Brain Serotonergic System: Is its role still determinant to develop new drugs against hyperphagia and obesity?
ANTONATOS S., GALANOPOULOU P.

The important role of 5-ΗΤ_2C receptors in the control of feeding in animals has been established through the use of selective 5-ΗΤ_2C receptor agonists and antagonists and transgenic mouse models. An early indication that the 5-ΗΤ_2C receptor might be important in regulating feeding came from studies using m-CPP (m-chlorophenylpiperazine) and TFMPP (trifluoromethylphenylpiperazine) agonists. These drugs show high affinity for the 5-ΗΤ_2C receptor, but are not selective and also have high affinity for the 5-ΗΤ_1B receptor. The agonist action of these piperazines at the 5-ΗΤ_2C receptor has been clearly demonstrated in vitro and both produce a marked decrease in food intake in food-deprived and free feeding rats. The use of 5-HT receptor antagonists such as mesulergine and mianserin, which show some selectivity for the 5-ΗΤ_2C site, strongly suggested that the 5-ΗΤ_2C receptor was largely responsible for mediating these anorectic effects. The use of more selective 5-ΗΤ_2C receptor antagonists in recent years, such as SB-200646 and SB-242084, which have also been shown to block m-CPP-induced hypophagia, has strengthened this argument. Recently, more selective 5-ΗΤ_2C receptor agonists have been described, and these drugs have also been shown to reduce food intake. It has been reported that the effects of two selective 5-ΗΤ_2C receptor agonists on feeding in a palatable food intake paradigm, namely Ro 60-175 and Ro 60-0332 significantly reduced food intake, when administrated orally in this test. Importantly, these compounds, in contrast to the piperazines described above, show selectivity for the 5-ΗΤ_2C receptor over the 5-ΗΤ_1B receptor (greater than 1000-fold).

The significance of the role of 5-ΗΤ_2C receptors in the serotonergic suppression of feeding is demonstrated in that a line of mutant mice lacking 5-ΗΤ_2C receptors were found to have elevations of body weight.

Moreover, detailed behavioural analysis suggests that a temporal advancement of the satiety sequence is induced by 5-ΗΤ_2C receptor agonists, providing evidence that these agents have a specific effect on feeding and probably reduce food intake by enhancement of satiety. Importantly, it appears from both preclinical and clinical data that 5-ΗΤ_2C receptors may be largely responsible for the clinical efficacy of the anorectic d-fenfluramine agent. Combined together, all these above data suggest that the 5-ΗΤ_2C receptor is an attractive target for the discovery of a novel treatment for hyperphagia and obesity.

Particular attention has focused on the hypothalamus as the locus of serotonergic effects on feeding. Systemic administration of indirect agonists such as dexfenfluramine and fluoxetine increases extracellular hypothalamic serotonin levels, and microinjections of serotonin into the paraventricular nucleus (PVN) of the hypothalamus have been found to suppress feeding by reducing meal size and feeding rate. Similar effects were also observed with microinjection of serotonin into the ventromedial (VMN) and dorsomedial (DMN) nuclei of the hypothalamus. 5-ΗΤ_2C receptors are expressed in these and other hypothalamic regions implicated in the regulation of energy balance. Furthermore, it remains possible that 5-ΗΤ_2C receptor expression at extrahypothalamic sites may also play a role in the serotonergic regulation of ingestive behaviour. For example these receptors are expressed in the pontine lateral parabrachial nucleus, which has been implicated in the anorectic actions of m-CPP and dexfenfluramine. Additional sites of expression within the basal ganglia, amygdale and hippocampal formation also warrant consideration.

While drugs, such as d-fenfluramine have undoubted efficacy as anorectic agents, they have ultimately failed as treatment options because of sideeffects and toxicity. 5-ΗΤ_2C receptors are apparently absent in peripheral tissues and therefore activation of 5-ΗΤ_2C receptors is unlikely to be responsible for the cardiac valvular toxicity and primary pulmonary hypertension associated with d-fenfluramine. Direct activation of 5-ΗΤ_2C receptors by administration of a selective 5-ΗΤ_2C receptor agonist, therefore, represents a potential opportunity to develop a safe and effective anti-obesity agent.

Key words: Serotonin, 5-ΗΤ_2C receptors, 5-ΗΤ_2C agonists, 5-ΗΤ_2C antagonists, d-fenfluramine, hyperphagia, obesity.