Coadministration antagonist dopamine receptor D4 with CB2 receptor agonist decreases binge-like intake of palatable food in mice

Abstract

Introduction: Food intake is regulated by two systems: homeostatic and hedonic. An imbalance between these systems can induce overconsumption, such as binge eating disorder (BED), and is associated with dysregulation of the dopamine reward system. The cannabinoid type 2 receptor (CB2R) has been identified in dopamine neurons and may play an important role in motivated behaviors, including food intake. Nevertheless, the interaction between the dopamine D4 (DRD4) receptor and CB2R in binge-like intake has not yet been identified. Therefore, the present study aims to evaluate the effects of intraperitoneal administration of DRD4 antagonist (L-745870), as well as the coadministration of DRD4 antagonist with either CB2R agonist (HU308) or antagonist (AM630), on binge-like intake of palatable food (PF) in adult male mice.

Methods: We used adult male 34 C57BL6/J mice. All animals were housed individually and had ad libitum access to standard diet (SD) and water. To evaluate binge-like intake, the animals had 1 h of access to PF during 12 baseline binge eating test (BET) sessions. Mice were then randomly assigned to the following treatment groups: 1) vehicle; 2) L-745870; 3) L-745870-HU308, 4) L-745870+AM630 to be evaluated under the effect of treatments for three additionally BET sessions.

Results: Our results show that DRD4 antagonist reduced binge-like intake of PF, and that a coadministration with a CB2R agonist induced an even more pronounced reduction of binge-like intake.

Conclusion: These findings suggest an interaction between the dopaminergic and endocannabinoid systems in the modulation of binge-like intake of PF in adult mice, where CB2R activation participates in modulating reward pathways and reducing binge-like behavior.

Keywords: CB2 receptor; binge-like intake; dopamine receptor D4; dopamine system; endocannabinoid system; palatable food.

Figure 1

Experimental timeline. Mice received 15 binge test sessions with intermittent access to PF for 1 h on access days (Monday, Wednesday, and Friday) for 5 weeks (1st to 15th). On binge test sessions 13th to 15th, treatment was administrated: VEH, L-7458-70, L-7458-70 + HU308, and L-7458-70 + AM630. Animals had ad libitum access to SD and water. All experiments took place in the animal’s home cage. After the 15th binge test session, all animals were evaluated in behavioral tasks: Open Field, Novel Object Recognition Test (NORT), Food Preference Test, and Forced Swim Test. BL, baseline; Mo, Monday; We: Wednesday; Fr: Friday. Figure made with Biorender^® software.

Figure 2

Proportion of PF caloric intake in binge test sessions. Data express the mean ± SEM (n = 7/group). (A) Point-plot of the PF intake in binge test sessions 1st to 12th. (B) The bar graph shows the bar plot of PF intake in binge test sessions 1st vs. 12th. (C) The bar graph shows the bar plot of PF intake in binge test sessions 12 to 15th and compares groups from binge test sessions 13th to 15th (binge test sessions under treatment). ****p < 0.0001, ***p < 0.001, **p < 0.01.

Figure 3

Effects of administration of treatments in behavioral tasks. Data express the mean ± SEM. (A,B) Open field test: the bar graph shows the bar plot of the distance traveled in the center (A) and in the periphery (B). (C) Forced swim test: the bar graph shows the bar plot of immobility time. (D) Food preference test: preference index between SD and PF. (E,F) Novel object recognition test. The bar graph shows the bar plot of the recognition index between familiar and novel objects in short-term memory (STM) (E) and long-term memory (LTM) (F). Data express the mean ± SEM. ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.01; & indicate a statistical difference (p < 0.01) between CON group; # indicate a statistical difference (p < 0.001) between VEH group.

Figure 4

Body weight. Data express the mean ± SEM. (A) Body weight per week. (B) Body weight analysis between groups on Week 4 (before starting treatment). (C) Body weight analysis between groups on Week 5 (BET sessions under treatment); *p < 0.01.