
• Rats MeSH
• 3,4-Dihydroxyphenylacetic Acid metabolism   MeSH
• Homovanillic Acid pharmacology   MeSH
• Microdialysis MeSH
• Morphine administration & dosage   pharmacology   MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Reward MeSH
• Analgesics, Opioid administration & dosage   pharmacology   MeSH
• Rats, Wistar MeSH
• Receptors, Ghrelin antagonists & inhibitors   metabolism   MeSH
• Stereotyped Behavior drug effects   MeSH
• Triazoles administration & dosage   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
• 3-methoxytyramine MeSH Browser
• Dopamine MeSH
• Ghrelin MeSH
• Glycine MeSH
• 3,4-Dihydroxyphenylacetic Acid MeSH
• Homovanillic Acid 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
• Analgesics, Opioid MeSH
• Receptors, Ghrelin MeSH
• Triazoles MeSH

RATIONALE AND OBJECTIVES: Behavioral, neurochemical and pharmaco-EEG profiles of a new synthetic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats were examined. MATERIALS AND METHODS: Locomotor effects, prepulse inhibition (PPI) of acoustic startle reaction (ASR), dopamine and its metabolite levels in nucleus accumbens (NAc), EEG power spectra and coherence in freely moving rats were analysed. Amphetamine was used as a reference compound. RESULTS: 2C-B had a biphasic effect on locomotion with initial inhibitory followed by excitatory effect; amphetamine induced only hyperlocomotion. Both drugs induced deficits in the PPI; however they had opposite effects on ASR. 2C-B increased dopamine but decreased 3,4-dihydroxyphenylacetic acid (DOPAC) in the NAc. Low doses of 2C-B induced a decrease in EEG power spectra and coherence. On the contrary, high dose of 2C-B 50 mg/kg had a temporally biphasic effect with an initial decrease followed by an increase in EEG power; decrease as well as increase in EEG coherence was observed. Amphetamine mainly induced an increase in EEG power and coherence in theta and alpha bands. Increases in the theta and alpha power and coherence in 2C-B and amphetamine were temporally linked to an increase in locomotor activity and DA levels in NAc. CONCLUSIONS: 2C-B is a centrally active compound similar to other hallucinogens, entactogens and stimulants. Increased dopamine and decreased DOPAC in the NAc may reflect its psychotomimetic and addictive potential and monoaminoxidase inhibition. Alterations in brain functional connectivity reflected the behavioral and neurochemical changes produced by the drug; a correlation between EEG changes and locomotor behavior was observed.

• MeSH
• Amphetamine pharmacology   MeSH
• Behavior, Animal drug effects   MeSH
• Dimethoxyphenylethylamine administration & dosage   analogs & derivatives   pharmacology   MeSH
• Dopamine metabolism   MeSH
• Electroencephalography MeSH
• Hallucinogens administration & dosage   pharmacology   MeSH
• Rats MeSH
• 3,4-Dihydroxyphenylacetic Acid metabolism   MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Motor Activity drug effects   MeSH
• Rats, Wistar MeSH
• Reflex, Startle drug effects   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
• Comparative Study MeSH
• Names of Substances
• 2-(4-bromo-2,5-dimethoxyphenyl)ethylamine MeSH Browser
• Amphetamine MeSH
• Dimethoxyphenylethylamine MeSH
• Dopamine MeSH
• Hallucinogens MeSH
• 3,4-Dihydroxyphenylacetic Acid MeSH