NEUROPHARMACOLOGY OF HUMAN APPETITE EXPRESSION Jason C.G. Halford * and Joanne A. Harrold Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of Psychology, University of Liverpool, Liverpool, United Kingdom The regulation of appetite relies on the integration of numerous episodic (meal) and tonic (energy storage) generated signals in energy regulatory centres within the central nervous system (CNS). These centers provide the pharmacological potential to modify human appe- tite (hunger and satiety) to increase or decrease caloric intake, or to normalize aberrant eating behavior. With regard to obesity, the sati- ety enhancing anti-obesity drug sibutramine has proved effective at reducing body weight. Additionally, the endocannabinoid CB 1 antag- onist rimonabant has recently been approved for use in Europe (but not in the US). A 5-HT 2C agonist lorcaserin is also currently under- going large-scale clinical trials, but the effect of the drug on human appetite is unknown as yet. Appetite enhancing drugs such as mages- trol acetate and dronabiol are currently used to promote weight gain. Finally, sibutramine, selective serotonergic reuptake inhibitors such as fluoxetine and some anti-epileptic drugs have all been used to nor- malise aberrant eating behaviour. All these drugs act by modifying the expression of human appetite. An assessment of a drug’s effects on caloric intake and feelings of hunger and satiety is neces- sary before they can be considered for clinical use. ' 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:158–164. Key Words: appetite; sibutramine; rimonabant; lorcaserin; dronabiol; food-intake; satiety; hunger APPETITE EXPRESSION H uman eating behavior, like that of other omnivores, has a distinct structure and can be characterized by discrete eating occasions (meals and snacks). This structure is a response to environmental demands but its expression is also underpinned by the numerous systems which inform the brain of the body’s energy status [Blundell, 1991]. These systems can be stimulatory (provoke and/or sustain eat- ing events, termed orexigenic), or inhibitory (prevent or fore- shorten eating events, termed anorexigenic). These systems can also be classed into either episodic or tonic signals [Halford and Blundell, 2000]. Episodic and tonic systems both contribute to the expression of feeding behavior, determining when and how much is eaten. They differ in the nature of the input and the duration of their effects, but fluctuations in both produce strong feelings of either hunger or satiety. Epi- sodic signals are those short-term inputs generated by meal intake, while tonic signals are those generated by the body’s constant metabolic need for energy. Both provide input into the CNS appetite regulating systems which are critical to long-term weight regulation. From the perspective of human appetite, it is worth- while considering the psychological experiences determining meal by meal eating behavior. Hunger can be defined as the motivation to seek and consume food. Conversely, the proc- esses that bring episodes of eating behavior to an end are termed satiation. These ultimately lead to the state of satiety in which the hunger drive, and consequently eating behavior, is inhibited [Blundell, 1991]. Despite the intimate link between meal intake and experiences of hunger and satiety, appetite is derived from the daily flux of physiology associated with meals and eating behavior. Appetite also responds to processes of energy storage and the status of the body’s energy stores (e.g., indicators of glucose metabolism, and fat storage). Blood carries various substances (insulin, glucagon, and leptin) generated by nutrient metabolism and energy storage from organs such as the liver, the pancreas and in adipose tissue layers [Mohamed-Ali et al., 1998]. A key adipose signal is the ob-protein leptin, named from the Greek ‘‘leptos’’ meaning thin [Zhang et al., 1994; Campfield et al., 1995; Halaas et al., 1995]. In general, circulating levels of leptin appear to reflect the current status of body fat deposition, and increase with the level of adiposity (demonstrating the responsiveness of en- dogenous leptin to weight gain and energy status) [Maffei et al., 1995; Considine et al., 1996]. Its absence causes vora- cious appetite and extreme adiposity [Farooqui et al., 1997; Montegue et al., 1997]. Table 1 shows key peripheral episodic and tonic signals as well as CNS orexigenic and anorexigenic. CNS CONTROL: OREXIGENIC AND ANOREXIGENIC SYSTEMS The CNS receives information generated by the sensory experiences of consumption (sight, smell, taste, and mouth feel), and from the periphery indicating the ingestion, absorp- *Correspondence to: Jason C.G. Halford, Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of Psychology, Eleanor Rathbone Building, Bedford Street South, University of Liverpool, Liverpool L69 7ZA, UK. Liverpool Obesity Research Network (LORN) www.liv.ac.uk/obesity. E-mail: j.c.g.halford@liverpool.ac.uk Received 27 May 2008; Accepted 27 May 2008 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddrr.20 DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 14: 158 – 164 (2008) ' 2008 Wiley -Liss, Inc.