Linking Between 5HT and Control of Both Food Intake and of Feeding Behavior

5-HT was linked to the control of both food intake and feeding behavior for the first time 40 years ago (Blundell 1977). Blundell (1977) proposed that the 5-HT system had not only an inhibitory role in feeding but also was a key satiety factor. Specifically, he noted that the changes in caloric intake produced by the 5-HT interventions did not disrupt feeding behavior but altered in it in manner consistent with the behavioral effects of ingestion. At the time of this theoretical notion, little was know about the pharmacology of the 5-HT system. However, over the next 20 years significant advances in the identification and classification of numerous novel 5-HT receptors occurred (Hoyer and Martin 1997). The main focus for appetite research became the 5-HT1 and 5-HT2 receptor families, and eventually, postsynaptic 5-HT1B and the 5-HT2C receptors were established to be those criticial to satiety (see later and Chap. 4) (Blundell and Halford 1998). 5-HT neurons involved in appetite control project up towards the hypothalamic region, an area rich in orexigenic and anorexigenic systems critical in energy regulation. These systems include the hypo-thalamic anorexigenic neuropeptide melanocortin (MC) system.

The involvement of MC system in the regulation of food intake and body weight is well established, and recently it has become evident that the MC system may modulate the effects of 5-HT drugs on rodent feeding behavior (Heisler et al. 2002, 2003). Heisler et al. (2006) demonstrated the role of downstream melanocortin 4 receptors (MC4R) in mediating 5-HT-induced hypophagia. Activation of both 5-HT2C and 5-HT1B receptors produces hypophagia by promoting the release of the endogenous agonist and inhibiting the release of the endogenous antagonist of the MC4R receptor. This effect appears dependent on three mechanisms. First, 5-HT inhibits orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus via 5-HT1B receptor activation. This inhibits the releases of the MC4R antagonist AgRP. Second, activation of axonal 5HT1B receptors on AgRP neuronal projections also decreases their inhibitory effect on adjacent anorexigneic pro-opiomelanocortin (POMC) neurons. This promotes the release of the MC4R agonist alpha-melanocyte stimulating hormone (a-MSH). Finally, as previous studies have shown, 5-HT also activates these anorexignic POMC neurons via activation of 5-HT2C receptors again promoting the release a-MSH. These data appear to confirm that the hypothalamus, specifically the MC system, is a key site of integration between the episodic signals via 5-HT and tonic signals via leptin (Halford and Blundell 2000). A recent study has uncovered a novel central 5-HT2C receptor pathway regulating physiologic fasted and fed motor activities, which may represent an integrated mechanism linking feeding behavior and gastrointestinal (GI) motor activities through the gut-brain axis (Fujitsuka et al. 2009). Indeed, 5-HT2C receptor seems to have also a major role through changes of endogenous ghrelin that are closely associated with feeding behavior. Therefore, a functional divergence of central 5-HT2C receptor pathway regulating physiologic GI motor activities that is different from that controlling food intake is likely to exist (Fig. 17.1).

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