Treat Endocrinol 2004; 3 (6): 345-360LEADING ARTICLE 1175-6349/04/0006-0345/$31.00/0

2004 Adis Data Information BV. All rights reserved.

Endocannabinoid Receptor AntagonistsPotential for Obesity Treatment

Tim C. Kirkham1 and Claire M. Williams2

1 School of Psychology, The University of Liverpool, Liverpool, UK2 School of Psychology, University of Reading, Reading, UK

Obesity has been described as a global epidemic. Its increasing prevalence is matched by growing costs, notAbstractonly to the health of the individual, but also to the medical services required to treat a range of obesity-relateddiseases. In most instances, obesity is a product of progressively less energetic lifestyles and the over-consump-tion of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in thesearch for effective anti-obesity therapies, so far with limited success. An important part of the process ofdeveloping new pharmacologic treatments for obesity lies in improving our understanding of the psychologicand physiologic processes that govern appetite and bodyweight regulation. Recent discoveries concerning theendogenous cannabinoids are beginning to give greater insight into these processes. Current research indicatesthat endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possiblymediating the craving for and enjoyment of the most desired, most fattening foods. Additionally, endocannabi-noids appear to modulate central and peripheral processes associated with fat and glucose metabolism. Selectivecannabinoid receptor antagonists have been shown to suppress the motivation to eat, and preferentially reducethe consumption of palatable, energy-dense foods. Additionally, these agents act to reduce adiposity throughmetabolic mechanisms that are independent of changes in food intake. Given the current state of evidence, weconclude that the endocannabinoids represent an exciting target for new anti-obesity therapies.

There is a growing prevalence of obesity in Western society, toward a level of daily consumption that may far exceed ourbodies’ caloric requirements.[6,7] In addition, as levels of physicaland increasingly also in those regions of the world with developingexercise have fallen, changing eating styles have accommodatedindustrial economies.[1,2] Obesity is associated with a wide spec-the over-consumption of a wide variety of manufactured foods thattrum of diseases, such as type 2 diabetes mellitus, cardiovascularappeal to our pre-programmed susceptibility to temptation; mealsmorbidity, and cancer, which together constitute a significant andare all too regularly supplemented by snacks that in themselvesgrowing burden on our health resources.[3-5] For the most part, thewould provide sufficient calories for our daily needs. Increasinglyunderlying causes of this global rise in bodyweight and its associ-across the world, and most notably in the US and the UK, chronicated problems lie in our evolutionary history and cultural develop-over-consumption of readily available, calorically dense, andment; there are only very rare occurrences of genetic anomalieshighly palatable foods has already resulted in a significant propor-with phenotypes that include overeating or significant accretion oftion of the population becoming overweight or obese.adipose stores.[6-9] Evolution and the pre-agricultural struggle for

survival programmed our species to maximize all opportunities to While logic tells us that the prevalent imbalance betweeneat, to be susceptible to food variety, to derive especial pleasure energy expenditure and consumption could be best attackedfrom high-energy foods, and to be particularly efficient at storing through encouraging more exercise, the natural motivation to eatexcess calories as fat in preparation for times of famine. Modern and the pleasure derived from eating is rather more compellingcultures are exemplified by progressively more sedentary life- than the satisfaction to be derived from greater physical activity.styles and, while daily caloric intake may not always differ dra- Indeed, for many people, the lifetime accumulation of adiposematically from that of 30 or 40 years ago, the balance between stores itself represents a significant obstacle to weight reductionenergy intake and expenditure has certainly shifted substantially through exercise, even when combined with restricted consump-

346 Kirkham & Williams

tion. Consequently, there have been considerable efforts to devel- article, but so far none has led to effective clinical applica-op alternative methods of reducing the weight of the morbidly tions.[10,21,22]

obese, largely through pharmacologic treatments aimed at reduc-ing the individual’s motivation to eat. Such anti-obesity treatments 2. Targeting Appetitive Processesrepresent a potential multi-billion dollar market for the pharma-ceutical industry. However, despite extensive research programs In the light of the biologic imperatives to eat already discusseddedicated to this field over the past few decades, it is apparent that (and one’s own, everyday experience), the prevailing notion thatfew effective treatments have resulted.[10] In this article, we review our bodies and brains employ multiple, redundant, physiologicrecent developments in the field of cannabinoid-appetite research, satiation signals to limit our intake may seem misconceived. Ifand consider the potential of cannabinoid receptor antagonists in such factors were effective in restraining eating, it is unlikely thatthe treatment of obesity. obesity would now constitute the problem that it does. At best, one

might argue that if the multiplicity of putative satiety signals dohave a true physiologic role in appetite control, then they may be1. Pharmacologic Approaches to the Treatmentnecessary to confine the fundamental and prepotent drive to ensureof Obesitynutritional integrity. Similarly, orthodox homeostatic conceptual-izations of energy balance, whereby food intake is regulated byInitially, appetite-suppressant treatments consisted essentiallysystems that monitor consumption and the accretion of fat stores,of stimulants such as the amphetamines. However, the abusemay not adequately model actual human feeding behavior andpotential of such drugs naturally became an obstacle to theirweight change.prescription.[10,11] Amongst the more successful compounds was

As opportunistic, omnivorous feeders, humans continuouslyan amphetamine derivative, dexfenfluramine, which was found todemonstrate their ability to over-consume – even to the point ofsuppress appetite while being largely devoid of the abuse potentialdiscomfort – in the face of a tantalizing array of palatable foods.of the stimulants.[12] Research from the 1970s onwards indicatedAnimal experiments also provide many instances of the failure ofthat dexfenfluramine exerted its psychologic actions by facilitatingsatiation models. For example, preventing the entry of food intobrain serotonergic activity associated with physiologic processesthe stomach (using esophageal fistulae), or the passage of foodmediating the satiation, or termination, of eating.[13,14] Dexfen-from the stomach into the intestinal tract (by pyloric occlusion orfluramine (and the neurochemically less selective d,l-fen-gastric fistulae), does not necessarily alter the normal patterning orfluramine) had a short commercial life due to occasionally fatalstructure of meals.[23-25] Sham feeding studies (in which food isadverse effects.[15] Nevertheless, the effectiveness of dexfen-recovered directly after ingestion, before it can reach receptors influramine spawned research into other serotonergic compoundsthe gut that might be linked to the generation of peripheral satietythat can suppress eating by promoting feelings of fullness, therebysignals) indicate the power and primacy over intake of psycholog-limiting meal size. Recently, emphasis has shifted to selectiveic factors such as conditioning and the immediate, pleasurableserotonin reuptake inhibitors.[10] For example, fluoxetine can sup-orosensory properties of food.[23,24,26,27] For example, in normalpress appetite and promote weight loss in obese individuals.[16]

laboratory rats, simple manipulations that enhance food palatabili-However, these beneficial effects appear to be transient, with long-ty (such as the addition of water to a powdered laboratory diet toterm treatments failing to sustain weight loss or even inducingmake a paste) can provoke daily consumption levels that farweight gain.[17] Augmenting noradrenergic function has also beenexceed those normally observed with the routine, dry, relativelylinked to weight loss, and a popular anorectic strategy was thebland diet, even though the nutritional complement of the twocombination of fenfluramine with the noradrenergic reuptake in-diets are identical.[28] In this instance, in spite of the considerablehibitor phentermine.[10] Latterly, this approach has been exploitedover-consumption of the more palatable food, the mechanismswith the availability of combined serotonin-norepinephrineproposed to monitor the passage and absorption of nutrients alongreuptake inhibitors.[18] A recently approved anti-obesity drug inthe gastrointestinal tract fail to impose any compensatory controlthis class is sibutramine, which combines appetite suppressionover eating. Availability of a desirable food is thus sufficient towith beneficial thermogenic effects; but health concerns may alsogenerate counter-regulatory over-consumption.restrict its use.[19] More generally, research has primarily targeted

an increasing list of putative hormonal and neurochemical signals The simple deduction from such observations is that the plea-believed to promote the satiation of eating and feelings of satie- sure derived from the taste, texture, flavour, and even the tempera-ty.[20] The variety of these candidate satiety signaling targets, many ture of food (orosensory reward in jargon terms) is by far the mostof them peptides, is too large for extensive discussion in this influential determinant of intake. Importantly, what is often de-

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Endocannabinoid Receptor Antagonists 347

scribed as a simple process of satiation – from the initial impulse to a family of G-protein-linked, cell-surface cannabinoid recep-eat, to the point of no longer being willing to eat a given food or tors.[36-38]

meal – does not give rise to an incontrovertible state of satie- Two main cannabinoid receptor subtypes have been identi-ty.[29,30] If we add variety, more food will be eaten than if only a fied.[39] These are classified as a ‘central-type’ CB1 receptor,single food item is provided. Even after a large meal, further widely distributed within the CNS and many peripheral tissues,provision of a particularly palatable food will engender yet more and a ‘peripheral-type’ CB2 receptor, which is not significantlyeating (the ‘dessert effect’). Additionally, we are all familiar with

expressed in the CNS.[40] It is generally agreed that the behavioralthe ability of the sight or smell of a favorite food to engender a

effects of cannabinoids are mediated by brain (CB1) cannabinoidstrong desire to eat even though eating may previously have been

receptors and, despite their wide distribution, the regional localiza-far from our thoughts.[31] These factors render simple satiety signal

tion of receptors corresponds closely with their behavioral ef-models somewhat less than adequate to account for human feeding

fects.[41,42]behavior and our tendency to over-consume.

The existence of specific receptor sites that can mediate theIn view of these considerations we can see the limitations ofeffects of plant-derived exogenous cannabinoids indicated thedrug treatments designed specifically to facilitate satiationexistence of chemicals produced within mammalian tissues, forprocesses. Unless accompanied by strict dietary control or behav-which the cannabinoid receptors are the target. That is, endoge-ior modification, satiety-enhancing drugs may not prevent the easynous ligands that compounds such as THC can mimic in order toover-consumption of calories from a few mouthfuls of forbidden

foods. Moreover, if temptation cannot be resisted, the initial induce their various effects. The 1990s saw the isolation of the firstpositive orosensory experience of a palatable food will accentuate ‘endocannabinoid’.[43] This compound, arachidonylethanolamide,our appetite and promote further consumption. Sadly, we need eat which is synthesized within brain tissue and binds with highonly a few hundred calories more than we expend each day for affinity to CB1 receptors, was named anandamide – from ‘anan-significant long-term bodyweight accumulation to occur, or to da’, a Sanskrit word meaning inner bliss. Subsequently, the searchnegate the generally modest weight loss produced by recently for additional endogenous ligands selective for the CB2 cannabi-prescribed appetite suppressants.[10]

noid receptor led to the identification of 2-arachidonoyl glycerolThus, we might seek a more effective focus for weight-reduc- (2-AG).[44,45] Although it exhibits a lower affinity for CB1 recep-

ing pharmacotherapy: our innate responsiveness to the incentive tors than anandamide, evidence suggests that 2-AG is present inand sensory properties of food may well be the key. It is in this the brain at higher levels than anandamide and is a full agonist atcontext that the latest developments in cannabinoid pharmacology CB1 receptors.[45]

are of particular interest, specifically the availability of the can-Both of these substances fulfill the necessary criteria for classi-nabinoid receptor antagonist rimonabant, which appears to possess

fication as neuromodulators: they are synthesized from arachidon-a novel profile of potentially therapeutic properties.[32] In theic acid through distinct biosynthetic routes; are released fromfollowing sections we will address the evidence relating endoge-neurons in response to membrane depolarization and calciumnous cannabinoid systems to the physiologic control of appetite,influx; have specific uptake mechanisms; and are hydrolyzed by aand discuss the potential of cannabinoid interventions to assist inselective fatty acid amide hydrolase.[46-48] Cannabinoids are alsoweight-loss programs.closely related to the arachidonic acid-derived eicosanoids, andmay have overlapping physiologic functions.[49,50] Other candidate3. Cannabis and Endogenous Cannabinoidsendocannabinoids have since been characterized, including no-ladin ether and virodhamine,[51-53] but anandamide and 2-AG areHumankind has been familiar with the psychotropic and medic-considered to be the primary ligands at CB1 and CB2 receptors,inal actions of Cannabis sativa (marijuana) for thousands of years,with both substances capable of exerting THC-like effects inbut it is only in the past decade that real progress has been made inanimal behavioral models.[43,54] Importantly, amphibian, rodent,understanding the cellular mechanisms underlying those ac-and human CB1 receptors show a high degree of homology.tions.[33] The psychoactive compounds contained in cannabis wereTogether with the occurrence of the endocannabinoids in a numberfirst characterized in 1964, when Gaoni and Mechoulam[34] isolat-of phylogenetically diverse species, a high degree of evolutionaryed ∆9-tetrahydrocannabinol (THC) and a group of related ‘can-conservation of cannabinoid signaling systems indicates that theynabinoid’ molecules.[35] Subsequently, it was demonstrated thatshould play an important physiologic role in vertebrate brainthese cannabinoids exert their effects via specific binding sitesfunction.[55,56]within the CNS and peripheral tissues. We now know that there is

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348 Kirkham & Williams

4. Cannabinoids and the Stimulation of Appetite observing substantial increases in daily caloric intake after canna-bis smoke inhalation, these workers reported that this excess wasprimarily obtained by an increase in the frequency and consump-In searching for the physiologic roles of the endogenous can-tion of snack foods, rather than of the set meals provided each day.nabinoids, there are many clues from the long-documented ac-Specifically, with ad libitum food access, marijuana increasedcounts of the effects of marijuana. Amongst the wide spectrum oftotal food intake by doubling the number of snacks, particularly ofmarijuana’s psychologic effects is the tendency of the drug tosweet, solid items such as candy bars, cookies, and cakes. Thestimulate eating and create what can be described as a voraciousintake of sweet drinks (e.g. cola, fruit juice) or savoury solid itemsappetite, known colloquially by cannabis users as ‘the(e.g. potato chips) was less affected. Similar effects of THC onmunchies’.[57] Following the characterization of the exogenous,food selection have been reported by Mattes et al.,[67] with in-plant-derived cannabinoids, it was soon demonstrated that THCcreases in energy intake derived principally from increased snackwas a particularly potent ‘orexigenic’ agent. This capacity toconsumption rather than self-selected meals.stimulate eating ultimately led to the drug’s clinical application in

Greater light has been thrown on the motivational specificity ofthe treatment of appetite loss and wasting in patients with cancercannabinoids through the use of animal models. The most com-and AIDS.[58-60]

monly used laboratory species, the rat, is a useful model as it hasWe are still awaiting well controlled, systematic analyses of thesimilar opportunistic, omnivorous tendencies and responsivity topsychologic and physiologic correlates of the hyperphagic actiontasty foods as do humans. In one of the first studies to demonstrateof THC in humans, not least because of the continuing politicalcannabinoid hyperphagia in rats, Brown et al.[68] found that low,and legal impediments that discourage research into cannabis.orally administered doses of THC increased the intake of food andHowever, there is now sufficient evidence to indicate that cannabi-particularly a palatable sucrose solution. Significantly, Anderson-noid-induced eating reflects the involvement of endocannabinoidsBaker et al.[69] reported that hyperphagia could be induced byin the normal regulation of appetite and feeding behavior. Indirect injection of THC into the lateral or ventromedial hypotha-addressing the empirical evidence from human and animal studies,lamic nuclei of freely feeding rats, brain areas that are heavilywe will initially focus on data that specifically relate to theimplicated in the physiologic regulation of appetite.[70]motivational factors described in section 2 (food incentive and

orosensory reward) and that represent rational targets for new anti- More recently, we demonstrated that oral THC was able toobesity treatments. induce particularly potent effects in animals that were thoroughly

Consistent themes that emerge in the marijuana-feeding litera- satiated by voluntary consumption of large amounts of palatableture are those of enhanced desire to eat, increased sensitivity to the food prior to drug administration. Thus, the most effective dose ofsensory properties of foods, and apparently preferential effects on THC (1 mg/kg) produced a >4-fold increase in consumption over apreferred, highly palatable foods (although as described below, it 1-hour test.[28] This effect was far greater than any previouslyis now clear that food does not have to be very palatable for reported with the drug, and comparable to the effects of the mostcannabinoid hyperphagia to be induced).[57] In 1970, Tart[61] de- potent orexigenic compounds previously reported. The ‘pre-satia-scribed marijuana users’ subjective accounts, noting such descrip- tion’ procedure was intended to ensure low baseline intake levelstions as: “taste sensations take on new qualities”; “I enjoy eating and so maximize our ability to detect drug-induced eating, but thevery much and eating a lot”; “if I try to imagine what something potency of THC in this model has particular significance. Firstly, ittastes like, I can do so very vividly”; “I crave sweet things to eat, reinforces our earlier remarks about the capacity of humans (orlike chocolate, more than other foods”. In one of the first con- rats) to eat, even in the face of repletion and positive energytrolled studies with THC, Hollister[62] examined its acute effects balance. Well satiated, THC-treated animals not only over-con-on the consumption of chocolate milk shakes. The drug signifi- sumed compared with control animals, but their intake levels werecantly increased intake, consistently elevated hunger ratings, and actually comparable to those typically seen in hungry, food-enhanced food appreciation. Similarly, albeit in a less well con- deprived rats. Secondly, as the test food in these experiments wastrolled experiment, Abel[63] observed that inhalation of cannabis an ordinary, bland maintenance diet, our effects demonstrate thecigarettes led individuals to eat as many as 50 marshmallows, compelling nature of cannabinoid-induced eating, and indicate thecompared with only four by control individuals. probable importance of endocannabinoid systems in the normal

A series of more systematic studies into marijuana-induced instigation of appetite and eating motivation, irrespective of theeating have been conducted by Foltin et al.,[64,65] using a relatively food type. Supporting that role, our subsequent experiments havenaturalistic, residential laboratory in which volunteers were confirmed that THC hyperphagia is mediated by central CB1housed for periods of up to 25 days.[66] In addition to consistently cannabinoid receptors, as it is attenuated by the selective CB1

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Endocannabinoid Receptor Antagonists 349

receptor antagonist rimonabant (SR141716), but not by cerebroventricular administration in satiated or food-deprivedSR144258, a selective antagonist of the peripheral CB2 recep- rats.[82]

tor.[71] The notion of endocannabinoid involvement in the normal, An important aspect of early studies of rimonabant was anphysiologic regulation of appetite was further strengthened by apparent action of the drug to preferentially attenuate the intake ofstudies demonstrating that acute or chronic CB1-receptor blockade preferred, palatable foods – an effect observed in both rats andcan reliably suppress food intake in laboratory animals (see be- marmosets.[72,73] It should be noted that, although palatable foodslow), suggesting that tonic endocannabinoid activity may be a key are generally more susceptible to the anorectic actions of rimona-component in the neurochemical regulation of appetite.[72-74] bant and its analogs, CB1 receptor antagonists are also effective in

This possibility was crucially supported by our demonstration reducing the intake of less appetizing foods, such as the nutrition-that peripheral administration of the endogenous cannabinoid ally balanced but bland diets fed to laboratory animals (commonlyanandamide also stimulated feeding, albeit less potently than referred to as ‘lab chow’).[74,82,83] This fact supports the widerTHC.[75] Moreover, anandamide hyperphagia was prevented by generality of endocannabinoid involvement in feeding regulationrimonabant, while the CB2 antagonist SR144258 was without but, as we shall see in section 7, the greater susceptibility ofeffect, showing that the overeating was specifically mediated by palatable foods to CB1-receptor blockade has very specific impli-central-type CB1 receptors. Subsequently, anandamide-induced cations for understanding the role of endocannabinoids in motiva-eating in rodent models has been confirmed by other groups, with tional processes.very low peripheral doses[76,77] and after direct administration into In addition to acute treatments, several chronic studies havethe ventromedial nucleus of the hypothalamus.[78] More recently, been reported in which systemic antagonist treatments have in-we demonstrated that another endocannabinoid, 2-AG, will also duced reliable intake suppression. In most instances, tolerance toinduce eating in free-feeding rats, after either peripheral injection the drugs’ anorectic actions appears to develop after several days.or bilateral infusion into the shell region of the nucleus accumbens However, these treatments do produce significant, and persistent,(AcbSh).[79] Additionally, both anandamide and 2-AG will pro- reductions in bodyweight that are at least partly a consequence ofmote feeding when administered into the lateral hypothala- the initial reduction in food intake.[74,83-85] These studies and theirmus.[57,80] Importantly, both the hypothalamus and the AcbSh are implications for anti-obesity applications are discussed in morebrain regions that are firmly associated with eating motiva- depth in sections 10 and 11.tion,[70,81] and their sensitivity to the hyperphagic actions of Overall, the consequences of CB1-receptor blockade on feed-anandamide and 2-AG provides further confirmation of a key role ing behavior in these experiments suggest that tonic release offor endocannabinoids in the control of eating. endocannabinoids is influential in controlling eating in adult ani-

mals, but there are also indications that cannabinoid processes may5. Anorectic Actions of Cannabinoid be crucial to feeding in the earliest developmental stages. Thus,Receptor Antagonists Fride and colleagues[86-88] have provided evidence that the initia-

tion of suckling in neonates is cannabinoid dependent. FollowingComplementing the actions of cannabinoid receptor agonists the discovery that anandamide and 2-AG are present in animal and

are data showing that cannabinoid-receptor blockade can suppress human milk,[89] these workers investigated the influence of endo-feeding. The ability of a CB1 receptor antagonist to alter feeding cannabinoids on suckling behavior. They demonstrated that CB1-behavior by blocking the actions of endogenous agonists clearly receptor knockout mice fail to suckle during the first day afterimplicates endocannabinoid-mediated events in the normal ex- birth, and that rimonabant administration to healthy mouse pupspression of feeding behavior. Soon after the isolation of CB1 prevents suckling during the same critical 24-hour period, ancannabinoid receptors several selective antagonists were devel- effect with potentially fatal consequences that can be reversed byoped. One of the most influential of these has been the CB1 administration of cannabinoid receptor agonists.[86-88] A recentreceptor antagonist rimonabant, originally synthesized by Rinaldi- study by Matias et al.[90] has further demonstrated that maternalCarmona and colleagues.[32] As already described, rimonabant will nutritional status during gestation and lactation can significantlyattenuate the hyperphagic actions of exogenous and endogenous affect neonatal levels of brain endocannabinoids. Thus, restrictioncannabinoids.[75,78,79] However, even before endocannabinoid-in- of essential polyunsaturated fatty acids in the maternal diet, andduced feeding had been demonstrated, acute peripheral adminis- specifically of the endocannabinoid precursor arachidonic acid,tration of the drug was shown to reduce food intake in laboratory was shown to result in reduced hypothalamic anandamide levels inanimals.[72-74] More recently, reliable anorectic actions of rimona- the brains of weaning rat pups. Given the dependence of develop-bant, or its analog AM281, have been reported following intra- ing animals on polyunsaturated fatty acids from maternal blood

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350 Kirkham & Williams

during gestation, and milk in neonatal stages, weaning rats in this Early evidence that cannabinoid interventions modify appeti-study were likely to suffer from low availability of anandamide tive-incentive processes was provided by Gallate and McGre-precursors. An associated reduction in the bodyweights of these gor,[92] who found that rats will work harder to obtain palatableanimals might therefore imply deficits in feeding, and is again ingesta after administration of CB1 receptor agonists.[93,94] Con-suggestive of an important role for endocannabinoids in the regu- versely, antagonist treatments attenuate responding for food orlation of ingestive behavior. palatable solutions. Using more detailed behavioral analysis, we

observed the open-field behavior of satiated rats following admin-istration of THC and anandamide.[95] Under control conditions rats

6. Motivational Targets of Cannabinoids:generally displayed little motivation to eat, with eating occurring

Interactions with Hunger and Food Palatabilityonly after many minutes engaged in exploratory behaviors. Bycontrast, both exogenous and endogenous cannabinoid treatments

As we have already emphasized, the subjective effects of stimulated feeding almost as soon as food became available.cannabis or THC in humans, and some aspects of the animal data, Crucially, once initiated, the subsequent pattern of feeding behav-have led to the speculation that endocannabinoids are implicated ior displayed by cannabinoid-treated rats in the open field isin the hedonic evaluation of ingesta. Put simply, it has been argued identical to that of untreated rats feeding freely in their homethat the pleasure we obtain from food is mediated to some signifi- cages.[57,95] Similarly, examination of the meal patterns of freelycant extent by the activity of brain endocannabinoids.[73] The feeding rats after peripheral or central treatment with anandamidereader is cautioned that this hypothesis was initially proposed on or 2-AG reveals that meal onset is consistently advanced.[57,95,96]

the basis of less than extensive animal experimentation, and was Such findings imply that stimulation of CB1 receptors enhanceslargely justified by essentially anecdotal accounts of the effects of the salience or incentive value of food, and hence increases thecannabis in humans. Just as we have criticized the prevailing motivation to approach food and begin eating. We thus begin tonotions of satiety mechanisms and energy homeostasis, we urge see the development of a model that links endocannabinoidscaution in extrapolating too far from the changes to food intake, directly to the processes that lead to the generation of appetite andoften measured over arbitrary intervals, in animal models after the initiation of feeding.CB1 receptor agonist or antagonist administration. There is only

To some extent, the effect of cannabinoid receptor agonists onso much that can be inferred from the measurement of changes ineating latency – the apparently greater urgency to eat after can-the weight of food remaining in rat cages after 1 hour or 24 hours;nabinoid administration – are similar to those that might be seen inand, at best, inferences made from animal experiments about thefood-deprived animals. In line with this proposition, CB1-receptormotivational specificity of cannabinoid actions must be con-knockout mice are distinguished from their wild-type littermatesstrained by the limited experimental contexts. Since we are stillby a reduced hyperphagic response to fasting.[97] Further supportawaiting detailed analyses of the psychologic correlates of can-for the notion comes from our examination of interactions betweennabinoid interactions with appetite, food palatability, and thefood deprivation and the anorectic potency of rimonabant on labpsychophysical aspects of taste in people, current hypotheses arechow intake. The antagonist was administered to rats that had beennecessarily tentative. Nevertheless, there are strong indicationsfood deprived for 18 hours or maintained on a schedule of restrict-from the recent literature on animal experiments to suggest veryed access to food. We found that, whereas ad libitum fed rats werespecific involvement of endocannabinoids in the motivational

processes that direct and energize eating behavior. only weakly affected by low doses of the drug, restricting foodavailability resulted in significant intake suppression by rimona-Current conceptions of eating motivation consider there to bebant.[57] As rimonabant acts as a competitive antagonist at CB1two principal and separable components that govern food seekingreceptors, the behavioral effects of CB1-receptor blockade areand actual consumption: ‘wanting’ and ‘liking’.[91] These compo-likely to become apparent only if there is endogenous cannabinoidnents respectively relate to the anticipation of, or craving for, foodrelease and receptor stimulation. Thus, the greater the level ofand its potentially rewarding properties, or the actual emotionalcannabinoid activity, the greater may be the behavioral conse-experience, or pleasure, arising from its ingestion. The hypothesesquences of rimonabant treatment. Werner and Koch[82] have con-about cannabinoids and feeding discussed in section 4 generallyfirmed the susceptibility of ordinary lab chow intake toemphasize the liking aspect of eating, arguing for enhanced palat-CB1-receptor blockade in food-deprived rats. In fact, they foundability of food after cannabinoid administration. However, there isthat intracerebroventricular injection of the CB1 antagonistgrowing evidence for a key role of endocannabinoids in theAM281 could produce almost complete suppression of eating.anticipatory, wanting aspect of eating motivation.

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Endocannabinoid Receptor Antagonists 351

These data thus suggest that deprivation induces, or enhances, The deprivation-induced changes in endocannabinoid levelsthat we observed are likely to reflect the specific activation ofendocannabinoid activity. We therefore hypothesized that endoge-neural systems involved in the appetitive components of eatingnous cannabinoid activity may normally increase during the inter-motivation, as opposed to those responsible for the active mainte-vals between meals (and particularly after deprivation), to reachnance of eating once food becomes available. The other significantsome critical level at which point motivation to eat is triggered.change in hypothalamic 2-AG that we detected may also supportAccordingly, the longer the time that has elapsed since the lastthis proposition. Specifically, we found that in nondeprived ani-meal, the greater will be the activity in relevant endocannabinoidmals given access to palatable food and sacrificed while stillcircuits, and the higher the motivation to eat. This propositionhighly motivated to continue eating, hypothalamic 2-AG levelsreceived support from subsequent experiments involving directwere actually significantly reduced. By contrast, in animals thatmeasures of brain endocannabinoid levels.ate the same food to satiety, hypothalamic 2-AG levels were

We examined regional brain anandamide and 2-AG levels inrestored to levels similar to those in our control animals, measured

animals after food deprivation, while consuming a palatable food,at a time when they were replete and their endogenous feeding

or after satiating on that food.[79] Endocannabinoid levels in theserhythms naturally suppressed eating.[79]

animals were compared against those from nondeprived rats, at aThe respective elevation of hypothalamic 2-AG levels with

point during their daily feeding cycle when motivation to eat wasdeprivation, and the decline evident during feeding suggest that,

minimal and feeding absent. We reasoned that if endocannabinoidonce initiated, eating is no longer dependent on endocannabinoid

activity is key to the appetitive phase of eating motivation thenactivity for its maintenance. Indeed, there may be specific mecha-

food deprivation, with its obvious ability to provoke hunger, nisms to suppress 2-AG activity during re-feeding to facilitatewould maximize our ability to detect relevant changes in satiation. Certainly, our observation of reduced hypothalamicanandamide and 2-AG. Alternatively, if endocannabinoid activity 2-AG levels in animals eating a palatable diet indicates thatwere to contribute more directly to orosensory reward during endocannabinoids are not crucial to food palatability – the orosen-ingestion, allowing animals to avidly consume a highly palatable sory reward that guides the rate, duration, and size of meals.food should maximize relevant changes. Finally, examining the A substantial increase in endocannabinoid levels in response tobrains of animals that had over-consumed a palatable food to the caloric deficit was also apparent within the limbic forebrain, in thispoint of satiation provided an additional control to indicate the case, for both 2-AG and anandamide. The magnitude of thesespecific involvement of endocannabinoids during all stages of deprivation-induced increases (and an absence of changes withappetite and eating. any other manipulation) suggests activation of circuitry with spe-

We found that acute food deprivation provoked significant cific involvement in the generation of appetite and food-seekingincreases in brain anandamide and 2-AG levels. These effects behavior. Notably, this region contains the AcbSh, an importantwere most marked in the limbic forebrain, with substantial in- component of brain reward pathways.[81]

creases in the levels of both endocannabinoids. Within the hypo-thalamus, only 2-AG was reliably increased. That the two cannabi- 7. Endocannabinoids andnoids were differentially regulated probably reflects the high Incentive-Reward Processesdegree of anatomical complexity in the distribution of appetite-related, cannabinoid-sensitive neurons. In particular, the hypothal- Central to these reward pathways are the mesolimbicamus contains a number of zones (e.g. lateral hypothalamic, dopaminergic neurons, arising in the ventral tegmental area andparaventricular, ventromedial, and arcuate nuclei) that are sepa- projecting to the nucleus accumbens.[100] Natural rewards, includ-rately implicated in the stimulation or inhibition of feeding, as well ing food, together with many drugs of abuse, have been found toas the regulation of energy metabolism.[70,98] Support for these stimulate dopamine release from terminals in the nucleus accum-findings comes from a recent study by Hanus et al.[99] who bens. Researchers now emphasize a specific role for these path-observed elevated 2-AG levels in whole mouse brains after acute ways in incentive motivation, i.e. the generation of emotionalfood deprivation for 24 hours. However, that group also found arousal and behavioral activation in response to stimuli, whichreduced hippocampal and hypothalamic 2-AG levels in mice that predict reward.[91,100,101] Ingestion of food causes dopamine releasewere chronically food restricted (to 40–60% of their ad libitum in the nucleus accumbens, especially after deprivation, or if theintake over 12 days). These latter changes were interpreted as an food is novel or palatable. In addition, food restriction is known toadaptation to semi-starvation, rather than to an acute state of enhance the rewarding properties of food and of drugs ofhunger as imposed in our experiments. abuse.[102,103] It is perhaps not coincidental, then, that doses of

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352 Kirkham & Williams

THC that we have found to produce hyperphagia have also been donic evaluation of food remains to be determined, but we believefound to stimulate dopamine release in the nucleus accum- that they may involve alterations to the activity of endogenousbens.[28,104] opioid systems in the brain.

The AcbSh, which contains a relatively high density of CB1 In addition to dopamine, the endogenous opioid peptides arereceptors,[41,105] has particularly strong associations with appetitive also linked to central reward processes. For example, in theprocesses. Neural activity in the shell is believed to signal incen- accumbens, dopamine neurons synapse with enkephalinergic neu-tive salience, and to facilitate the generation of motor patterns rons that are critical to the processing of reward.[104] Evidence hasorienting an animal toward potentially rewarding stimuli, such as accumulated to support overlapping endogenous opioid and endo-food in a hungry animal.[81,106] Given this association, it is notable cannabinoid mechanisms in relation to a wide range of physiologicthat we have found that the AcbSh is a particularly sensitive site processes, including reward and appetite.[108] For example,for the induction of cannabinoid-induced feeding. Specifically, we CB1-receptor knockout mice are not only unresponsive to can-have shown that feeding can be induced by direct administration of nabinoids, but display a reduced sensitivity to the rewarding2-AG into this region of the rat brain, with substantial short-term properties of opiate drugs.[109] Importantly, Gallate and McGre-increases in food intake being observed.[79] As with anandamide gor[92] found that the facilitatory effects of a CB1 receptor agonistand THC, 2-AG significantly advances the onset of feeding. on responding for palatable solutions were reversed by both a CB1Moreover, the rapidity of onset and magnitude of 2-AG receptor antagonist and the general opioid receptor antagonist,hyperphagia when injected into the AcbSh far outweigh the rela- naloxone. In addition, THC-induced Fos immunoreactivity intively weak effects of anandamide so far seen after peripheral or appetite-related brain regions can be modified by naloxone.[110]

central administration.[75-78] Such findings again imply that cannabinoids may modulate themotivation to ingest via actions on both endocannabinoid andAlthough the data described above indicate a primary role foropioid systems. Such a link may be anticipated since opioids areendocannabinoids in appetitive, incentive, or ‘wanting’ aspects offirmly implicated in the mediation of food reward. Opioid receptoreating motivation, we will now address the possibility of cannabi-agonists and antagonists respectively increase or reduce foodnoid influences on the consummatory, ‘liking’ component ofintake by altering the hedonic evaluation of foods during inges-feeding. Recently, we examined this issue directly by examiningtion. For example, opioid antagonists are reported by humans tothe effects of CB1 receptor ligands on the microstructure ofreduce the perceived palatability of normally preferred foods andsucrose drinking, a technique that permits the direct comparison offluids.[111,112]drug effects on ingestive responses with those produced simply by

altering the palatability of sucrose (by varying its concentra- We have obtained convincing evidence for interactions be-tion).[107] Crucially, we found that both exogenous and endoge- tween cannabinoids and endogenous opioids in relation to feeding.nous cannabinoids altered drinking in a way that mimics the effect For example, we found that even low, subanorectic doses ofof increasing sucrose palatability. Conversely, the actions of naloxone effectively blocked cannabinoid-induced over-consump-rimonabant on licking microstructure replicated the effects of tion.[71] We also examined whether combined administration of thesucrose dilution, indicating that the drug effectively reduced the CB1 receptor antagonist rimonabant with naloxone could providereward value of the sucrose solution. further evidence of co-operative interactions between cannabinoid

and opioid systems.[113] We chose a range of doses of each antago-We have argued that the apparent dual actions of cannabinoidsnist, which alone is capable of reversing the actions of selectiveon appetitive and consummatory components of ingestive behav-agonists at their respective binding sites but exert no significantior are not incompatible. Certainly, motivation systems that areeffect on lab chow intake. Thus, neither naloxone alone, nordesigned to increase the salience of food stimuli, encourage foodrimonabant alone, produced any reliable effects on food intake.seeking, and initiate ingestion would be less than effective if theyHowever, when given in combination, every dose of rimonabantwere not paired with activation of those systems responsible forpotentiated the effects of all doses of naloxone. Significant intakemaintaining intake once food becomes available. The activation ofsuppression occurred with every combination of the two drugs,systems subserving wanting, together with the priming of likingrelative to controls (vehicle only, vehicle/rimonabant, and vehicle/motivation components makes sense in terms of the biologicnaloxone).[113] Similarly, supra-additive effects of rimonabant andimperatives discussed in the introduction. Thus, the behavioralnaloxone have also been demonstrated by Rowland and col-actions of cannabinoids may be indicative of a general activationleagues.[114]of incentive-reward circuitry that both instigates feeding and en-

ables a greater appreciation of food once eating commences. The Those data seem to indicate a synergistic interaction betweenprecise nature of cannabinoid mechanisms in the intra-meal he- the effects of opioid and cannabinoid receptor antagonists, and go

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Endocannabinoid Receptor Antagonists 353

a long way toward supporting an important functional relationship take-suppressing (‘anorexigenic’) actions. Orexigenic peptides in-between cannabinoid and opioid systems in the normal regulation clude neuropeptide Y, orexins, melanin-concentrating hormone,of appetite. Apparent effects of cannabinoid receptor ligands on and galanin. Anorexigenic neuropeptides include α-melanocyte-palatability responses are therefore likely to involve some direct stimulating hormone, corticotropin-releasing hormone (CRH), andinfluence on the opioid systems that contribute to the instantane- cocaine and amphetamine-related transcript.[20,70]

ous hedonic evaluation of ingesta. Whatever the actual mecha- Current homeostatic models propose that hypothalamic orex-nisms, these findings do strengthen the role of endocannabinoids igenic and anorexigenic neuropeptides are regulated by peripheralin the processes that underlie our sensitivity to, and over-consump- signals related to energy status, such as the peptide hormone leptintion of palatable foods. that is secreted by adipocytes in proportion to the level of stored

A noteworthy corollary to these data comes from recent find- fat.[118,119] It is therefore of interest that there is evidence thatings by Harrold et al.[115] that also link the consumption of palat- hypothalamic anandamide and 2-AG biosynthesis may be subjectable food to endocannabinoid activity. They compared regional to negative regulation by leptin. Thus, leptin administration sup-CB1-receptor density in the brains of rats maintained on lab chow presses hypothalamic levels of endocannabinoids in normal rats,with those of animals given a palatable food supplement for 10 while in genetically obese, chronically hyperphagic rats and miceweeks. Over-consumption and accelerated weight gain in the with deficient leptin signaling, the elevated hypothalamic expres-palatable food group resulted in the downregulation of CB1 recep- sion of anandamide or 2-AG is reversible in response to leptin.[97]

tors, with receptor density reduced by as much as 50% in some Of the several hypothalamic nuclei-assigned roles in the regula-areas, including within the nucleus accumbens and other areas tion of energy balance, the lateral hypothalamus is of particularassociated with the hedonic aspects of eating. Moreover, the extent interest. This region has reciprocal neural links with the nucleusof downregulation was correlated with the extent of over-con- accumbens, and may be critical to the translation of the motivationsumption of the palatable diet. These authors concluded that this to eat into actual feeding behavior, and as a component of theeffect was consistent with increased activation of these receptors brain’s incentive-reward systems, to the hedonic evaluation ofby endocannabinoids, and that anandamide and 2-AG may drive food.[81,106] Chemical or electrical stimulation of the lateral hypo-the appetite for palatable foods. In the light of those findings, it is thalamus induces intense feeding activity even in satiated animals,interesting to note the finding by Poncelet et al.[116] that, in apparently by raising the incentive value of food stimuli throughcomparison to normal animals, CB1-receptor –/– mice show a the activation of reward circuitry.[106,120] Importantly, appetite-reduced hyperdipsic response to a palatable, sucrose solution. inducing manipulations within the nucleus accumbens (which is a

sensitive site for 2-AG-induced eating) may induce the coordinat-ed activation of hypothalamic neurons that express orexigenic8. Endocannabinoids and Hypothalamic Integrationpeptides, and the suppression of those neurons expressing anorexi-genic peptides.[121] Lateral hypothalamic feeding circuits are alsoSurprisingly, the study by Harrold et al.[115] failed to detect anysensitive to cannabinoid modulation. For example, THC facilitateschange in CB1-receptor density in the hypothalamus, which isfeeding induced by electrical stimulation of this region, reducingclassically associated with food intake and bodyweight regulation.the threshold level of stimulation required to induce the behav-This result would suggest that hypothalamic cannabinoids are notior.[122] Electrical stimulation of the brain also mimics the rewardinvolved in the processes controlling palatable food intake. Possi-associated with eating, and rats will work to obtain such stimula-bly, this failure may be related to the fact that hypothalamic CB1-tion alone. Interestingly, the threshold level at which rats willreceptor levels are relatively low compared with other regions.[105]

respond for lateral hypothalamic stimulation is reduced by foodHowever, within the hypothalamus, higher CB1-receptor expres-restriction.[123] Thus, in line with our earlier arguments aboutsion is evident within the lateral hypothalamic nuclei that arecannabinoid actions on feeding resembling those of food depriva-linked to mechanisms that initiate feeding, and that are alsotion, THC and fasting exert similar effects. Conversely, leptin,anatomically and functionally associated with the nucleus accum-which will naturally have higher circulating levels in repletebens.[106,117] Moreover, it has been found that CB1-receptor coup-animals,[124] has been found to elevate stimulation thresholds.[125]ling to G-proteins is more efficient within the hypothalamus thanImportantly, rimonabant, which reduces the motivation to eat, hasin brain regions with higher receptor densities.[42]

been shown to have a similar effect to leptin.[126]Despite these complexities, the hypothalamus has been thefocus of several investigations which have examined potential Such data suggest that leptin may act, through the downregula-relationships between cannabinoids and a range of hypothalamic tion of endocannabinoids, to reduce the general incentive value ofneuropeptides that have intake-stimulating (‘orexigenic’) or in- food and so restrict feeding. Food deprivation and the concomitant

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354 Kirkham & Williams

suppression of circulating leptin levels would therefore be ex- expressed within the PVN.[105,132] It is significant, therefore, thatpected to release endocannabinoids from this control, with in- Verty et al.[133] have recently reported that feeding induced bycreased hypothalamic levels (as in our study[79]) and a consequent direct injection of morphine into this site can be reversed byincrease in the attractiveness of food. Moreover, in spontaneously rimonabant. The full implications of these data require furtherfeeding human volunteers, circulating leptin levels have been investigation, but they again reinforce the intimate relationshipshown to increase during inter-meal intervals and decline before between endocannabinoids and intake regulatory mechanisms atthe onset of a meal.[124] It is therefore possible to predict a many levels within the brain.reciprocal relationship between leptin and hypothalamic endocan-

9. A Role for Peripheral Cannabinoid Systems?nabinoids in the regulation of meal patterns. It should be noted,however, that some workers have questioned whether leptin plays

The preceding discussion seems to provide strong evidence thata role in controlling cannabinoid-mediated intake of palatablethe alterations to feeding induced by CB1 receptor ligands arefood. For example, there appears to be no correlation betweenmediated through actions on central processes. Clearly, the psy-plasma leptin levels and brain CB1-receptor expression in normalchologic representation and behavioral expression of altered eat-animals that become obese and hyperleptinemic through the over-ing motivation require processing within the brain, particularly inconsumption of a palatable diet.[115] More research is obviouslysituations where the incentive or reward value of food is evaluated.required to resolve these contradictions.Nevertheless, it has been argued that the feeding actions of sys-

Recently, Hilairet and coworkers[127] obtained evidence oftemically administered CB1 receptor ligands predominantly in-

functional interactions between endocannabinoids and orexin A,volve peripheral sites of action. Thus, Gomez et al.[77] compared

an orexigenic peptide that is selectively expressed in the lateralthe hyperphagic and anorectic potencies of anandamide and

hypothalamus.[128,129] More specifically, evidence was obtained forrimonabant when administered intraperitoneally or intracerebro-

cross-talk between CB1 receptors and the orexin receptor OX1R,ventricularly. Contrary to the positive findings of several other

such that activation of CB1 receptors can enhance orexin signal-groups noted above, Gomez et al. observed drug effects only after

ing.[127] Together with this group’s finding that rimonabant canperipheral but not central injection. Moreover, the actions of

block orexin A-induced feeding, these data indicate that there maysystemic anandamide and rimonabant were abolished by capsai-

be a range of important functional associations between endocan-cin-induced deafferentiation of peripheral sensory nerves, sug-

nabinoids and other putative central appetite control systems.gesting a possible mechanism whereby stimulation/blockade of

Indeed, other workers have detected potentially significant rela-peripheral CB1 receptors may influence central motivation

tionships between cannabinoids and appetite-related hypothalamicprocesses. These workers also demonstrated that anandamide is

peptides. Thus, Cota et al.[130] found that CB1 receptors are co-synthesized within intestinal tissues, with increased levels after 24

expressed with CRH, amphetamine-related transcript, prepro-hours of fasting.[77] These results were interpreted as indicating a

orexin, and melanin-concentrating hormone in mouse hypotha-possible role for peripheral anandamide as a hunger signal. How-

lamic neurons. Additionally, CB1-receptor knockout mice (whichever, in contrast to reports by other groups showing elevated brain

are characterized by hypophagia, reduced bodyweight, and re-endocannabinoid levels in starved animals,[79,99] these workers

duced fat mass compared with their wild-type littermates) showdetected no change in brain anandamide levels. While the findings

higher levels of mRNA for the anorexigen CRH. These findingsby Gomez et al. do support potentially important contributions of

may indicate a possible oppositional relationship between hypo-peri-pheral cannabinoid systems to feeding regulation, the incon-

thalamic cannabinoids and CRH in the normal regulation of appe-sistencies relating to the reported effectiveness of centrally admin-

tite.[130]

istered CB1 ligands and brain anandamide levels need to beRecalling our discussion of functional relationships between resolved by further investigation.

opioids and cannabinoids, there is also evidence for an importantrelationship between these neuromodulators within the hypothala- 10. The Potential of Cannabinoid Antagonists asmus, and particularly the paraventricular nucleus (PVN). The PVN Anti-Obesity Treatmentsis the focus of converging orexigenic and anorexigenic neuropep-tide pathways, and is believed to be crucial to the hypothalamic The preceding sections have highlighted the accumulating evi-integration of metabolic, hormonal, and neural factors regulating dence for a role of endocannabinoids in the complex mechanismsenergy homeostasis.[70,131] Importantly, the PVN is a sensitive site that regulate food intake. Combining our comments on the princi-for the hyperphagic actions of cannabinoid receptor agonists. pal factors that contribute to obesity and the apparent involvementMoreover, in addition to CB1 receptors, opioid receptors are also of endocannabinoids in incentive and reward processes, it is not

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Endocannabinoid Receptor Antagonists 355

unreasonable to consider that the anorectic actions of CB1 recep- foods. Administration of appetite suppressants in obese individu-tor antagonists have potential in the treatment of obesity. Several als would normally be paired with dietary restriction of some kind.pharmaceutical companies are actively pursuing this possibility. However, there is always the potential for individuals to succumbIndeed, phase III clinical trials with rimonabant are already being to the attractions of favorite foods, and maintaining a strict dietaryconducted in patients with obesity,[134] with preliminary reports regimen, even with the aid of drugs, is a substantial obstacle to thesuggesting significant benefits in terms of food intake and weight maintenance of weight loss. This issue has been more directlyreduction. In line with the animal data and our hypotheses relating addressed by recent studies of the effects of CB1 receptor antago-to appetitive processes, the drug is reported to reduce subjective nists in mice made obese through the provision of a high-fat diet.ratings of hunger.[135] This diet-induced obesity is a good model for the most common

form of human obesity and its consequences, including visceralIn developing cannabinoid antagonist treatments for obesity,obesity and type 2 diabetes.the results of chronic effects of rimonabant are obviously of

importance. In an early study, Colombo and colleagues[74] demon- Ravinet-Trillou et al.[84] examined the chronic actions ofstrated that daily administration of the antagonist suppressed appe- rimonabant in dietary obese mice. Once again, daily administra-tite for lab chow and induced persistent weight loss in rats. tion of the drug induced a substantial early reduction of energyAlthough tolerance to the drug’s effect on appetite was apparent intake, with food intake reduced by almost 50% during the firstafter 5 days, suppression of bodyweight gain was evident across week of a 5-week study. This initial suppressive effect graduallythe full course of a 14-day experiment. waned, but intake remained suppressed compared with vehicle-

treated control mice throughout the whole test period. Overall,More recently, Vickers et al.[83] demonstrated that sub-chronic,bodyweights were reduced substantially after 1 week and stabi-oral treatment with the antagonist dose-dependently decreasedlized at that lower level until the end of the experiment. Post-food (lab chow) intake and bodyweight gain in both lean andtreatment carcass analysis showed that rimonabant significantlygenetically obese Zucker (fa/fa) rats. Once again, tolerance to thereduced adipose stores, halving the proportion of body fat seen inintake-reducing effects was evident after 4 days in lean animals,control mice fed the same high-fat diet, while preserving leanbut the reduction of bodyweight gain was maintained over 28mass. A follow-up study confirmed these effects and demonstrateddays. The inhibition of food intake and bodyweight gain wasthat the drug-induced changes in food intake and body composi-greater in obese Zucker rats than in lean control rats, with dailytion were dose dependent. Additionally, elevated plasma levels offood intake initially reduced by as much as 40% and persistentinsulin and leptin, and insulin resistance that accompanied theweight loss evident over the first 2 weeks of treatment. Moreover,development of obesity (and which are also features of humanthe development of tolerance to the drug’s anorectic action wasobesity[136]) were substantially reduced by antagonist treatment.considerably delayed (until day 13) in obese animals, although

their intake subsequently remained lower than in vehicle-treated Hildebrandt and colleagues[85] confirmed the general effective-control animals. Even after tolerance developed, the rate of weight ness of chronic CB1-receptor blockade in diet-induced obesitygain remained significantly suppressed in antagonist-treated rats. using another CB1 receptor antagonist, AM251 (a close structuralThe withdrawal of rimonabant on day 28 resulted in rebound analog of rimonabant[137]). In their hands, the drug dose-hyperphagia and significant weight gain. As mentioned earlier, dependently suppressed food intake, initially by as much as 60%obese Zucker rats have elevated hypothalamic levels of 2-AG.[97] below control levels. Significant dose-related weight loss wasIt is therefore possible that differences in endocannabinoid tone evident after 3 days of treatment, and was maintained over anwithin the hypothalamus could account for the increased effective- initial 2-week period of daily oral administration, with significantness of rimonabant in these animals. intake suppression evident until day 12. Hyperphagia was apparent

Both of these studies indicate that rimonabant can chronically during a subsequent drug-free inter-treatment phase, but body-attenuate the intake of relatively bland laboratory diets. This effect weight gain was negligible until after 4–5 drug-free days. Reliableis contrary to some of the data discussed in section 5 that pointed anorexia and weight loss was reinstated when AM251 treatmentto selective effects of the antagonist on palatable food intake. was given for a further 2 weeks, again with very marked initialNevertheless, the chronic effectiveness of rimonabant on relative- suppression of food intake. In this second-drug stage, tolerance toly bland food intake points to the possibility that the drug would be the intake-suppressing actions of the drug were evident somewhatuseful in reinforcing the restraint of obese patients maintained on earlier (day 7), but weight loss was maintained, resulting inrelatively unpalatable, calorically restricted diets. However, a bet- marked overall reductions in adipose tissue mass. Plasma leptinter test of the intake- and weight-attenuating potential of the drug and cholesterol levels were also significantly reduced at the high-is whether it can be effective in suppressing the intake of palatable est dose, with an additional tendency for plasma insulin levels to

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356 Kirkham & Williams

be reduced. The ability of AM251 to attenuate eating and acceler- not only are CB1 receptors expressed by adipocytes, but also thatate weight loss with an interrupted administration regimen sug- agonist stimulation of these receptors will dose-dependently stim-gests that tolerance to the effects of CB1 receptor antagonists may ulate lipogenesis. Interestingly, Bensaid et al.[141] subsequentlynot be an obstacle to the long-term application of these drugs in the reported that CB1-receptor expression is upregulated in adipocytestreatment of obesity. of obese Zucker rats (relative to the levels observed in lean

littermates) and during differentiation of cultured mouse adipo-cytes. The findings by Cota et al. suggest that rimonabant treat-11. Cannabinoid Receptor Antagonists andment may cause direct interference with cannabinoid-mediatedMetabolic Factorsprocesses that regulate fat deposition in adipose tissues, raising thepossibility of important anti-obesity actions of cannabinoid recep-Each of these chronic studies has noted that weight loss persists

after marked anorectic effects of the antagonist have subsided. tor antagonists that are mediated by both central and peripheralAlthough it is possible that cumulative weight loss predominantly mechanisms.reflects the early, marked intake reduction, Ravinet-Trillou et Recently, Bensaid and colleagues[141] described a possible routeal.[84] provided evidence for an additional action of the antagonists by which the food intake-independent actions of rimonabant onon metabolic processes. For example, pair-feeding tests, in which bodyweight could be mediated – involving cannabinoid-sensitivecontrol animals receive the same amount of food voluntarily adipose factors. They specifically examined the role of a proteinconsumed by the antagonist-treated animals, showed that weight exclusively expressed and secreted by adipose tissue, adiponectinloss was greater with rimonabant.[84] In other words, although both (or adipocyte complement-related protein; Acrp30).[142-145] Plasmagroups ate the same amount, antagonist-treated animals lost signif-

levels of the protein and levels of adiponectin mRNA have beenicantly more weight. Additionally, when deprived of food for 24

shown to vary inversely with adiposity in animals and humans.[146]

hours, rimonabant-treated obese mice lost more weight than simi-Moreover, adiponectin has a number of effects that closely match

larly deprived control mice, and displayed fasting glycemia andthose of rimonabant. Thus, adiponectin has been found to regulate

insulin sensitivity that were similar to those in lean animals.[84]

hyperglycemia, hyperinsulinemia, and fatty acid oxidation.[147-149]

The combined behavioral and metabolic changes induced byImportantly, systemic adiponectin administration will also reduce

CB1-receptor blockade may reflect alterations to the hypothalamicthe bodyweight of obese animals through a mechanism that is

integrative systems discussed in section 8, to affect not onlyindependent of food intake levels.[150] Replicating the earlier

feeding motivation but also the processes controlling energy ho-chronic studies,[83,84] Bensaid et al.[141] examined the effects ofmeostasis. For example, the PVN has been ascribed a critical roledaily administration of rimonabant in obese Zucker rats. Asin the autonomic control of energy balance as part of the hypotha-before, the drug produced an initial, short-lasting anorexia andlamic-pituitary-adrenal axis, through its sensitivity to the actionsmarked, persistent weight reduction. After 4 days of treatment,of glucocorticoids secreted by the adrenal cortex.[138] Recently Diadiponectin mRNA expression was significantly increased, withet al.[139] obtained evidence that the established orexigenic actionsgreater effects apparent with longer periods of treatment. A similarof glucocorticoids[140] in the PVN may be mediated by endocan-action was also observed in lean Zucker rats, but to a lesser extentnabinoids, possibly through the inhibition of anorexigenic pep-and with a slower rate of onset. In vitro studies with culturedtides such as CRH.mouse adipocytes showed that rimonabant stimulation of adi-Given that weight loss in animals treated chronically with CB1ponectin mRNA expression was CB1-receptor mediated, since noreceptor antagonists persists after the initial anorectic actions ofeffect of the drug was apparent in adipocytes from CB1-receptorthe drug have dissipated, there may be other important metabolicknockout mice. Paralleling the rimonabant-induced changes tofactors that contribute to their actions on bodyweight. One possi-adiponectin mRNA expression and associated weight loss,bility is that rimonabant may enhance fatty acid oxidation, since itrimonabant also reduced the hyperinsulinemia that is characteristicwas found to lower plasma-free fatty acid levels in dietary obeseof obesity. It remains to be determined the extent to which thesemice.[84] Similarly, the reported effects of rimonabant to correctexperiments have unmasked important peripheral mechanisms byhyperglycemia, reduce plasma insulin levels, and counter insulinwhich endocannabinoids can affect bodyweight regulation. How-resistance suggest that the drug may also improve glucose homeo-ever, the ability of rimonabant to regulate hormones linked to fatstasis. Additionally, rimonabant may act via hypothalamic mecha-and glucose metabolism, promote weight loss, and suppress foodnisms to increase sympathetic nervous system activity that stimu-intake raises intriguing possibilities for this class of drugs in thelates lipolysis.[84] These propositions may be extended by the

results of recent in vivo studies by Cota et al.,[130] who found that treatment of obesity.

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Endocannabinoid Receptor Antagonists 357

Despite the emphasis of this review on cannabinoid receptor- of foods. Stimulation of central CB1 cannabinoid receptors canmediated processes in relation to appetite and bodyweight, an provoke feeding even in the face of nutritional repletion. Addition-interesting corollary to the preceding discussion is found in recent ally, there is evidence that activation of endocannabinoid systemswork on a natural analog of anandamide, oleoylethanolamide affecting appetitive motivation can also produce a positive gain in(OEA), which is synthesized within the gut.[77] Like anandamide, the activity of other systems that mediate food palatability, such asOEA is produced in cells in a stimulus-dependent manner and is those utilizing the endogenous opioids. These combined functionsrapidly eliminated by enzymatic hydrolysis, suggesting a function suggest a crucial role for endocannabinoids in both stimulatingin cellular signaling. Although OEA does not activate cannabinoid and maintaining appetite, particularly for palatable foods. Further-receptors and its biologic functions are still unknown, Rodriguez more, a growing body of data links endocannabinoids to otherde Fonseca and colleagues[77,151] have proposed that intestinal components of the complexing range of putative neural and hor-OEA may play a role in the peripheral components of feeding monal systems implicated in feeding regulation and energy home-regulation, and particularly on satiation processes. Thus, OEA ostasis. Importantly, this research is helping to shift the focus ofsynthesis in the small intestine is stimulated by feeding and academic and industrial research efforts from ‘satiety signals’inhibited by food deprivation, and OEA reduces food intake in toward the long-neglected, but behaviorally more influential neu-free-feeding and starved animals, primarily by delaying the onset ral underpinnings of hunger, incentive processes, and orosensoryof meals.[151,152] Additionally, OEA can respectively attenuate the reward.feeding actions of cannabinoids or enhance rimonabant anorex- As we argued earlier, the modern problem of obesity is aia.[77] product of our capacity to desire and enjoy foods that possess an

Recent research suggests that OEA actions on feeding and intrinsic attractiveness derived from their energy-providing com-bodyweight may be mediated through adiponectin-related mecha- ponents. Evolutionary pressures, combined with cultural ingenuitynisms. Thus, OEA has been found to be an agonist of the perox- in devising appetizing cuisines and modern societal pressures,isome-proliferator-activated receptor-α (PPARα), a subtype of conspire to provide us with all the gastronomic delights we couldnuclear hormone receptor.[153] Both OEA and synthetic PPARα desire, but also a surfeit that far exceeds our physical needs. Theagonists reduce food intake and bodyweight in animal models, developments we have described indicate that endocannabinoidwith comparable alterations to serum lipids.[153] Clearly, there are systems, by potentially mediating our food cravings and pleasures,obvious parallels between these effects and the actions of adi- are a promising – and probably highly effective – target forponectin. Indeed, a physiologic link may be evidenced by the fact pharmacologic interventions designed to control the kinds ofthat stimulation of PPARα has also been shown to alter adiponec- eating that are least susceptible to current therapies. Thus, we havetin expression in genetically obese db/db mice (although, problem- seen how cannabinoid antagonists may preferentially suppress theatically, both reduced and enhanced adiponectin expression have intake of the most palatable, highly caloric foods. Additionally,been observed).[154-156] Interestingly, exogenous cannabinoids, these drugs seem to have enhanced potency under conditions oftheir metabolites, and synthetic analogs have been reported to bind hunger induced by food restriction, such as might commonly applyto PPARγ receptors,[157] stimulation of which is known to increase with calorie-controlled diets in obese patients. In effect, cannabi-adiponectin expression in obese mice and insulin-resistant obese noid receptor antagonists may facilitate weight loss by counteringhumans.[158] The full implications of these findings remain to be the most potent psychologic factors underlying over-consumptionelucidated, but the possibility of significant interactions between and obesity. The further possibility that drugs such as rimonabantcannabinoid receptor ligands and factors regulating lipid and can also have beneficial actions on glucose or fat metabolismglucose metabolism suggests potentially fruitful avenues for phar- provides for even broader, more effective therapeutic possibilities.maceutical treatments of obesity. Of course, there is much that remains to be understood, and many

complex issues to be resolved. But we are still in the early stagesof what should prove to be an exciting chapter in the psychology12. Conclusionand physiology of appetite, and of medicinal approaches to theglobal epidemic of obesity.The data presented here summarize the latest developments in

the accelerating field of cannabinoid-appetite research. There isAcknowledgmentsnow overwhelming evidence that endocannabinoids are important

to the regulation of appetite. More specifically, there is strong T.C. Kirkham is supported by a grant from the UK BBSRC. The authorsevidence that these neuromodulators play a role in orienting us have no conflicts of interest that are directly relevant to the content of this

review.toward food stimuli, by enhancing the incentive value or salience

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358 Kirkham & Williams

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