Endocannabinoids in the Regulation of Appetite and Body Weight T
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Review 297 Endocannabinoids in the regulation of appetite and body weight T. C. Kirkham The discovery of cannabinoid receptors, together with ingesta. Moreover, there is strong evidence of an the development of selective cannabinoid receptor endocannabinoid role in energy metabolism and fuel antagonists, has encouraged a resurgence of cannabinoid storage. Recent developments point to potential clinical pharmacology. With the identification of endogenous benefits of cannabinoid receptor antagonists in the agonists, such as anandamide, scientists have sought management of obesity, and of agonists in the treatment of to uncover the biological role of endocannabinoid other disorders of eating and body weight regulation. systems; initially guided by the long-established actions of Behavioural Pharmacology 16:297–313 c 2005 Lippincott cannabis and exogenous cannabinoids such as D9-tetra- Williams & Wilkins. hydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in Behavioural Pharmacology 2005, 16:297–313 appetite, eating behaviour and body weight regulation. Keywords: eating, feeding, obesity, incentive, reward, cannabis, rimonabant, It is now confirmed that endocannabinoids, acting at anorexia brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with School of Psychology, University of Liverpool, Liverpool, England. more established orexigenic and anorexigenic signals. Sponsorship: The author’s research is supported by the United Kingdom Key structures such as the nucleus accumbens and Biotechnology and Behavioural Sciences Research Council. hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity Correspondence and rtequests for reprints to Professor T.C. Kirkham, School in these regions varies in relation to nutritional status of Psychology, University of Liverpool, Eleanor Rathbone Building, Bedford Street South Liverpool, L69 7ZA, England. and feeding expression. Behavioural studies indicate e-mail: [email protected] that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of Received 13 June 2005 Accepted 26 July 2005 Cannabinoids, endocannabinoids and Two main cannabinoid receptors subtypes have been cannabinoid receptors identified. The CB1 receptor is widely distributed within The appetite-stimulating action of the cannabis plant the central nervous system and many peripheral tissues (Cannabis sativa) and its extracts has been documented for Devane et al., 1988; Matsuda et al.,1990.TheCB2 receptor many centuries (Abel, 1975; Kirkham and Williams, was until recently considered not to be significantly 2001a). This effect appears to be largely attributable to expressed in the central nervous system, being localized D9-tetrahydrocannabinol (THC), one of a large family of primarily in immune cells (Munro et al.,1993;Mackie, related ‘cannabinoid’ molecules first characterized in the 2005); however, there is new evidence for its expression 1960s (Gaoni and Mechoulam, 1964; Mechoulam et al., within brain neurons and glia (Onaivi et al.,2005).Bothof 1970). The physiological basis for the efficacy of plant- these are cell membrane receptors belonging to the G- derived cannabinoids in people has now been explained protein-coupled family of receptors (GPCR; Howlett, by the discovery within mammalian systems of cannabi- 2005). There is also growing evidence to support at least noid receptors and their endogenous ligands, the one other, non-CB1/non-CB2 cannabinoid receptor sub- ‘endocannabinoids’ (Pertwee, 2005a). The psychoactive type, but genes encoding other receptors have not been effects of the exogenous cannabinoids are thus explained identified (Fride et al.,2003;Begget al.,2005;Pertwee, by their ability to mimic the neural actions of the 2005a). It is generally accepted that the predominant endogenous agonists. It is increasingly apparent that the behavioural effects of cannabinoids are mediated by brain changes in eating motivation associated with cannabis CB1 cannabinoid receptors. However, these receptors are intoxication, or the administration of THC, reflect a also expressed in gastrointestinal, adipose and hepatic crucial role for these endocannabinoid systems in the tissues, so linking the endocannabinoids to important normal processes governing appetite, ingestive behaviour, peripheral processes related to energy storage and energy metabolism and body weight. This review will metabolism that may also affect appetite (Cota et al., examine primarily the evidence supporting endocannabi- 2003; Osei-Hyiamen et al., 2005). The availability of noid involvement in the behavioural and motivational selective CB1 receptor antagonists has been the prime aspects of these processes. mover in driving research in this area. 0955-8810 c 2005 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 298 Behavioural Pharmacology 2005, Vol 16 Nos 5 & 6 The endocannabinoids are eicosanoid compounds, humans may be summarized briefly in relation to a few synthesized from arachidonic acid. The first of these key studies. substances to be identified was arachidonoylethanola- mine, now known as anandamide (Devane et al., 1992). For example, in an early study, Hollister (1971) examined Subsequently, 2-arachidonoylglycerol (2-AG) was isolated acute THC effects on the consumption of chocolate milk (Mechoulam et al., 1995; Sugiura et al., 1995), followed by shakes and found significantly increased intake, elevated the identification of the putative endocannabinoids hunger ratings and enhanced food appreciation. Over noladin ether (2-arachidonyl glyceryl ether), N-arachido- several years Foltin, Haney and colleagues have con- noyldopamine (NADA), and O-arachidonoylethanolamine ducted the most in-depth analyses, using a residential (virodhamine) (Hanus et al., 2001; Porter et al., 2002). laboratory setting (e.g. Foltin et al., 1986, 1988; Haney These substances are agonists at CB1 receptors, while et al., 1999, 2005; Hart et al., 2002). Early studies virodhamine is apparently a partial agonist that also has demonstrated substantial increases in daily caloric intake antagonist activity at the CB1 receptor (Porter et al., 2002; after cannabis smoke inhalation, primarily through an Howlett, 2004; Pertwee, 2005a). The neuromodulatory increase in the frequency and consumption of sweet actions of the endocannabinoids involve novel mechan- snack foods. It is likely, however, that these apparently isms that, as with the discovery of the endogenous opioid selective actions may be partly attributed to the peptides, are likely to revolutionize thinking about neural prevailing test conditions. For example, increased food regulation. Thus, endocannabinoids are thought to act intake was predominantly observed during social access primarily as retrograde signals: released by postsynaptic periods, suggesting a degree of social facilitation. By neurons, they bind to presynaptic heteroceptors to contrast, we have found that oromucosal application of modulate the release of inhibitory and excitatory THC will increase intake, but this effect is not restricted neurotransmitters through multiple GPCR-linked effec- to sweet foods, as the drug also significantly increased the tor mechanisms (Schlicker and Kathmann, 2001; Howlett size of savoury set meals. Moreover, these effects were et al., 2004; Vaughan and Christie, 2005). The metabolic obtained when volunteers were tested individually, pathways of anandamide and 2-AG have now been suggesting that cannabinoids can have broad effects on characterized in great detail, and we can anticipate that appetite that are not limited to specific flavours, food these pathways – together with endocannabinoid uptake types or the context in which food is available (Townson mechanisms – will complement receptors as targets for and Kirkham, unpublished observations). the pharmacological analysis of the physiological functions of these substances (Fowler et al., 2001; Di It is probable, although so far untested, that these actions Marzo et al., 2005). are CB1 receptor-mediated, since the broader psycholo- gical actions of cannabis in people are reversed by the Cannabinoids and human appetite selective CB1 antagonist rimonabant (SR141716; Huestis The established behavioural actions of cannabis and the et al., 2001). Finally, in addition to studies in healthy exogenous cannabinoids invited speculation that the individuals, a small number of clinical trials have been newly discovered endocannabinoids might be of impor- conducted to assess the possible benefits of cannabinoids tance to appetite processes. To date only anandamide and in the treatment of conditions involving wasting and 2-AG have been investigated to any significant extent appetite loss, such as cancer cachexia and AIDS. Although with respect to their actions on feeding behaviour, but it these trials were hampered by the nature of the seriously is clear that endocannabinoids do play a significant role in ill populations in which they were tested, beneficial behavioural and metabolic aspects of energy regulation. effects were uncovered. Notably, treatment with THC (generally as the synthetic form, dronabinol) leads to improvement in both appetite ratings and actual con- Despite recent discoveries, much of our theorizing about sumption levels; while weight loss is attenuated – with cannabinoid