Introduction

The predominant models that guide current development of drugs designed to address obesity and its associated diseases concentrate on homeostatic regulation of energy balance and body weight. However, it is arguable that neither body weight nor food intake are regulated variables in the generally accepted physiological sense. The increasing prevalence of obesity-arising from the overconsumption of palatable, energy-dense foods and from sedentary lifestyles-indicates the failure of any efficient mechanisms to curtail energy intake with increasing adiposity and of any effective break on the accumulation of body weight once the much vaunted 'set points' for weight or adiposity are attained. Rather, the mechanisms that underlie hunger, and particularly food-craving and hedonic responses to food, are considerably greater influences on the frequency, quantity, and variety of consumption. Consequently, should we wish to develop pharmaceutical interventions to restrict food intake, these positive motivational factors represent crucial targets for investigation and are likely to provide more effective therapies than agents that aim to reinforce putative inhibitory 'satiety signals'. The endocannabinoids appear to be critical to the normal biopsychological mechanisms that create appetite and stimulate eating, specifically contributing to incentive processes and the hedonic evaluation of food stimuli.

State of the Art

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Figure 1:

Endocannabinoids modulate activity in mesolimbic dopaminergic (DA) incentive pathways and opioidergic reward circuits, and these actions underlie the orexigenic potency of cannabinoids. Cannabinoid-induced eating is prevented by DA and opioid receptor antagonists as well as by CB1 blockers. Stimulation of CB1 receptors facilitates activity in incentive pathways, promoting orientation to food stimuli and stimulating the motivation to eat. CB1 agonists also act in the accumbens to facilitate opioid mediation of the sensory pleasure of food as it is ingested. Incentive and reward circuits are likely to interact through cannabinoid-mediated mechanisms: cannabinoid activity may thus contribute to the anticipation of orosensory pleasure that is experienced when we are hungry or food is craved.

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The well-documented appetite-stimulating actions of Cannabis sativa result from agonist actions of phytocannabinoids, such as delta-9-tetrahydrocannabinol (THC), at CB1 receptors. That these actions reflect a physiological role of endocannabinoids in appetite control was confirmed by the demonstration in animal models that 1-CB1 blockade suppresses food intake and 2-the endogenous CB1 ligands anandamide, 2-arachidonoylglycerol (2-AG), and noladin ether all promote eating [1-4]. More detailed behavioural analysis indicates that endocannabinoids specifically modulate food wanting and liking. Thus, CB1 agonists and antagonists respectively increase or reduce the amount of effort an animal will expend to obtain food [5-7]. Additionally, CB1 knockout mice exhibit lower levels of responding for sweet food than wild-type mice [8]. THC, 2-AG, or anandamide advance the onset of meals, inducing eating even in fully-satiated animals [9-11]. The orexigenic actions of cannabinoids resemble the changes that occur with food deprivation, and regional brain levels of anandamide and 2-AG increase after fasting [12].

In humans, a principal effect of THC is the amplification of preprandial hunger [13]. Conversely, rimonabant selectively lowers hunger and desire to eat at the start of a meal, while having no effect on postmeal ratings of hunger or fullness. Importantly, with repeated administration, rimonabant reduces the frequency and strength of food cravings [14]. These data are compatible with the known effects of CB1 agonists and antagonists on mesolimbic dopaminergic neurons that subserve incentive motivation (Figure). For example, the accumbens dopamine release that is provoked by presentation of a novel, palatable food is blocked by rimonabant [15]. Overall, the data imply that endocannabinoids may be essential to the orientation to motivationally significant stimuli, the attribution of incentive salience and reward anticipation, and the elicitation of food seeking and eating initiation.

Endocannabinoids also appear to have a secondary role in mediating the liking of food. Positive hedonic reactions to sweet fluids are respectively enhanced or diminished by CB1 agonists and antagonists [16-18]. Moreover, the nucleus accumbens shell that mediates palatability responses is highly sensitive to the stimulatory actions of endocannabinoids. Anandamide and 2-AG are effective orexigens in this region, as are agents that increase endocannabinoid levels by blocking their enzymatic breakdown or reuptake [19]. Intra-accumbens administration of anandamide specifically enhances the hedonic impact of sweet taste [20], while accumbens CB1 receptors are down-regulated in rats that overconsume palatable food supplements [21], which is consistent with increased endocannabinoid activity.

Opioid receptor agonists and antagonists respectively increase or reduce food intake by altering the hedonic evaluation of foods [22-26]. There is now convincing evidence for interactions between endocannabinoids and endogenous opioids in relation to feeding. Thus, THC hyperphagia is attenuated by sub-anorectic doses of naloxone [27], and THC stimulates beta-endorphin release in the accumbens [28]. Importantly, the facilitatory effects of both CB1 and opioid receptor agonists on responding for palatable ingesta are reversed by either rimonabant and naloxone [5, 6]. Moreover, low doses of rimonabant and opioid antagonists that are behaviourally inactive when administered singly, combine synergistically to produce a profound anorectic action when co-administered [29, 30]. As with anandamide, administration of morphine into the accumbens shell increases the liking of sweet solutions, with a very close correspondence between opioid- and cannabinoid-sensitive sites [20, 31].

Independent manipulations of endocannabinoid or opioid processes produce distinct behavioural/motivational consequences, indicating that cannabinoids primarily affect appetitive processes while opioids mainly influence consummatory processes. We suggest that endocannabinoids principally mediate the motivational processes that drive us to eat, but-through interactions with opioid peptide systems-may also contribute significantly to the hedonic evaluation of foods during eating. Arguably, endocannabinoid-opioid activity underlies food craving, the anticipation of delight from eating, and the actual experience of pleasure derived from the sensory properties of food [9].

Priorities for Future Studies

As this paper indicates, central endocannabinoid systems are implicated in the principal psychological processes that govern eating motivation and may represent critical components of the mechanisms that lead us to overconsume, a major contributor to weight gain. As such, the endocannabinoids are potentially important therapeutic targets for pharmacological treatments designed to modify eating behaviours and attitudes/responsiveness to foods. Modification of endocannabinoid activity or blockade of CB1 receptors may allow us to limit our susceptibility to the temptations of food and to learn to restrain our excessive appetites. As these factors contribute more than any others to the development of obesity, there is an urgent need to define the psychological consequences of CB1 receptor manipulations in human studies. Insights obtained from the exploration of the subjective effects of CB1 ligands would shed important light on the true physiological role of endocannabinoids in appetite control.