How Can Drug Addiction Help Understand Obesity PDF

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F E E D I N G R E G U L AT I O N A N D O B E S I T Y C O M M E N TA RY How can drug addiction help us © 2005 Nature Publishing Group http://www.nature.com/natureneuroscience understand obesity? Nora D Volkow & Roy A Wise To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry. Until recently in our evolutionary history, physiological stimulation of reward pathways contribution to the variability of smoking in addictive agents have been ingested in foods. by drugs not only stamps in response habits women is greater now than in earlier decades Many are secondary plant metabolites that and stimulus preferences, but also triggers when social restrictions on females were evolved because they discourage ingestion by neurobiological adaptations that may make stronger and fewer women tried cigarettes3. animals1. The hungers that arise from bodily the behavior increasingly compulsive and lead Just as the genetic influences in addiction vary needs are non-directive; they merely encourage to further loss of control over intake. between cultures with differential availability us to put things in our mouth. The more acute Not all humans who are exposed to habit- of alcohol, so too is the genetic contribution the hunger, the greater the range of substances forming drugs become addicted, just as not to obesity likely to differ between societies we will ingest2. We learn to return to the yellow all humans who are exposed to high-fat, high- that differ in the acceptance and availability banana, the purple fig, the pink peach. We also calorie foods become obese. Although some of high-calorie, high-fat foods. learn to chew the tobacco leaf and drink the classes of obesity can be linked to known Genetic studies have revealed point muta- nectar of fermented fruits and grains. Because genetic polymorphisms, the recent epidemics tions that are of importance for obesity7 and of the need for the nutrients in plants con- of obesity and of certain addictions are more for addiction8. However, addiction and obesity taining addictive substances, many species clearly correlated with the increased avail- are also thought to be under polygenetic con- have learned to accept mildly intoxicating ability of ‘comfort foods’ and of drugs or drug trol. Addiction-prone and addiction-resistant amounts of these compounds. Paradoxically, forms such as methamphetamine and ‘crack’ rat phenotypes are associated with differing some of the poisons that evolved in plants to cocaine than to drift in the genome. Thus sensitivity to the various stressors in the envi- discourage animals from returning are—like obesity, like addiction, is linked strongly with ronment9,10, and stress has a potential role the nutrients that the plants offer—habit- exposure to powerful reinforcers. in obesity11as well as addiction12. Moreover, forming in their own right. broad-based factors such as gender affect both Addiction and obesity each results from Genetic factors in obesity and addiction feeding13 and drug taking14. Thus, it is very foraging and ingestion habits that persist Individuals suffering from addiction or from possible that there are polygenic genotypes that and strengthen despite the threat of cata- obesity are stigmatized in part by the belief confer risk for both obesity and addiction. strophic consequences. Feeding and drug use that the decision to overeat or to take drugs is involve learned habits and preferences that completely under voluntary control. Yet addic- Environmental factors are stamped in by the reinforcing properties tion and obesity are multifactorial disorders Of the environmental factors that influence of powerful and repetitive rewards. Palatable that have significant genetic components. obesity and addiction, the availability of food activates brain reward circuitry through As much as 40–60% of the vulnerability seductive foods and drugs is the most obvious. fast sensory inputs and through slow post- to addiction3,4 and 50–70% of the variability For the greater part of human evolution, sweet ingestive consequences (such as raising glucose in body mass index5 might be attributed to taste was associated with fruits that afforded concentration in blood and brain), whereas genetic differences under the specific circum- quick energy. However, genes that were favored drugs activate these same pathways mostly stances of the studies. However, estimates of under conditions of food scarcity have become through their direct pharmacological effects heritability under one set of circumstances are a liability in societies where high-energy, on the reward circuitry. The repeated supra- not necessarily valid for others. The contribu- highly refined foods are prevalent and read- tions of genetic and environmental factors are ily affordable. Indeed, the recent escalation in Nora D. Volkow and Roy A. Wise are at the National not simply additive; rather, they interact in the prevalence of obesity has developed over a Institute on Drug Abuse, National Institutes of complex and sometimes counterintuitive ways. period when the genome has changed little but Health, Bethesda, Maryland 20892, USA. For example, the contribution of genotype to the availability of low-cost, high-fat, high-car- e-mail: [email protected] variability in the body mass of sheep is greater bohydrate foods has changed dramatically (for Published online 26 April 2005; doi:10.1038/nn1452 in September than in June6 and the genetic instance, in vending machines, convenience NATURE NEUROSCIENCE VOLUME 8 | NUMBER 5 | MAY 2005 555  C O M M E N TA R Y Table 1 Comparison of food and drugs as reinforcers sumption and drug taking. Experimentation with drugs often starts in early adolescence23. Food Drug Behaviors such as risk-taking, novelty-seek- ing and response to peer pressure increase Potency as a reinforcer* ++ Oral: ++ Snorted: +++ the propensity to experiment with drugs. The Smoked, injected: ++++ adolescent onset of these behaviors may reflect delayed maturation of the prefrontal cortex, Delivery Oral Oral, snorted, smoked, a brain region involved with judgment and injected inhibitory control24. In addition, drug expo- © 2005 Nature Publishing Group http://www.nature.com/natureneuroscience Mechanism of reward Somatosensory (palatability), Chemical (drug) sure during adolescence can result in different chemical (glucose) neuroadaptations from those that occur during Regulation of intake Peripheral and central factors Mostly central factors adulthood. For example, in rodents, exposure to nicotine during the period corresponding to Adaptations Physiologic Supraphysiologic adolescence, but not during adulthood, leads Physiological role Necessary for survival Unnecessary to significant changes in nicotine receptors and Learning Habits, conditioned responses Habits, conditioned an increased reinforcement value for nicotine responses later in life25. Exposure to drugs during fetal development may also increase the vulnerabil- Role of stress +++ +++ ity to drug use later in life. Indeed, smoking *Potency as reinforcer is estimated based on the magnitude and duration of increases in dopamine induced by either during pregnancy increases the risk of nicotine food or drugs in the nucleus accumbens, and is an approximate comparison, as potency will be a function of the dependence in the offspring26. Interestingly, it particular foodstuff or of the particular drug and its route of administration. also increases their risk for obesity27. Similarly, early exposure to certain diets during fetal stores and fast food restaurants). Similarly, hood18 and also with a higher risk of substance life and the immediate postnatal period can recent epidemics of addiction to cocaine and abuse and addiction19. The role of stress is influence the food preferences of an individual heroin have accompanied increased availabil- mediated in part by the corticotropin-releas- later in life28. Moreover, the marked increases ity and lower cost of these drugs. ing factor (CRF) and related peptides20. CRF in childhood and youth obesity in the United The quality of the reinforcer is another not only controls the pituitary-adrenal axis States (which has tripled in the past 30 years) factor of importance for addiction and obe- but also serves as a neuropeptide cotransmit- highlights the importance of investigating the sity (Table 1). In addiction, the strength of a ter in neurons orchestrating the central effects interactions between developmental variables drug as a reinforcer depends on its route of of stress21. CRF is well-known to be involved and the environment in this disorder. administration (intravenous and smoking in the regulation of energy balance and food routes are more reinforcing than snorting or intake22. Similarly, in addiction, CRF is rec- Neurobiological mechanisms oral administration) and dose. This is partly ognized for its involvement in stress-induced The biological mechanisms of feeding and because smoked or injected drugs reach the reinstatement of drug taking and vulnerability addiction have overlapped throughout our brain more quickly and partly because they to relapse20 and in the responses to acute drug evolutionary history. The opiate antagonist reach the brain in higher concentration15. In withdrawal12. naloxone inhibits feeding in mammals29, in addition, drugs of abuse are not equally addic- slugs and snails30 and even in amoebae31. tive. When animals are given unlimited access Developmental factors The most clearly established commonality to intravenous amphetamine or cocaine16, Developmental processes also seem to influ- of the mechanisms of food and drug intake they self-administer the drug to the point of ence the behaviors associated with food con- is their ability to activate the dopamine- death, whereas animals given unlimited access to intravenous nicotine17 do not. Just as different drugs establish different levels of compulsive behavior, so do different foods. Individuals in a high-fat, high-carbohy- drate environment are at considerably greater risk than those in a vegetarian environment. Notably, low-carbohydrate and low-fat diets have each been recommended as methods for weight loss, and each is effective for the time it is practiced. The common denominator of such diets is that neither allows consumption of the very caloric and seductive foods that combine high fat with high carbohydrates. Another important environmental factor is stress. Acute as well as chronic stress influ- Figure 1 Dopaminergic pathways. (a) Dopaminergic pathways. PFC, prefrontal cortex; CG, cingulate ences both food intake and the propensity to gyrus; OFC, orbitofrontal cortex; NAcc, nucleus accumbens; Amyg, amygdala; STR, striatum; take drugs. For example, childhood stress has TH, thalamus; PIT, pituitary; HIP, hippocampus; VTA, ventral tegmental area; SN, substantia nigra. been associated with elevated risk for problems (b) Increases in dopamine in nucleus accumbens induced by food and by amphetamine as assessed by with weight during adolescence or early adult- microdialysis in rodents. Graphs modified from ref. 60. 556 VOLUME 8 | NUMBER 5 | MAY 2005 NATURE NEUROSCIENCE © 2005 Nature Publishing Group http://www.nature.com/natureneuroscience C O M M E N TA R Y Figure 2 Relationship between dopamine (DA) D2 receptors in the brains of cocaine abusers and methamphetamine abusers, and metabolic activity in orbitofrontal cortex. containing link in brain reward circuitry32 bland food37. Indeed, the endogenous opioid and cholinergic modulation of the ventral (Fig. 1). Pharmacological blockade of, or exper- system seems to underlie the rewarding prop- tegmental area and medium spiny neurons in imental damage to, forebrain dopamine systems erties of palatable foods38. feeding and reward—considerable cross-fer- attenuates free feeding and lever-pressing for Thus the mesolimbic dopamine system tilization between the two literatures can be food reward, as well as the rewarding effects of and its afferents and efferents contribute expected to occur. cocaine, amphetamine, nicotine and alcohol33. to the rewarding effects of various addic- Although the mesolimbic dopamine projection tive drugs and of foods. These systems also Neurobiological adaptations from the ventral tegmental area to the nucleus seem to be modulated by substrates of energy The regulation of food consumption is much accumbens is most frequently implicated in regulation that are the topic of other papers more complex than that of drug consumption reward function, other forebrain dopamine in this issue. Not only does food deprivation because food intake is modulated by multiple projections are almost certainly involved34. potentiate the rewarding effects of food39, peripheral and central signals, whereas drugs Endogenous opioid systems interact at each chronic food restriction also potentiates the are modulated mostly by the drug’s central end of the forebrain dopamine systems. In the rewarding effects of lateral hypothalamic effects. However, addictive drugs, like addic- midbrain, µ opioid receptors are localized on brain stimulation40 and of most addictive tive foods, activate brain circuitry involved in GABAergic neurons that normally inhibit the drugs41. The adipocyte hormone leptin, reward, motivation and decision-making43. dopamine systems; µ opioids inhibit this input, which is lacking in obese ob/ob mice, not In addiction, it seems almost as if the brain thus disinhibiting the dopamine system and only suppresses food intake, but also reverses responds to the drug as it would respond to causing dopamine release in nucleus accum- the effects of food restriction on brain stimu- food under conditions of severe deprivation. bens and related target regions. In nucleus lation reward thresholds40 and on the rein- What leads to the increasing desire for the accumbens, µ opioid receptors are localized on statement of drug-seeking42 in an animal drug as addiction progresses? Researchers have GABAergic neurons that receive input from the model of addiction relapse. postulated that neurobiological adaptations mesolimbic dopamine system. Injections of µ Thus, in broad sketch, there is considerable initiated by chronic and intermittent supra- opioids into each of these regions is rewarding overlap between brain circuitry that evolved physiological perturbations in the dopamine in its own right35, and injections into each of in the service of body-weight regulation and system by a drug trigger changes in some of these regions potentiate feeding36. The role of brain circuitry that is usurped by exogenous the regions and neurotransmitter systems opiates in these areas seems to be to augment drugs of abuse. As the finer details of the brain modulated by dopamine44. Advances in neu- the intake of high-fat, high-sugar foods rather mechanisms of addiction and feeding are roscience have begun to provide insight into than to mimic the effects of nutritive deficit on worked out—such as the role of GABAergic the nature of these adaptations. NATURE NEUROSCIENCE VOLUME 8 | NUMBER 5 | MAY 2005 557  C O M M E N TA R Y cingulate gyrus) are implicated in motiva- tion to feed54. These prefrontal regions could reflect a neurobiological substrate common to the drive to eat or the drive to take drugs. Abnormalities of these regions could enhance either drug-oriented or food-oriented behav- iors, depending on the established habits of the subject. Neuroadaptations are also documented in © 2005 Nature Publishing Group http://www.nature.com/natureneuroscience the opioid system in cocaine abusers55 and in alcoholics56. Though there are no pub- lished studies in humans, preclinical studies show adaptations in the opioid system after administration of palatable foods (reviewed Figure 3 Role of dopamine D2 receptors in obesity. (a) Dopamine D2 receptors in controls and in obese individuals. (b) Relationship between D2 receptors and body mass index (BMI). in ref. 57). The neuroadaptations resulting from chronic food intake are likely to be more complex than those observed with drugs and are known to include changes in neuronal cir- Neurotransmitter adaptations are docu- is largely a search within the brain circuitry cuitry that modify the motivation to eat, as mented not only for dopamine but also for through which drugs exert their reinforcing well as neuroadaptations that modify energy glutamate, GABA, opiates and CRF, among effects. To the degree that the same circuitry is efficiency and metabolic thresholds57. others45. Some of these changes disrupt brain important for the reinforcing effects of food, function. For example, in cocaine-addicted neuroadaptations in this circuitry should Prevention subjects, imaging studies show that changes in affect food intake as well as drug intake. One of the most successful prevention inter- dopamine brain activity (reductions in dopa- The relevance of dopamine to obesity has ventions in public health in the last century mine D2 receptors and in dopamine release also been documented by both preclinical and was in promoting smoking cessation. Over a in striatum) are associated with disruption in clinical studies. In animal models of obesity period of 30 years, the prevalence of smoking the activity of the prefrontal cortex46 (Fig. 2). (including leptin-deficient ob/ob mice, obese in adults in the United States dropped from Disrupted function of the orbitofrontal cor- Zucker rats, obesity-prone Sprague-Dawley 42.4% in 1965 to 24.7% in 1995 (ref. 58). The tex (OFC) and the anterior cingulate gyrus, rats and seasonally obese animals), dopamine success of this intervention can be linked to regions of the prefrontal cortex involved activity is reduced in the tuberoinfundibular an effective educational campaign based on with salience attribution and with inhibitory pathway that projects to the hypothalamus49. solid scientific information about the deleteri- control, are particularly informative for the In these animals, treatment with dopamine ous health effects of smoking. Policy changes understanding of addiction, as their disrup- agonists reverses the obesity, presumably by that made cigarettes more expensive, selling of tion is linked to compulsive behaviors and activating dopamine D2 and D1 receptors49. cigarettes to minors illegal and smoking much poor impulse control46. In preclinical studies, In humans, brain imaging studies show reduc- more restricted in public spaces also contrib- drug-related adaptations in the prefrontal cor- tions in dopamine D2 receptors in the stria- uted to its success. The campaign also alerted tex specifically enhance activity of the cortico- tum of obese individuals that are similar in the medical community to the importance of striatal glutamatergic pathway that regulates magnitude to the reductions reported in drug- evaluating and treating smokers. All of these dopamine release in the nucleus accumbens47. addicted subjects50 (Fig. 3a). In obese subjects, factors were effective in producing dramatic Adaptations in this pathway have been linked but not in controls, dopamine D2 receptor changes in the attitude of the public toward to drug- and cue-induced relapse into drug- abundance is inversely related to body mass smoking. seeking in animal models. The extent to which index, suggesting that the dopamine system is The success of this intervention for an addic- the prefrontal abnormalities in addicted sub- involved in compulsive food intake (Fig. 3b). tion (to nicotine) can be used to suggest and jects (reported by imaging studies) result in Further support for this idea is provided by design an effective campaign to reduce obesity. disruption of corticostriatal glutamatergic clinical studies showing that chronic treatment As for the antismoking campaign, this should pathways (reported in preclinical studies) with drugs that block dopamine D2 receptors include education regarding healthy eating requires further investigation. (antipsychotics) is associated with a higher risk and exercising (as sedentary lifestyles have In addition to the adaptations in the targets of obesity51. Though decreases in dopamine also contributed to the increase in obesity). of the dopamine mesocortical pathway, there D2 receptors have been documented across a Interventions should be initiated in early child- is also evidence of adaptations in the targets of wide variety of drug addictions and in obesity, hood, because this is when children develop the dopamine mesolimbic circuit (including by themselves they are insufficient to account life-long eating habits and start to become neurons of the nucleus accumbens, amygdala for these disorders, and their role is likely to be overweight. It should also involve the medi- and hippocampus), which may underlie the one of modulating vulnerability. cal community, which should be prepared to enhanced motivation for the drug and condi- Similarly, imaging studies in obese subjects evaluate and treat obesity, along with the food tioned responses. Adaptations may also occur document abnormalities in prefrontal cor- industry, which should be encouraged to make in the targets of the dopamine nigrostriatal cir- tex52. When food-related stimuli are given to healthy foods more attractive, palatable and cuit (including the dorsal striatum)48, which obese subjects (as when drug-related stimuli less expensive, and policy makers, who should might underlie habits that are linked with the are given to addicts46), the OFC is activated consider incentives to facilitate these changes. rituals of drug consumption. The search for and cravings are reported53. Several areas of Finally, a campaign to reduce obesity should neuroadaptations associated with addiction the prefrontal cortex (including the OFC and involve institutions such as schools, with 558 VOLUME 8 | NUMBER 5 | MAY 2005 NATURE NEUROSCIENCE  C O M M E N TA R Y efforts to remove junk foods from dispensing Like addiction, obesity is a chronic condi- 7. Friedman, J.M. & Leibel, R.L. Tackling a weighty prob- lem. Cell 69, 217–220 (1992). machines and cafeterias where they help to tion with periods of protracted abstinence 8. Volkow, N.D. & Li, T.K. Drug addiction: the neurobiol- seduce young people into obesity, just as read- (restriction of seductive foods) and periods of ogy of behaviour gone awry. Nat. Rev. Neurosci. 5, ily available cigarettes helped, until recently, relapse (compulsive eating). Thus, treatment 963–970 (2004). 9. Kosten, T.A. et al. Acquisition and maintenance of seduce them into addiction. will in most cases require continuous care. intravenous cocaine self-administration in Lewis and One unique challenge for the prevention Large-scale prevention and treatment pro- Fischer inbred rat strains. Brain Res. 778, 418–429 (1997). of obesity arises because food, unlike drugs, grams for obesity (like those for addiction) 10. Ranaldi, R., Bauco, P., McCormick, S., Cools, A.R. is indispensable to survival. Thus, it will be will require the participation of the medical & Wise, R.A. Equal sensitivity to cocaine reward in much harder for a society to implement regu- community. The engagement of pediatricians addiction-prone and addiction-resistant rat genotypes. © 2005 Nature Publishing Group http://www.nature.com/natureneuroscience Behav. Pharmacol. 12, 527–534 (2001). lations to constrain the easy access to food that and family physicians might facilitate early 11. Dallman, M.F., Pecoraro, N.C. & la Fleur, S.E. Chronic can facilitate compulsive eating. What can be detection and treatment of obesity in child- stress and comfort foods: self-medication and abdomi- hoped for, however, is more restricted access to hood and adolescence. Unfortunately, as with nal obesity. Brain Behav. Immunity (in the press). 12. Kreek, M.J. & Koob, G.F. Drug dependence: stress and high-fat, high-calorie foods that are seductive addiction, physicians, nurses and psycholo- dysregulation of brain reward pathways. Drug Alcohol and unnecessary for good health, particularly gists receive little training in the management Depend. 51, 23–47 (1998). 13. Geary, N. Is the control of fat ingestion sexually dif- in public places such as schools. of obesity. ferentiated? Physiol. Behav. 83, 659–671 (2004). 14. Hu, M., Crombag, H.S., Robinson, T.E. & Becker, J.B. Treatment Conclusion Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology As in the treatment of drug addiction, scientific Obesity and addiction are special cases of the 29, 81–85 (2004). knowledge about the involvement of multiple consequences of ingestive behavior gone awry. 15. Volkow, N.D. et al. 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