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

Fortin, Samantha M.; Roitman, Mitchell F.

doi:10.1016/j.physbeh.2017.03.019

Cited by 53 publications

(34 citation statements)

References 101 publications

(116 reference statements)

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“…For example, pharmacological activation of GLP-1Rs in the VTA, NAc core, and NAc shell reduces palatable food intake and body weight ( 144 ) and affects responses to drugs of abuse ( 145 – 147 ). Moreover, GLP-1R action within the VTA can alter phasic dopamine signaling as, in our laboratory, we demonstrated that LiCl-induced reductions in stimulated phasic dopamine release can be attenuated by GLP-1R blockade ( 58 ) and that ventricular injections of the GLP-1R agonist, exendin-4, can reduce cocaine-induced phasic dopamine signaling in the NAc core ( 148 ). These effects appear to be due, in part, to altered excitatory drive onto dopamine cell bodies as GLP-1R activation does not alter evoked NAc phasic dopamine release as measured in ex vivo brain slices ( 149 ).…”

Section: Homeostatic Signals Are Relayed To Mesolimbic Pathwaysmentioning

confidence: 99%

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

2018

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Motivated behaviors are often initiated in response to perturbations of homeostasis. Indeed, animals and humans have fundamental drives to procure (appetitive behaviors) and eventually ingest (consummatory behaviors) substances based on deficits in body fluid (e.g., thirst) and energy balance (e.g., hunger). Consumption, in turn, reinforces motivated behavior and is therefore considered rewarding. Over the years, the constructs of homeostatic (within the purview of the hypothalamus) and reward (within the purview of mesolimbic circuitry) have been used to describe need-based vs. need-free consumption. However, many experiments have demonstrated that mesolimbic circuits and “higher-order” brain regions are also profoundly influenced by changes to physiological state, which in turn generate behaviors that are poised to maintain homeostasis. Mesolimbic pathways, particularly dopamine neurons of the ventral tegmental area (VTA) and their projections to nucleus accumbens (NAc), can be robustly modulated by a variety of energy balance signals, including post-ingestive feedback relaying nutrient content and hormonal signals reflecting hunger and satiety. Moreover, physiological states can also impact VTA-NAc responses to non-nutritive rewards, such as drugs of abuse. Coupled with recent evidence showing hypothalamic structures are modulated in anticipation of replenished need, classic boundaries between circuits that convey perturbations in homeostasis and those that drive motivated behavior are being questioned. In the current review, we examine data that have revealed the importance of mesolimbic dopamine neurons and their downstream pathways as a dynamic neurobiological mechanism that provides an interface between physiological state, perturbations to homeostasis, and reward-seeking behaviors.

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Section: Homeostatic Signals Are Relayed To Mesolimbic Pathwaysmentioning

confidence: 99%

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

2018

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“…The administration of leptin in the VTA decreases dopamine in the NAc (Fulton et al, 2006), possibly via a decrease in firing (Hommel et al, 2006) or excitatory synaptic transmission (Thompson & Borgland, 2013) onto dopamine neurons. Similarly, a GLP-1 receptor agonist, extendin-4, decreases excitatory synaptic transmission onto NAc-projecting dopamine neurons (Wang et al, 2015) and decreases dopamine release in the NAc (Fortin & Roitman, 2017b). Both intra-VTA leptin or GLP-1 agonists decrease food intake (Fulton et al, 2006;Hommel et al, 2006;Alhadeff et al, 2012;Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Insulin in the ventral tegmental area reduces cocaine‐evoked dopamine in the nucleus accumbens in vivo

Naef

Seabrook

Hsiao

et al. 2018

Eur J of Neuroscience

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Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet‐induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon‐like peptide‐1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long‐term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in vivo FSCV to detect rapid fluctuations in dopamine concentration, we showed that intra‐VTA insulin via action at insulin receptors reduced pedunculopontine nucleus‐evoked dopamine release in the NAc. Furthermore, intra‐VTA insulin reduced cocaine‐potentiated NAc dopamine. Finally, intra‐VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra‐VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin.

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“…Recent studies have shown that systemic and intra-VTA administration of EX4 can attenuate cue-induced cocaine seeking at doses that do not impact food intake (Hernandez et al, 2018). Central administration of EX4 has recently been shown to attenuate cocaine-induced phasic dopamine signaling in the NAc (Fortin and Roitman, 2017), possibly by increasing GABAA receptor mediated inhibition (Farkas et al, agonists impact reward-seeking behaviors by disrupting the motivational salience attributed to reward predictive incentive cues.…”

Section: Discussionmentioning

confidence: 99%

“…EX4 decreases both amphetamine-induced accumbal dopamine release and conditioned place preference (Egecioglu et al, 2013). ICV delivery of EX4 suppresses cocaine-induced phasic dopamine release in the NAc core, but not shell, with no effect on electrically stimulated release (Fortin and Roitman, 2017).…”

Section: Introductionmentioning

confidence: 98%

Exendin-4 disrupts responding to reward predictive incentive cues in rats

Feja

et al. 2018

Preprint

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Exendin-4 (EX4) is a GLP-1 receptor agonist used clinically to control glycemia in Type-2 Diabetes Mellitus (T2DM), with the additional effect of promoting weight loss. The weight loss seen with EX4 is attributable to the varied peripheral and central effects of GLP-1, with contributions from the mesolimbic dopamine pathway that are implicated in cue-induced reward seeking. GLP-1 receptor agonists reduce preference for palatable foods (i.e. sweet and fat) as well as the motivation to obtain and consume these foods. Accumulating evidence suggest that GLP-1 receptor activity can attenuate cueinduced reward seeking behaviors. In the present study, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg i.p.) on incentive cue (IC) responding. This rat model required rats to emit a nosepoke response during an intermittent audiovisual cue to obtain a sucrose reward (10% solution). EX4 dose-dependently attenuated responding to reward predictive cues, and increased latencies of the cue response and reward cup entry to consume the sucrose reward. Moreover, EX4 dose-dependently decreased the number of nosepokes relative to the number of cue presentations during the session. There was no drug effect on the number of reward cup entries per reward earned during the session, a related reward-seeking behavior with similar locomotor demand. Interestingly, there was a dose-dependent effect of time on the responding to reward predictive cues and nosepoke response latency, such that 2.4 µg/kg of EX4 delayed responding to the initial IC of the behavioral session. Together, these findings suggest that agonism of the GLP-1 receptor with EX4 modulates the incentive properties of cues attributed with motivational significance.

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

Cited by 53 publications

References 101 publications

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

Insulin in the ventral tegmental area reduces cocaine‐evoked dopamine in the nucleus accumbens in vivo

Exendin-4 disrupts responding to reward predictive incentive cues in rats

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