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

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

RATIONALE: Flumazenil, a competitive antagonist of benzodiazepine receptors (BZRs), has been used as a probe to detect effects of putative endogenous ligands for BZRs in anxiety. Flumazenil is renowned for its highly inconsistent behavioral effects. OBJECTIVE: To ascertain effects of flumazenil in the social conflict test in mice, which provides complex measures for prediction of anxiolytic and anxiogenic activity of drugs in behaviorally different groups of animals. METHODS: Singly housed male mice treated with flumazenil (5, 20 or 80 mg/kg i.p.) or vehicle were paired with untreated non-aggressive group-housed male mice in a novel cage. Behavior was analyzed from video tapes of the social interactions in three populations of mice: timid (n=21), aggressive (n=11), and sociable (n=7). Levels of gamma-aminobutyric acid (GABA) were measured in vivo in the prefrontal cortex. RESULTS: Flumazenil reduced timid (defensive-escape) and increased locomotor activities in timid mice. The drug reduced aggressive and increased sociable (social investigation) activities in aggressive mice. These behavioral changes were produced at the lowest dose of flumazenil tested (5 mg/kg) and were not increased further by higher doses of the drug (20 mg/kg or 80 mg/kg). A tendency to increased timidity was found after flumazenil in sociable mice. Concentrations of GABA were markedly higher in the prefrontal cortex of sociable mice than in timid or aggressive mice. CONCLUSIONS: Flumazenil produced moderate anxiolytic-like behavioural changes and a slight anxiogenic-like effect. The present data might be reflecting antagonism of corresponding endogenous BZR ligands. However, these putative ligands seem to exert only modest modulatory influence.

• MeSH
• Aggression drug effects   physiology   MeSH
• Flumazenil pharmacology   MeSH
• Conflict, Psychological * MeSH
• Mice, Inbred ICR MeSH
• Mice MeSH
• Motor Activity drug effects   physiology   MeSH
• Social Behavior * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Flumazenil MeSH