Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine

Schmidt, Heath D.; Mietlicki‐Baase, Elizabeth G.; Ige, Kelsey Y.; Maurer, John J.; Reiner, David J.; Zimmer, Derek J.; Nest, Duncan S. Van; Guercio, Leonardo A.; Wimmer, Mathieu E.; Olivos, Diana R.; Jonghe, Bart C. De; Hayes, Matthew R.

doi:10.1038/npp.2015.362

Cited by 98 publications

(104 citation statements)

References 53 publications

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“…With respect to cocaine, Exendin-4 decreases cocaine-induced locomotion, conditioned place preference and self-administration [35–37,39]. GLP-1R agonism also suppresses hyperactivity induced by the non-selective dopamine agonist apomorphine [84].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, they are found in the VTA, which receives direct projections for GLP-1 producing neurons of the nucleus of the solitary tract [32], and can be targeted selectively to reduce motivated behavior for food and drug reward (see [38,83,92] for review). In support of this hypothesis, a recent study has demonstrated a reduction in cocaine self-administration behavior by intra-VTA agonism of GLP-1Rs [37]. There is evidence to suggest that VTA receptor activation may differentially modulate dopamine signaling depending on the NAc subregion targeted by the dopamine projection – with effects predominantly in the NAc core [32,33].…”

Section: Discussionmentioning

confidence: 99%

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Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

Fortin

Roitman

2017

Physiology & Behavior

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Drugs of abuse increase the frequency and magnitude of brief (1–3 s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release – possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

Fortin

Roitman

2017

Physiology & Behavior

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“…A recent study showed that activation of VTA GLP-1Rs reduces the reinforcing efficacy of cocaine [39]. Further, this VTA GLP-1R-mediated affect on voluntary cocaine taking was shown to be physiologically relevant.…”

Section: Central Actions Of Glp-1 On Food and Drug Rewardsmentioning

confidence: 99%

GLP-1 influences food and drug reward

Hayes¹,

Schmidt

2016

Current Opinion in Behavioral Sciences

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Natural rewards, including food, water, sleep and social interactions, are required to sustain life. The neural substrates that regulate the reinforcing effects of these behaviors are also the same neurobiological mechanisms mediating mood, motivation and the rewarding effects of pharmacological stimuli. That the neuropeptide glucagon-like peptide-1 (GLP-1) is under investigation for both the homeostatic and hedonic controls of feeding is not surprising or novel. However, if the neural substrates that underline food reward are shared with other reward-related behaviors generally, then future research should investigate and embrace the likelihood that endogenous and exogenous GLP-1 receptor activation may influence multiple reward-related behaviors. Indeed, studies of the neurobiological mechanisms underlying motivated feeding behavior have informed much of the basic research investigating neural substrates of drug addiction. An emerging literature demonstrates a role for the GLP-1 system in modulating maladaptive reward behaviors, including drug and alcohol consumption. Thus, if GLP-1-based pharmacotherapies are to be used to treat drug addiction and other diseases associated with maladaptive reward behaviors (e.g. obesity and eating disorders), the neuroscience field must conduct systematic, mechanistic neuropharmacological and behavioral studies of each GLP-1 receptor-expressing nucleus within the brain. It is possible that behavioral selectivity may result from these studies, which could inform future approaches to targeting GLP-1R signaling in discrete brain nuclei to treat motivated behaviors. Equally as likely, non-selective effects on natural reward and maladaptive reward behaviors may be observed for GLP-1-based pharmacotherapies. In this case, a better understanding of the effects of increased central GLP-1R activation on motivated behaviors will aid in clinical approaches toward treating aberrant feeding behaviors and/or drug dependence.

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“…Furthermore, the presence of or even the expectancy of cocaine depresses leptin concentrations, while leptin administration inhibits cocaine-induced seeking behavior and reward (You et al, 2016). The administration of the GLP-1 analog exendin-4 to rodents reduces the rewarding effects of cocaine, cocaine self-administration and cocaine-induced CPP (Egecioglu et al, 2013; Graham et al, 2013; Reddy et al, 2016; Schmidt et al, 2016; Sørensen et al, 2015). In contrast, insulin enhances the function of cocaine-sensitive dopamine and norepinephrine transporters in the rat NAc by acting at the presynaptic level (Schoffelmeer et al, 2011).…”

Section: 0 Introductionmentioning

confidence: 99%

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses

Bouhlal

Ellefsen

Sheskier

et al. 2017

Drug and Alcohol Dependence

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Background Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. Methods We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25 mg intravenous (IV) cocaine. Results Serum concentrations of GLP-1 (p = 0.014) and PYY (p = 0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p = 0.055) and amylin (p = 0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p’s > 0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). Discussion These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations.

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Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine

Cited by 98 publications

References 53 publications

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

GLP-1 influences food and drug reward

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses

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