Glucagon-like peptide-1 receptors modulate the binge-like feeding induced by µ-opioid receptor stimulation of the nucleus accumbens in the rat

Abstract

Neuropeptides and peptide hormones affect food-directed motivation, in part, through actions on brain regions associated with reward processing. For instance, previous reports have shown that stimulating glucagon-like peptide-1 (GLP-1) receptors in the nucleus accumbens (NAc), an area that directs motivational processes towards food and drugs of abuse, has an anorectic effect. In contrast, µ-opioid receptor activation of the NAc increases feeding, particularly on highly palatable diets. While both neurotransmitters act within the NAc to impact food intake, it is not clear if and how they might interact to affect feeding. Therefore, these experiments tested the effects of NAc injections of the GLP-1 receptor agonist Exendin 4 (EX4) or antagonist Exendin 9 (EX9) on the consumption of a sweetened fat diet, with and without simultaneous µ-opioid receptor stimulation. Male Sprague–Dawley rats (n = 8/group, EX4 or EX9) underwent surgery to place bilateral cannula above the NAc core. After recovery, animals were tested following NAc injections of saline or the µ-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (0.025 µg/side), combined with varying doses of EX4 (0, 0.05, or 0.10 µg/side) or EX9 (0, 2.5, 5.0 µg/side), counterbalanced across 6 testing days. Food and water intake, along with locomotor activity, was monitored for 2 h. Mu-opioid receptor stimulation significantly increased feeding, and this effect was reduced by GLP-1 receptor stimulation. In contrast, GLP-1 antagonism with EX9 altered the dynamics of DAMGO-induced binge-like feeding, extending µ-opioid-induced binging, and increasing food consumption. These findings are the first to demonstrate an interaction between NAc µ-opioid and GLP-1 receptors on palatable food intake.

Ghrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward

“…While the role of GLP-1 in food anticipatory behavior has not been as extensively investigated as ghrelin, GLP-1 s effects appear to oppose those of ghrelin. For example, infusion of the GLP-1R agonist exendin-4 into the ACB of rats with scheduled access to a high fat/sugar diet prevented the enhanced FAA and food consumption induced by mu opioid receptor agonism [58]. Paradoxically, however, both ghrelin and GLP-1 levels in circulation are increased prior to meal access in meal-entrained rats, as alluded to above in the work from Woods and colleagues.…”

Gut peptide regulation of food intake – evidence for the modulation of hedonic feeding

“…GLP‐1‐based therapies, therefore, may reduce the reinforcing properties of rewarding pathways if the right region of the CNS is targeted (Fortin & Roitman, 2017). μ‐Opioid receptor activation in the NAc increases the consumption of a sweetened fat diet in rats – treatment with Ex4 attenuated this effect, while GLP‐1R antagonism with exendin‐9 (Ex9) altered μ‐opioid receptor agonist‐induced binge‐like feeding, extending feeding bouts and therefore increasing food consumption (Pierce‐Messick & Pratt, 2020). Interestingly, Ex4 decreased food intake when infused into the NAc core and shell in female rats (Abtahi et al .…”

Effects of linagliptin on morphine dependence in larval zebrafish (Danio rerio)

“…They confirmed that injections of the GLP-1 peptide analogue, exendin-4, into the nucleus accumbens and into VTA decreased food intake [19], suggesting that the GLP-1 peptide receptors in the reward system structures mentioned are involved in the action of rewarding addictive substances, including morphine, which exerts a pharmacological effect through the µ opioid receptors located in the mesolimbic system. Recent reports confirm the GLP-1 peptide receptor interaction with the opioid system -exendin-4 has been shown to inhibit the recovery of heroin- [33] and oxycodone-seeking [34] behaviour in rats, and to inhibit the binge-like feeding induced by µ-opioid receptor stimulation of the nucleus accumbens in rats [35].…”