Obesity is a complex disease of appetite regulation and energy metabolism that is controlled by many factors. The etiology includes genetics, psychology (learning, abnormal eating behavior), sociology (culture), diet (high fat), and lack of physical activity.1 Obesity can result from several possible genetic and environmental interactions2 some of which may entail a more direct genetic association (a genetically regulated response to sweet food which is perceived as reinforcing),3 or an indirect association that makes the individual genetically more susceptible to environmental stressors that will then favor food consumption.4
Among the genetic factors there are neuromodulators (leptin),5 and multiple neurotransrnitter systems involved with the reinforcing properties of food (Y-aminobutyric acid, dopamine, opiates, serotonin). These neurotransmitters also play an important role in feeding behavior and satiation.6 Considerable effort has been devoted to me development of weight control medications that target neurotransmitters in the brain that regulate food intake.7 Most of the recent pharmacologic efforts have focused on serotonin, which plays an important role in satiety.8 However, there is a large amount of evidence to suggest that dopamine may be one of the target neurotransmitters linking the genetic and environmental factors that contribute to obesity.9
THE INVOLVEMENT OF DOPAMINE IN OBESITY
Dopamine plays a role in pathological feeding behavior, since low levels of dopamine may interfere with the drive and motivation to eat. Bulimic nervosa patients have been found to have normal dopamine metabolite levels; however, high frequency binge eaters have reduced cerebrospinal fluid dopamine levels.10 Increased dopamine metabolite plasma levels have been found, but they are not associated with symptomatology of binge eating disorder.11 To this day, it is difficult to determine whether a trait disturbance on me dopaminergic system plays a role in the etiology of binge eating disorder.
There is better evidence for the causal role of dopamine in obesity. Human studies have shown a higher prevalence of the Taq I A allele for the dopamine D2 receptors in obese subjects.12 Though not replicated by all studies,13 the Taq 1 A allele has been linked with lower levels of dopamine D2 receptors.14 Variants of the human obesity gene and the dopamine D2 receptor gene have been examined in relationship to obesity. These two polymorphisms together account for about 20% of the variance in body mass index (BMI), particularly in younger women.15 The association of the Taq 1 A allele with reduced number of dopamine D2 receptor levels suggests that obese individuals with the Al allele may use food to increase dopamine stimulation to a more desirable level.16 This is consistent with the finding in binge eating disorder patients with frequent binge episodes who are reported to have low dopamine metabolite concentrations in cerebrospinal fluid.10 These results indicate that low dopamine brain activity (either due to decreased dopamine release or to decreased stimulation of postsynaptic dopamine receptors) may be associated with dysfunctional eating patterns. The dopamine system has also been targeted for therapy of obesity since dopamine agonists have anorexigenic effects17 whereas drugs that block dopamine D2 receptors increase appetite and result in weight gain.18
BRAIN DOPAMINE AND ADDICTIVE BEHAVIORS
The role of dopamine in addiction (loss of control and compulsive drug intake) is poorly understood. Cocaine is considered to be the most reinforcing of drugs of abuse. Animal studies have shown that the ability of cocaine to block the dopamine transporters appears to be crucial for its reinforcing effects. In humans, the reinforcing effects of cocaine used intravenously or smoked can lead to rapid escalation of drug intake and compulsive drug administration. Animal studies indicate dopamine D2 receptor levels mediate reinforcing responses to drugs of abuse. This is evidenced by the decrease in the reinforcing effects of alcohol and morphine in mice that lack dopamine D2 receptors (D2 receptor knockout)19,20 and by the decrease in the reinforcing effects of cocaine in aniniais given drugs that block dopamine D2 receptors.21 Moreover, we have shown that overexpression of dopamine D2 receptors in the nucleus accumbens, which is the brain region associated with the reinforcing effects of drugs of abuse, in animals previously trained to self-administer alcohol resulted in a marked reduction in alcohol intake that returned to baseline levels as the D2 receptors decreased to their prior levels.22,23
While the studies on the effects of dopamine D2 receptor antagonists in the reinforcing effects of psychostimulants in humans have not been as conclusive as those in laboratory animals, they have shown a decrease in the subjective ratings of pleasant sensations and of the craving induced by cocaine.24 The lower efficacy of dopamine D2 receptor antagonists reported in studies may reflect the fact that the doses used were lower than those used in laboratory animals and resulted in incomplete dopamine D2 receptor blockade.
USE OF POSITRON EMISSION TOMOGRAPHIC IMAGING TECHNOLOGY TO STUDY DRUG ADDICTION
Positron emission tomography (PET) is a medical imaging technology that uses radioactive positron-emitting atoms (carbon- 1 1 and fluorine- 18) to label and measure the concentration and movement of positron labeled compounds in living tissue. Positron emitter labeled radiotracers are used to label proteins that are of physiological relevance (receptors, transporters and enzymes) in the human brain. The measurement of dopamine D2 receptor using PET and [llc]raclopride has been used to assess neuropsychiatrie disorders, substance abuse and aging (reviewed25). Since [llc]raclopride is sensitive to endogenous dopamine concentration and its binding is reproducible,26 it can also be used to measure relative changes in dopamine concentration secondary to pharmacologic interventions. Methylphenidate is a cocaine-tike psychostimulant that increases extracellular dopamine by blocking dopamine transporters. Methylphenidate-induced changes in [ll^raclopride striatal binding are interpreted as reflecting changes induced by dopamine occupancy of D2 receptors secondary to the changes in dopamine synaptic concentration.26 The measure has been used as an indication of the responsivity of the dopamine system to pharmacologic challenge. This strategy allowed us to evaluate me relationship between dopamine changes as assessed by me levels of dopamine D2 receptors occupancy and subjective perception of pleasure or euphoric "high," which is associated with rewarding effects of the drug.27 We found the intensity of the high induced by methylphenidate was significantly correlated with the levels of released dopamine. The subjects who reported the most intense high were those who had the greatest increases of dopamine release. It appears that dopamine and dopamine D2 receptors play an important role in the reinforcing response to psychostimulants.
Figure 1. Distribution volume images of [11c]raclopride PET scans for a cocaine addict, an alcoholic, an opioid addict and their age-matched control subjects at the level of the striatum. The images are scaled with respect to the maximum absolute value obtained on the control subjects and presented using the rainbow scale where red represents the highest value and dark violet represents the lowest value. Drug addicts have significantly lower measures of striatal dopamine D2 receptor availability than the control subjects. Adapted from.32,34,35
Figure 2. Croup average images of raclopride (distribution volume) PET images for obese and control subjects (n = 1 0 each) at the level of the striatum. The images are scaled with respect to the maximum absolute value obtained on average image of the control subjects and presented using the rainbow scale where red represents the highest value and dark violet represents the lowest value. Obese subjects have significantly lower measures of striatal dopamine D2 receptor availability than control subjects. Adapted from Wang G), Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001;357:354-357.
Even tfiough die reinforcing effects of cocaine may involve the initial drugtaking behavior, other factors might also contribute to the compulsive drug taking and the loss of control behaviors in addicts. Repeated self-administration of cocaine occurs even when there is acute tolerance to the pleasurable response and sometimes even in the presence of an averse drug reaction.28,29 Acute tolerance to the ability of cocaine to increase extracellular dopamine can occur in recreational levels of cocaine consumption. This neurochemical response to cocaine is primarily caused by direct pharmacologic effects of the drug rather than by conditioning to external environmental cues.30 Chronic administration of cocaine will significantly increase impact on me brain dopamine system and me reward circuits that may contribute to addiction.31 In fact, our prior [llc]raclopride-PET studies in addicts of drug of abuse (cocaine,32 methamphetamine,33 alcoholics,34 and heroin35) showed significant dopamine D2 receptor reductions in striatum (Figure 1). It has been hypothesized that compulsive disorders such as drug addiction, gambling and sex reflect a "reward deficiency syndrome,"36 that is speculated to be due in part to a reduction in dopamine D2 receptors.
THE ROLE OF DOPAMINE IN OBESITY AND FOOD INTAKE
Dopamine apparently regulates food intake37 by modulating food reward via the meso-limbic circuitry of the brain.38 There are also projections from the nucleus accumbens to the hypothalamus that directly regulate feeding.39 The dopaminergic reward pathways of the brain are critical for survival since they provide the pleasure drive for eating. It is one of the natural reward mechanisms. However, unnatural rewards such as drugs of abuse (eg, cocaine, alcohol, nicotine), also release dopamine.36 Furthermore, because most of the drugs abused by humans lead to increased dopamine concentration in the nucleus accumbens, this has been suggested as being a common mechanism for reinforcement.28
USE OF IN VIVO IMAGING TO STUDY OBESITY
Compulsive overeating in obese subjects shares many of the same characteristics as drug addiction. Very few brain imaging studies have been done in obese subjects. This is partly due to the engineering and mechanical constraints of the scanners, which cannot support weights greater than 350 pounds. Using a PET scanner bed redesigned to support more than 600 pounds, we have shown a significant reduction in dopamine D2 receptor availability in obese subjects (Figure 2, 107).40 These subjects have body mass indexes (BMI: weight in kilograms divided by the square of height in meters) between 42 and 60 (mean 51.2 ± 4.8 kg/mp 2, body weight: 274 to 416 pounds). These subjects do not have current or past psychiatric and/or neurological disease, hypertension, diabetes, or medical conditions that may alter cerebral functioning. Interestingly, in the obese subjects, but not in the controls, the dopamine D2 receptors were significantly associated with their BMI (Figure 3, page 109). The results indicate that the dopamine D2 receptors are not involved in modulating body weight per se but may regulate compulsiveness in the pathological eaters. This would imply that the role of the dopamine D2 receptors is not to enable obesity but if the pertinent genetic or environmental variables that predispose to obesity are present, then it will favor a more severe presentation. The obese subjects share in common with drug addicts the inability to restrain from using the reinforcer and its compulsive administration. Thus dopamine D2 decrements are unlikely to be specific for any one of these compulsive behavioral disorders including obesity and may relate to vulnerability for addiction.
DOPAMINERGIC INVOLVEMENT IN THE MOTIVATION FOR FOOD INTAKE
Though the effects of dopamine in the nucleus accumbens are the ones traditionally implicated in motivation for food,41 a study in dopamine deficient knockout mice provided vance of the dorsal striatum in the motivation for food consumption. In dopamine deficient mice that might die because of lack of food consumption, rescuing dopamine in the dorsal striatum but not in the nucleus accumbens restored feeding.42 In these animals rescuing dopamine in the nucleus accumbens restored the ability of the mice to choose between a palatable and a nonpalatable solution but did not prevent them from dying due to inadequate caloric consumption. The latter study points to two separate processes regulating food intake; one to maintain the caloric requirements necessary for survival that implicates the dorsal striatum and another one that relates to the rewarding properties of food (palatability) that implicates the nucleus accumbens.
To assess the involvement of dopamine in the dorsal striatum in the nonhedonic motivation for food intake in human subjects, we evaluated changes in extracellular dopamine in striatum in response to food stimulation (visual, olfactory and gustatory display of food in food-deprived subjects) after placebo and after methylphenidate.43 In this study, methylphenidate was given as a strategy to amplify dopamine signals. Neither the neutral stimuli (with or without 20 mg of oral methylphenidate) nor the food stimuli when given with placebo increased dopamine or increased the desire for food. However, the food stimuli when given with methylphenidate increased both extracellular dopamine and the desire for food. We found that changes in extracellular dopamine in striatum in response to food stimulation were significant in dorsal but not in ventral striatum and were significantly correlated with the increases in self-reports of hunger and desire for food. Such a relationship was not observed for the ventral striatum where the nucleus accumbens is located. Our results showing an effect in the dorsal but not in the ventral striatum is likely to reflect the fact that the food stimulation to the subjects was not rewarding (in this study subjects were not permitted to consume the food).
COMPULSIVE OVEREATING AND DRUG PREFERENCES
One of the challenging questions regarding the neurobiological mechanism(s) underlying these disorders is why some subjects abuse drugs while others do not. We investigated this problem in drug-naive normal individuals in whom we measured dopamine D2 receptor levels and assessed their response (pleasant or unpleasant) to a challenge dose of die stimulant drug, methylphenidate (0.5 mg/kg), given intravenously. We found that normal subjects who reported the methylphenidate as pleasant had lower dopamine D2 receptor levels.44 Those who did not like methylphenidate had higher dopamine D2 receptor levels. However, the variability in the drug liking responses could not be explained solely on the differences in dopamine D2 receptor availability. This indicated that there were other variables that modulate these responses. It is also possible that the relative role that the dopamine D2 receptors had on eating behavior may differ between obese and control subjects; so in obese subjects, dopamine D2 receptors may play a greater role in regulating eating behavior than in control subjects. Studies to assess if low levels of dopamine D2 receptors affect the responses to food in nonobese subjects are required to determine if low dopamine D2 levels may in fact be associated with a higher vulnerability for addictive behaviors.
Figure 3. Linear regression between dopamine receptor availability (Bmax/Kd) and body mass index (kg/m2) for obese and control subjects separately, dopamine D2 receptors availability was significantly decreased in the obese subjects in proportion to their body mass index, while not in the control subjects.
Adapted from Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet. 2001; 357:354-357.
MODULATION OF BRAIN DOPAMINE AND OBESITY
The results from these studies have implications for the treatment of obesity since they would suggest that strategies aimed at improving dopamine function might be beneficial in the treatment of obesity. In fact, psychostimulant drugs (amphetamine,45 cocaine,46 and metfiylphenidate47), which increase extracellular dopamine, are anorexigenic and this effect is blocked by dopamine receptor antagonists. Unfortunately the therapeutic benefit of these drugs is limited by their addictive and psychoactive properties. To our knowledge there are currently no dopaminergic anorexigenic drugs that are not reinforcing. However, strategies to enhance dopaminergic function could involve behavioral interventions such as exercise.
Even though obese individuals have either normal or high absolute levels of energy expenditure,48 studies of physical activity in obesity have reported that physical activity decreases as percentage of overweight increases.49 Dopamine is the principal neurotransmitter of tile brain, directly involved in motor control in the striatum and is key to the mechanism underlying increased and maintained efficiency of physical activity. In vivo microdialysis studies in laboratory animals have shown that the release of dopamine is influenced by exercise.30 Endurance exercise training can also alter the number of dopamine D2 binding sites and the metabolism of dopamine in young adult animals.51
SENSORY PROCESSING OF THE FOOD AND OBESITY
What makes obese subjects different from drug addicts? Would obese subjects have an enhanced sensitivity in the brain regions involved with sensory processing of tiie food? Signals that affect food intake originate from internal sources that directly regulate food intake (hunger, satiety) and those that regulate emotional responses to factors such as stress or boredom as well as from environmental sources (food availability, food related cues, alternative reinforcers).52 Disruption in die sensitivity of the brain to these sources could lead to obesity from excess eating. Irrespective of the source, a particularly relevant variable in the regulation of food intake is the sensory appeal that the food conveys to the subject. Thus we questioned whether obese subjects would have an enhanced sensitivity in the brain regions involved in sensory processing of the food associated with eating. We compared brain metabolism of obese subjects with lean control subjects using PET and 2-deoxy-2[18F]fluoro-D-glucose, an analog of glucose, which has been served as an indicator of brain function. This method has been used to assess cerebral dysfunction in neurological and psychiatric disorders.53 The brain metabolic images were analyzed using statistical parameter map, which showed that obese subjects had significantly greater glucose metabolism in the vicinity of postcentral gyrus of left and right parietal cortex (Brodmann 's areas I).54 This area of the parietal cortex is where me somatosensory maps of the mouth, lips, and tongue are located and is an area involved with taste perception.55 The enhanced activation of these parietal regions is consistent with an enhanced sensitivity to food palatability (consistency, taste) in obese subjects. The enhanced activation in somatic parietal areas for mouth, tongue, and lips in obese subjects suggests that enhanced sensitivity in regions involved in the sensory processing of food may make food more rewarding and may be one of the variables contributing to excess food consumption in these obese individuals.
MODULATION OF SENSORY PROCESSING OF THE FOOD IN OBESE INDIVIDUALS
Because foods with high palatability tend to have high energy content but are not satiating (fatty foods) in contrast to foods with low energy density that are more satiating but less palatable,56 enhanced sensitivity to food palatability could lead to food over-consumption and obesity. Palatability increases food intake through a positive-feedback reward mechanism that involves the opioid and Y-aminobutyric acid/benzodiazepine systems.57,58 Thus interventions that include the use of pharmacological treatments known to decrease palatability (opioid receptor antagonist)59 in association with behavioral therapies to reduce the likeness of food with high energy content may prove beneficial in reverting the enhanced sensitivity of the somatosensory areas processing food palatability and reducing food intake in obese subjects.
Though obesity is the product of many interacting variables, there is mounting evidence that the motivation and reward circuits regulated by dopamine play a role. Our PET studies show obese individuals have significantly lower dopamine D2 receptor levels, a finding that is similar to findings in PET studies in addicts of substance of abuse. Lower D2 receptors in obese individuals would make them less sensitive to reward stimuli, which in turn would make them more vulnerable to food intake as a means to temporarily compensate for this deficit. In addition, obese individuals show an enhanced activity of brain regions that process food palatability, which is likely to increase the rewarding properties of food and could account ** the powerful salience that food has in obese individuals. Understanding the mechanism in food intake will help in the treatment of obesity.
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