Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats

Sustkova-Fiserova, Magdalena; Jerabek, Pavel; Havlickova, Tereza; Kačer, Petr; Kršiak, M

doi:10.1007/s00213-014-3466-9

Cited by 50 publications

(42 citation statements)

References 36 publications

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“…We found dopamine transients increased in frequency for a much longer duration (460 min) than in Vander Weele et al (2014), which could arise due to differences in baseline stress or the slower time course of drugs delivered s.c. compared with i.v. This dose of morphine produced immobility in rats, aligning with a previous study showing morphine increased immobility and catalepsy similar to the timing of elevated basal dopamine in the NAc (Sustkova-Fiserova et al, 2014). After drug administration, animals undergo spontaneous withdrawal dependent on the half-life of the drug.…”

Section: Discussionsupporting

confidence: 88%

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

Fox

Rodeberg

Wightman

2016

Neuropsychopharmacol

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Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an α 2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode.

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Section: Discussionsupporting

confidence: 88%

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

Fox

Rodeberg

Wightman

2016

Neuropsychopharmacol

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“…A wealth of new studies have shown that ghrelin (both agonists and antagonists) have a powerful effect on drug responses and subsequent use. Specifically, ghrelin antagonists (JMV2959) when injected alone do not appear to change general behavioral activity which includes locomotion, catalepsy, immobility, and stereotyped activity (Sustkova-Fiserova et al, 2014). Ghrelin itself shows reinforcement properties akin to drugs of abuse by causing increases in locomotion, release of dopamine in the accumbens, and induction of conditioned place preference (Jerlhag, 2008).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Ghrelin Antagonists [D‐Lys³]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice

Gómez

Ryabinin

2014

Alcoholism Clin & Exp Res

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Background Alcohol use and abuse patterns have created a need for novel treatment models. Current research has turned its focus on reward pathways associated with intrinsic necessities, such as feeding. Theories suggest that drugs of abuse seize control of natural reward pathways and disregulate normal function, leading to chronic addiction. One such pathway involving the hunger stimulating peptide, ghrelin, is the focus of our study. Methods Male C57BL/6 mice were randomly assigned to groups and treated with vehicle or a ghrelin antagonist, either [D-Lys3]-GHRP-6 (DLys) or JMV2959. Three experiments tested ghrelin antagonism using different doses; Experiment 1 – 12mg/kg JMV2959; Experiment 2 – 15mg/kg DLys; Experiment 3 – 9mg/kg JMV2959. Using a two-bottle choice 24-hour access paradigm, data was collected for ethanol intake, preference, water intake, and food intake at 4- and 24-hours after injection. Results Experiment 1 showed that 12mg/kg of JMV2959 decreased ethanol, water, and food intake, without affecting preference. Experiment 2 showed that 15mg/kg of DLys decreased ethanol intake, preference, and water intake only on the first day of treatment. Experiment 3 showed that 9mg/kg of JMV2959 decreased only ethanol and food intake. No change was seen during deprivation and JMV2959 was still effective at reducing ethanol intake upon reintroduction. Despite the change in food intake, there were no differences in body weight throughout the experiments. It should be noted that the majority of significant effects were only found 4-hours post injection. Conclusion The results show that compounds that block ghrelin receptor activity are effective at decreasing ethanol intake. However, DLys was only effective at reducing intake and preference on the first day, suggesting a quick tolerance and selectivity for ethanol. JMV2959 consistently reduced ethanol intake, but at the higher dose also reduced all other consummatory behaviors. Thus, ghrelin antagonists provide a viable potential for treatment of alcohol abuse disorders, but further research is needed to determine an appropriate dose and administration paradigm.

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“…This demonstrates a role for the GHSR-1a in the pathogenesis of addiction, while also suggesting the importance of ligand access to less accessible brain areas. These findings also generalise to opioid-induced dopamine release [336,339]. Notably, Jerlhag and colleagues have also concluded that BBB penetrant GHSR-1a antagonists may have potential in alcohol use disorders [340].…”

Section: Ghrelin and Ghrelin Ligands: Pharmacokinetic Perspectivesmentioning

confidence: 92%

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

Howick

Griffin

Cryan

et al. 2017

IJMS

135

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Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.

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Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats

Abstract: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

Cited by 50 publications

References 36 publications

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

The Effects of Ghrelin Antagonists [D‐Lys³]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

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Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats

Abstract: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

Cited by 50 publications

References 36 publications

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

The Effects of Ghrelin Antagonists [D‐Lys3]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

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Product

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The Effects of Ghrelin Antagonists [D‐Lys³]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice