HT Receptors Feeding Behavior and Body Weight in Rodents

The role of 5-HT in the control of appetite on the structure of rodent feeding behavior were first examined in a series of studies using the 5-HT releasing and reuptake-inhibiting drug fenfluramine (Blundell 1977). Fenfluramine produced reductions in caloric intake that corresponded to changes in feeding behavior normally brought about by ingestion, rather than hyperactivity, sedation, or malaise. Measurements

5ht2c Receptor Alzheimer

Fig. 17.1 Functional divergence in 5-HT2C receptor pathway. Serotonin (5-HT) inhibits feeding-stimulatory NPY/AgRP neurons through 5-HT1B receptor, while activating feeding-inhibitory POMC/CART neurons through 5-HT2C receptors. The primary effect by 5-HT receptor on energy metabolism requires downstream activation of MC4R. A novel 5-HT2C receptor pathway that regulates physiologic gastrointestinal (GI) motility, requiring sympathetic activity and leading to inhibition of ghrelin but not MC4R. 5-HT indirect agonist-selective serotonin reuptake inhibitors activate both 5-HT2C receptor pathways, but not the 5-HT1B pathway, for the anorexia and GI motor effects produced. AgRP agouti-related peptide, CART cocaine- and amphetamine-regulated transcript, DVC dorsal vagal complex, IML intermediolateral nucleus of the spinal cord, NPY neuropeptide Y, POMC pro-opiomelanocortin, SNS sympathetic nervous system (Reproduced from Fujitsuka et al. 2009. With permission)

Fig. 17.1 Functional divergence in 5-HT2C receptor pathway. Serotonin (5-HT) inhibits feeding-stimulatory NPY/AgRP neurons through 5-HT1B receptor, while activating feeding-inhibitory POMC/CART neurons through 5-HT2C receptors. The primary effect by 5-HT receptor on energy metabolism requires downstream activation of MC4R. A novel 5-HT2C receptor pathway that regulates physiologic gastrointestinal (GI) motility, requiring sympathetic activity and leading to inhibition of ghrelin but not MC4R. 5-HT indirect agonist-selective serotonin reuptake inhibitors activate both 5-HT2C receptor pathways, but not the 5-HT1B pathway, for the anorexia and GI motor effects produced. AgRP agouti-related peptide, CART cocaine- and amphetamine-regulated transcript, DVC dorsal vagal complex, IML intermediolateral nucleus of the spinal cord, NPY neuropeptide Y, POMC pro-opiomelanocortin, SNS sympathetic nervous system (Reproduced from Fujitsuka et al. 2009. With permission)

or meal number, meal duration, eating rate, and activity demonstrated that fenfluramine (and then latter the more selective isomer d-fenfluramine) reduced food intake without disrupting feeding behavior (Blundell 1977). Fenfluramine and d-fenfluramine were also found to adjust feeding behavior in a manner consistent with the operation of satiety (Blundell and Latham 1978, 1980; Blundell and McArthur 1981; Halford and Blundell 1993).

With the availability of selective serotonin reuptake inhibitors (SSRIs) it became clear that drugs that inhibited the reuptake of 5-HT such as the fluoxetine and ser-traline and as well as the serotoninegeric and noradrenergic reuptake inhibitors

(SNRI) sibutramine, produced similar changes in rodent feeding behavior. All of these drugs enhanced the behavioral satiety sequence (BSS) in rodents (a biobehav-ioral assay of drug action) indicating drug-induced hypophagic was associated with the natural development of satiety (Halford and Blundell 1996a, b; Halford et al. 1998; Clifton et al. 1989; Simansky and Viadya 1990; McGuirk et al. 1992). However, the 5-HT receptors underlying these satiety indicating behavioral effects remained to be elucidated.

5-HT receptor subtype agonists, antagonists, and knockout rodent strains have over time allowed researchers to identify the 5-HT receptors critical for satiety. To summarize these data, selective agonists of 5-HT1B and the 5-HT2C receptors have be shown to produce changes in feeding behavior consistent with the operation of satiety, notably the 5-HT1B receptor agonist CP-94 253, the preferential 5-HT1B/2C receptor agonists meta-chlorophenylpiperazine (mCPP) and trifluromethylphenylpiperazine (TFMPP), and the selective 5-HT2C receptor agonists (Halford and Blundell 1996a, b; Halford et al. 1998; Simansky and Viadya 1990; Lee and Simansky 1997; Lee et al. 2002). Importantly, drugs that have also been shown to agonize other 5-HT receptor subtypes, for example, DOI (5-HT2A/2C) or RU-24 969 (5-HT1A/1B), have been shown to disrupt the BSS by inducing hyperactivity, a critical side effect (Halford et al. 1998; Kennett and Curzon 1988a; Kitchener and Dourish 1994; Hewitt et al. 2002).

The importance of 5-HT1B and 5-HT2C in the control of rodent feeding behavior has also examined through the pharmacological challenge of 5-HT releasing and reuptake inhibiting drugs using selective receptor subtype antagonists. For d-fenfluramine in particular, strong evidence exists that drug-induced hypophagia is mediated by 5-HT1B and/or 5-HT2C (Clifton 1994; Neill and Cooper 1989; Samanin et al. 1989; Neill et al. 1990; Simansky and Nicklous 2002; Vickers et al. 2001). Similarly, whilst the effects of reuptake inhibitors are notorious difficult to block with antagonists (Wong et al. 1988; Grignaschi and Samanin 1992; Lee and Clifton 1992; Lightowler et al. 1996), the effects of fluoxetine are blocked by 5-HT1 and 5-HT2 antagonism, which also reverses the effect of fluoxetine on the BBS confirming the behavioral as well as the pharmacological specificity of the SSRIs' effect (Halford and Blundell 1996b). Antagonist studies have also demonstrated the importance of and 5-HT2C receptor subtypes in the hypophagic effects of the anti-obesity drug sibutramine (Halford et al. 2007; Jackson et al. 1997). In conclusion, antagonist studies demonstrate that the effects of 5-HT promoting drugs on both intake and behavior are mediated by 5-HT1 and 5-HT2 receptors, the effects of d-fenfluramine specifically by 5-HT1B and 5-HT2C receptor subtypes.

Finally, the key role of 5-HT1B and the 5-HT2C receptors in the hypophagic effects of endogenous 5-HT has also been demonstrated using knockout mice models (see Chap. 4). Mice lacking functional 5-HT2C receptors display marked hyperphagia leading to the development of obesity (Tecott et al. 1995; Nonogaki et al. 2003). These mice were also partly resistant to d-fenfluramine-induced hypophagia (Vickers et al. 1999), confirming the role of this receptor subtype in fenfluramine-induced hypophagia. Additionally, 5-HT1B receptor knockout mice are significantly heavier than wild types (Bouwknecht et al. 2001), an effect associated with significantly greater food consumption.

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