A combination of central and peripheral mechanisms control food intake. Indeed, hypothalamic nuclei and the brainstem act as input stations for hormonal and gastrointestinal information (10,11). Furthermore, peripheral satiety factors such as cholecystokinin (CCK) activate CCK1 receptors on vagal afferents, which transmit signals to hindbrain nuclei such as the nucleus tractus soli-tarius (NTS). The NTS in turn communicates with several hypothalamic nuclei, which play critical roles in appetite regulation. In addition, adipose tissue secretes the hormone leptin, which enters the CNS and stimulates the arcuate nucleus within the hypothalamus. Leptin appears to be the main signal via which the hypothalamus senses nutritional states and modulates food intake. Leptin directly affects neurons in which either the anorexigenic (appetite-reducing) peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) or the orexigenic (appetite-stimulating) peptides neuropeptide Y (NPY) and agouti-related protein (AGRP) are co-localized. The NPY/AGRP-expressing neurons increase feeding, while those expressing POMC/CART inhibit feeding.
The stimulatory effects of cannabis extracts on human appetite have been anecdotally known for over hundreds of years. A9-THC and other exogenous cannabinoid agonists also induce hyperphagic effects under laboratory conditions in most human and animal models (61-64), but no effect (65) or a reduction in food intake (66) has also been reported. In addition, the cannabinoid CBi receptor antagonist SR141716A (Rimonabant) suppresses feeding in animals (67,68) and is currently under phase II clinical trials as an appetite-suppressing agent. The design of acute food-intake studies generally includes feeding rodents (e.g., rats) for 1 h at the onset of dark period in their home cages. Thereafter, any remaining food is removed and different groups of animals are treated with varying doses of a cannabinoid agonist or antagonist. Approximately an hour or so later, each animal is placed in an observation chamber with access to preweighed food and water, and its feeding and other behaviors are recorded. At the end of the test, each animal is returned to its home cage and food and water intake are determined by weighing the remaining food (plus spillage) and water (69). Cannabinoid agonists or antagonists are administered either peripherally (e.g., orally  or subcutaneously ) or via central injections through implanted cannulae in specific brain loci such as the ventromedial hypothalamus (70) or the nucleus accumbens shell (71). Although earlier studies have mainly been confined to direct measurement of food and water intakes, more recent published studies have additionally utilized video recording techniques to measure several aspects of feeding behavior followed by their subsequent analysis via commercial software (e.g., the Observer, Noldus InformationTechnology). Thus, these studies have recorded numerous additional behaviors such as eating (may consist of biting, gnawing, or swallowing food), drinking (licking at the water bottle spout), rearing, grooming (scratching, licking or biting of coat), sniffing, locomotion, resting/inactive, or sleeping (69). On the other hand, in chronic cannabinoid exposure studies, only measurement of daily food and water intake is generally carried out (e.g., ref. 67). The effects of cannabinoid CB1 receptor ligands on feeding are summarized (2) as:
1. A9-THC and other synthetic cannabinoids reliably induce hyperphagia and increase food intake in laboratory animals (61-64). These hyperphagic actions are mediated via cannabinoid CB1 receptors since they are selectively blocked by the cannabi-noid CB1 receptor antagonist SR141716A but not with the CB2 antagonist SR 144258 (71).
2. Most studies indicate that SR141716A by itself suppresses appetite and food intake in rodents (e.g., refs. 73 and 74), which can lead to a reduction in body weight (67). In addition, CB1 receptor knockout mice eat less and are leaner than their wild-type littermates (19,75). These findings indicate an important role for endocannabinoids in the control of feeding.
3. Administration of either endocannabinoids (2-AG or anandamide) induces overeating in laboratory animals in a SR141716A-sensitive manner (70-72,76-78). Endocannabinoids are implicated in appetite and body weight regulation.
4. Leptin administration suppresses hypothalamic endocannabinoid levels in normal rats, while genetically obese, chronically hyperphagic rodents express leptin-reversible, elevated hypothalamic anandamide and 2-AG levels (19). Moreover, fasting seems to increase levels of both anandamide and 2-AG in the limbic fore-brain and, to a lesser extent, of 2-AG in the hypothalamus, whereas in fed animals the hypothalamic content of 2-AG declines (72). However, another study has shown that while food deprivation failed to alter anandamide levels in whole brain, hunger did increase intestinal anandamide content, which normalized following feeding (79).
5. Cannabinoid CBx receptor markers are found in epidydimal fat pads (75) and are co-expressed in hypothalamic neurons that contain neuropeptides known to modulate food intake such as CART (75). The cannabinoid system appears to be an essential endogenous regulator of appetite and energy balance, which acts via both central orexigenic as well as peripheral lipogenic mechanisms (72,75,79).
6. Both cannabinoid CBx/CB2 receptor agonists (A9-THC [Dronabinol] and nabilone [Cesamet]) and selective cannabinoid CBx receptor antagonists (e.g., SR141716A [Rimonabant]) can be clinically used to respectively increase and decrease appetite (1).
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