Binge eating disorder (BED) is characterized by uncontrollable episodes of eating in a short period of time, with a subjective loss of control and overconsumption behavior [1,2]; it is also the most prevalent of eating disorders [3,4]. Additionally, in BED, overconsumption of palatable food (PF) suggests that the behavior is driven by the rewarding properties of food rather than homeostatic signals [5]. Furthermore, adolescents with BED are at increased risk of being overweight and obese [6]. Food intake involves metabolic and nutritional signals that regulate homeostatic eating and reward signals that code pleasurable aspects of food that drive hedonic consumption [7]. In this regard, an equilibrium is important between eating to provide energy consumption for homeostatic functions and reward-induced overconsumption [8].

The endocannabinoid system (ECS) plays a major role in the regulation of food intake, both centrally and in the periphery [1]. The ECS comprises the endogenous ligands anandamide (AEA) and 2-arachydonyl glycerol (2AG) [9,10], as well as the enzymatic machinery in charge of synthesis and degradation. AEA is synthesized from phosphatidylethanolamine and degraded by fatty-amino-acid-hydrolase (FAAH) [11], while 2AG is synthesized from phosphatidylinositol and degraded by the enzyme monoacylglycerol-lipase (MAGL) into arachidonic acid and glycerol [12]. Both AEA and 2AG are synthetized by postsynaptic neurons in response to neurotransmitter release, functioning as negative feedback regulators that inhibit further neurotransmitter release. Thus, ECS is a retrograde messenger system that inhibits neurotransmitter release at excitatory or inhibitory synapses [8,13]. Additionally, the ECS includes two cannabinoid receptors: Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). In particular, the CB2R is expressed on dopaminergic cell bodies at the ventral tegmental area (VTA) [14,15] and nucleus accumbens (NAc) [7,16]. Furthermore, it has been suggested that CB2R is mainly expressed in the postsynaptic [17]. Regarding this, activation of CB2R reduces intracellular cAMP levels and enhances M-type K⁺ channel function, leading to a reduction in the excitability of VTA neurons [18].

When CB2R is activated, it couples to Gi/o proteins, with more affinity to Gi than to Go, and their activation is associated with different cellular pathways, including adenylate cyclase (AC), cAMP, protein kinase A (PKA), ERK 1/2, p38 mitogen-activated protein kinase (MAPK p38) and AKT [19,20]. Specifically, the activation of CB2R results in the inhibition of AC [19,20,21], the cAMP/PKA dependent pathway [20], and activation of intracellular kinases, such as PI3K-Akt pathway, and extracellular signal-regulated (ERK) kinases, which ultimately results in the suppression of neuronal activity [21]. Furthermore, CB2R may modulate mesolimbic dopaminergic neurons and participate in cocaine self-administration behavior [15] and sugar consumption [7].

Research shows there is a clear relationship between ECS and BED. It has been identified that binge-like intake in stress and repeated food restriction induces the down-regulation of FAAH [22] and up-regulated gene expression of CB1R in the hypothalamus in female rat adults [23]. Furthermore, CB2R has been found in brain areas that are part of the reward system and are involved in food intake regulation [1,24]. Also, CB2R has been identified in dopamine neurons, which may play important roles in the modulations of psychomotor behaviors, anxiety, depression, and the rewarding effects of alcohol, cocaine [25] and methamphetamine [26]. Furthermore, it has been shown that reduced CB2R signaling by administration of antagonists leads to increased intake of standard diet in food-deprived mice [27]. In this regard, Amancio-Belmont et al. [28] show that there is an age-related expression of CB2R in the prefrontal cortex (PFC), NAc, and Hippocampus (Hipp), where adolescent rats show lower expression of CB2R than adult and aged rats which may be related to motivation and decision-making modulation.

Studies indicate there is a clear role of CB2R in food intake regulation. For example, increased CB2R expression in the hypothalamus and high-fat food intake has been reported to be induced by maternal high-fat diet in male and female rat offspring at weaning and adulthood [29]. Furthermore, overexpression of CB2R induces food addiction after exposure to PF in mice [30]. Also, Bourdy et al. [7] show that high sugar intake is induced by an increased expression of CB2R in the NAc, while Bi et al. [31] report that administration of a selective CB2R agonist produced a reduction in sucrose self-administration in mice adults. Additionally, Amancio-Belmont et al. [28] also report that adolescent rats, who express less CB2R in the PFC, Nacc, and Hipp, ingest significantly more chocolate pellets in a fixed ratio and progressive ratio paradigm than adult and aged rats, showing a higher motivation to obtain a reinforcer.

Recently, the role of CB2R in binge intake has been identified [1]. However, few studies have evaluated the role CB2R has in the modulation of binge-like intake of PF in adolescent mice, which is important given that CB2R expression undergoes changes in an age-related manner and may be involved in motivation for PF intake. Here, we evaluate the effect of the administration of CB2 cannabinoid receptor agonist, antagonist, or both on binge-like intake of PF in adolescence in mice.