A contemporary neurobiological approach to eating disorders
ANTONATOS S., GALANOPOULOU P.

The major categories of eating disorders are anorexia nervosa, bulimia nervosa, binge eating disorder and obesity. Eating disorders of various kinds have been reported in up to 4 percent of adolescent and young adult students. The treatment of eating disorders is based on a multimodal model, which recognizes that these disorders do not have a single cause or a predictable course. Biological, genetic, social, psychological and psychodynamic factors are implicated in the causes of eating disorders.

Biological vulnerability concerning eating disorders can include dysfunction of neurotransmitters such as serotonin, dopamine and norepinephrine that regulate feeding. Studies have shown that all three neurotransmitters, especially the serotonergic system, are dysfunctional in eating disorders.

The involvement of the serotoninergic system in the control of food intake is wellestablished and is inhibitory in promoting satiety. There exists a close link between nutritional intake and serotonin (5-Hydroxytryptamine,5-HT) activity. Of the 14 serotonin receptor subtypes currently identified, the 5-HT_1B and 5-HT_2C receptors are believed to mediate the 5-HT induced hypophagia associated with the process of satiety, while activation of the 5-HT_1A receptors results in an increase of food intake. Much interest has been generated by the possible effects of 5-HTergic drugs on food choice and macronutrient selection. However, there is no current evidence that any specific 5-HT receptor subtype mediates the intake of a specific macro nutrient. The data from early dietary choice paradigms are particularly contradictory.

The aim of the present study was to investigate and differentiate the role of 5-HT_1A and 5-HT_2C receptor subtypes on food intake and dietary choices (carbohydrate or protein enriched diet). For this purpose, Buspirone (5-HT_1A agonist), Mesulergine (5-HT_2C antagonist/D_A agonist), 1-(3-chlorophenyl)-piperazine dihydrochloride - m-CPP (5-HT_1B/2C agonist) and Apomorphine (dopamine-D₂ agonist) were used. Twenty groups of 2-month old male Wistar rats were used (8 animals/group), mean body weight 235±5g, that received single ip doses of: saline (control group), Buspirone (0.05-0.1-2.0-4.0 mg.kg^-1), Mesulergine (1.0-3.0 mg.kg^-1), m-CPP (5.0-10.0 mg.kg^-1) and combinations of Mesulergine with Buspirone or m-CPP, as well as Buspirone with m-CPP in the same doses. One group of rats received Apomorphine in a single dose of 1.0 mg.kg^-1.The second drug was injected 30 minutes later. Animals were individually housed in cages and were freely fed by two feeders with equal amounts of isocaloric diets, which differed in their carbohydrate and protein content but fat content was constant. Carbohydrate Enriched Diet (CED), which contained 80% D-glucose with starch, Protein Enriched Diet (PED), which contained 80% casein. The proportions (W/W) of corn oil, vitamin and mineral mixtures were similar in both diets. Feeders were alternated daily to minimize place preference development. Experimental studies were performed according to food deprivation schedule (16hrs food deprivation and free access to food the next 32hrs) after an acclimatization period of 3 days. On the final day of the experiment PED, CED and Total Diet (TD) intakes were measured during refeeding period 4 hours after saline, drug or last drug injections.

According to our results we have drawn the following conclusions: Mesulergine, a serotonin receptor antagonist (at 5-HT_2C sites) and dopamine D₂ agonist, leads to food intake and diet selection by a dual mode of action: Due to its simultaneously antiserotoninergic and dopaminergic activity causes hyperphagia accompanied by an increase of both PED and CED intakes. Buspirone due to its interference in 5-ΗΤ_1Α autoreceptors, which are located on raphe nuclei, brings about significant hyperphagia due to an increase on CED intake and seems to affect diet selection indirectly. Both of the 5-ΗΤ_1Α and 5-ΗΤ_2C receptors regulate the protein-sparing effect, which characterizes the inhibitory role of serotoninergic system in the control of appetite. On the other hand, the stimulation of D₂ receptors is responsible for the increase of PED intake. Taking into account these results it is possible to have interactions between the adjacent areas of ventromedial part of hypothalamus, which is full of 5-ΗΤ_2C receptors and the ventrolateral striatum, as well as the lateral hypothalamus which are full of D₂ receptors in order to be achieved the above action on appetite behavior.

However, the blockade of 5-ΗΤ_2C receptors from mesulergine constitutes the most significant reason for the increase of carbohydrate intake instead of the inhibition of 5-HT release through the 5-ΗΤ_1Α receptors. The above data suggest that 5-ΗΤ_2C receptors may have a prominent role on anorexigenic properties of 5-HT. It seems that any intervention on 5-ΗΤ_1Α receptors is transmitted to the post-synaptic 5-HT_2C receptors directly, if not exclusively, involved on 5-HT induced food and carbohydrate intake suppression.

These findings extend our understanding on neurobiological substrate of appetite and eating disorders and contribute to the studies related to new drugs against hyperphagia, bulimia and obesity, especially those referred to 5-HT_2C compounds with agonistic properties.

Key words: Eating disorders, serotonergic system, 5-HT_2C receptors, isocaloric diets, protein, carbohydrate, food deprivation schedule, wistar rats, buspirone, mesulergine, m-CPP, apomorphine.