The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This review is focused on the role of DRD4 and DRD4 genetic polymorphism in these neuropsychiatric disorders in both clinical and preclinical studies. However, further research is needed to better clarify the complex DRD4 role, by using validated preclinical models and novel compounds more selective for DRD4.

The dysfunction of melanocortin signaling has been associated with obesity, given the important role in the regulation of energy homeostasis, food intake, satiety and body weight. In the hypothalamus, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) contribute to the stability of these processes, but MC3R and MC4R are also localized in the mesolimbic dopamine system, the region that responds to the reinforcing properties of highly palatable food (HPF) and where these two receptors seem to affect food reward and motivation. Loss of function of the MC4R, resulting from genetic mutations, leads to overeating in humans, but to date, a clear understanding of the underlying mechanisms and behaviors that promote overconsumption of caloric foods remains unknown. Moreover, the MC4R demonstrated to be a crucial modulator of the stress response, factor that is known to be strictly related to binge eating behavior. In this review, we will explore the preclinical and clinical studies, and the controversies regarding the involvement of melanocortin system in altered eating patterns, especially binge eating behavior, food reward and motivation.

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Changes in functionality and composition of gut microbiota (GM) have been associated and may contribute to the development and maintenance of obesity and related diseases. The aim of our study was to investigate for the first time the impact of Lactiplantibacillus (L.) plantarum IMC 510 in a rat model of diet-induced obesity, specifically in the cafeteria (CAF) diet. This diet provides a strong motivation to voluntary overeat, due to the palatability and variety of selected energy-dense foods. The oral administration for 84 days of this probiotic strain, added to the CAF diet, decreased food intake and body weight gain. Accordingly, it ameliorated body mass index, liver and white adipose tissue weight, hepatic lipid accumulation, adipocyte size, serum parameters, including glycemia and low-density lipoprotein levels, in CAF fed rats, potentially through leptin control. In this scenario, L. plantarum IMC 510 showed also beneficial effects on GM, limiting the microbial imbalance established by long exposure to CAF diet and preserving the proportion of different bacterial taxa. Further research is necessary to better elucidate the relationship between GM and overweight and then the mechanism of action by which L. plantarum IMC 510 modifies weight. However, these promising results prompt a clear advantage of probiotic supplementation and identify a new potential probiotic as a novel and safe therapeutic approach in obesity prevention and management.

The Neuropeptide S (NPS), a 20 amino acids peptide, is recognized as the endogenous ligand of a previously orphan G protein-coupled receptor, now termed NPS receptor (NPSR). The limited distribution of the NPS-expressing neurons in few regions of the brainstem is in contrast with the extensive expression of NPSR in the rodent central nervous system, suggesting the involvement of this receptor in several brain functions. In particular, NPS promotes locomotor activity, behavioral arousal, wakefulness, and unexpectedly, at the same time, it exerts anxiolytic-like properties. Intriguingly, the NPS system is implicated in the rewarding properties of drugs of abuse and in the regulation of food intake. Here, we focus on the anorexigenic effect of NPS, centrally injected in different brain areas, in both sated and fasted animals, fed with standard or palatable food, and, in addition, on its influence in the gastrointestinal tract. Further investigations, regarding the role of the NPS/NPSR system and its potential interaction with other neurotransmitters could be useful to understand the mechanisms underlying its action and to develop novel pharmacological tools for the treatment of aberrant feeding patterns and obesity.

In this paper the benzo-cracking approach was applied to the potent sigma1 (σ1) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3. To evaluate the effect of the increase of the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at σ1 receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over σ2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over dopamine transporter. Docking results supported the structure-activity relationship studies. Due to its interesting biological profile, derivative 3, selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging-rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of σ1 receptor in the compulsive-like eating behavior and supported σ1 receptor as a promising target for the management of eating disorders.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.