Several nuclei in the hypothalamus and brainstem act as input stations for hormonal and GI information and control several aspects of feeding (Halford and Blundell, 2000; Chiesi et al., 2001). During and after a meal, several peripheral satiety factors (such as cholesystokinin [CCK], bombesin, gastrin-releasing peptide, and glucagons) are released from GI secretory cells in response to the physical and chemical presence of food in the GIT. Of these factors, CCK is thought to activate CCK1 receptors on vagal afferents that transmit signals to the hindbrain, particularly to the NTS. The NTS communicates with several hypothalamic nuclei that play critical roles in appetite regulation (Halford and Blundell, 2000; Broberger and Hokfelt, 2001; Chiesi et al., 2001). In addition, the hormone leptin, which is secreted from adipose tissue, enters the CNS and stimulates the arcuate nucleus within the hypothalamus. Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake. Leptin directly affects neurons in which either the anorexigenic (appetite-reducing) peptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) or the orexigenic (appetite-stimulating) peptides neuropeptide Y (NPY) and agouti-related protein (AGRP) are colocalized. These two neuronal populations project in parallel into other brain centers where they exert antagonistic actions on food intake. Thus, the NPY/AGRP expressing neurons increase feeding, whereas those that express POMC/CART inhibit feeding. The stimulatory effects of cannabis products on appetite has been anecdotally known for centuries. A9-THC as well as other exogenous cannabinoids also produce hyperphagic effects under laboratory conditions in most human and animal models (Kirkham and Williams, 2001; Croxford, 2003; Berry and Mechoulam, 2002, Mattes et al., 1994); however, no effect (Graceffo and Robinson, 1998) or a reduction in food intake (Miczek and Dixit, 1980) has been reported. The hyperphagia induced by A9-THC is cannabinoid CB1-receptor mediated as it is reversed by the selective CB1 antagonist SR141716A and not by SR144528, an antagonist for the CB2 receptor (Williams and Kirkham, 2002). In addition, following temporary food restriction, CBj knockout mice eat less than their wild-type littermates (Di Marzo et al., 2001). In line with the latter findings, most but not all studies indicate that SR141716A suppresses appetite and food intake in rodents (Arnone et al., 1997; Simiand et al., 1998; Colombo, Agabio, Diaz, et al., 1998; Williams and Kirkham, 1999; Koch and Werner, 2000, Jamshidi and Taylor, 2001). These findings suggest an important role for endocannabinoids in feeding behaviors. Indeed, both anandamide and 2-AG induce overeating in laboratory animals in an SR141716A-sensitive manner (Williams and Kirkham, 1999; 2001; Hao et al., 2000; Jamshidi and Taylor, 2001). Leptin administration reduces food intake, in part, via the inhibition of the actions of the cited orexigenic neurotransmitters (Ammar et al., 2000). In regard to endocannabinoids, elevated hypothalamic levels of anandamide and 2-AG have been found in hyperphagic, genetically obese rodents with defective leptin signaling (Di Marzo et al., 2001). Moreover, leptin treatment was shown to reduce the hypothalamic anandamide content. Paradigms with palatable rich diets used to induce obesity in rats have been shown to reduce cannabinoid CB1 receptors in several brain areas, including those loci involved in the hedonic aspects of eating (e.g., nucleus accumbens and hippocampus) (Harrold et al., 2002). However, the CB1 receptor density was not altered in the hypothalamus of these obese rats. Taken together, the discussed data strongly suggest that the endocannabinoids' contribution to the stimulation of feeding and enhancement of appetite occurs via the activation of cannabinoid CB1 receptors. The rationale for the potential use of CB1 receptor ligands in the clinic is clearly based on observations that A9-THC (Dronabinol or Marinol) improves appetite and food intake in acquired immunodeficiency syndrome (AIDS) and cancer patients suffering from anorexia/cachexia (Beal et al., 1995; 1997; Mattes et al., 1994; Nelson et al., 1994; Struwe et al., 1993), whereas SR141716A (Rimonabant) is undergoing clinical trials as an appetite suppressant.
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