Share this page 

The DRD2 and OPRM1 genes function in the brain reward system. Variations in these genes are associated with emotional eating and weight gain. About 11% Caucasians and 14% Asians carry a combination of these two genes that increase their risk for binge eating disorder.


Emotional eating is driven by emotional cues like depression, anxiety, happiness, sadness, and boredom rather than hunger. By engaging in emotional eating, we are subconsciously seeking comfort or pleasure from food.

Emotional eating can lead to weight gain for people who also have a low satiety. In severe cases, it can lead to binge eating, also known as compulsive eating. Binge eating is a subtype of emotional eating. When emotional eating is out of control over what or how much an individual eats, it becomes binge eating disorder. About 3.5% of women and 2% of men in the United States are diagnosed with binge eating disorder at some point in their life.

Emotional eating is mainly regulated by the reward systems in the brain. The four aspects of the brain reward system: motivation (wanting), outcome (liking), memory (learning) and habituation (adapting) determine how a cue (food, drug, money, promotion etc.) is perceived, liked, memorized, expected or even forgotten.

The rewarding properties of foods, mainly the palatability, act like addictive substance (such as alcohol or marijuana) in the reward system of human brain to produce the feeling of pleasure. Palatability is the overall attractiveness of a food judged by its flavor, taste and texture. In human population, sweet (i.e., high-sugar) and high-fat diets are generally considered palatable. Although most people like fatty and sugary foods to various levels, not all of us are “sweet tooth”.  Some people are rather indifferent to the tasty pleasures of life. The difference is explained in part by the genetic variations in the emotional eating genes. And there are many of them. The DRD2 and OPRM1 genes are two better understood ones.

The DRD2 gene is a key player in the dopamine neuronal circuits. Dopamine is the “feel good” neurotransmitter that motivates people for pleasure. Low level of dopamine is often blamed for depression related conditions. The OPRM1 gene, on the other hand, is a key play in the opioid neuronal circuits. Activation of the opioid neuronal circuits leads to the production of dopamine. Activities of the opioid system also determine how much you enjoy the pleasure.  These neuronal circuits interact with each other and with other neuronal circuits to produce an overall “reward value” of a food. This “reward value” influences eating behaviors. An imbalanced activity among various neuronal circuits often leads to emotional eating. People suffering from binge eating disorder appear to be highly active in both the dopamine and the opioid systems.

A variation in the DRD2 gene results in a reduced dopamine function in the brain. People carrying this variation have an increased risk for addiction disorders as well as increased risk for obesity. In these individuals, palatable foods are used as passive compensatory means for the decreased dopamine activity during emotional eating. In other words, they have to eat more to get the same satisfaction (“reward value”) from the foods. This variation is distributed in about 18% of Caucasians, 38% of Africans and 39% of Asians (Table 1).

A variation of OPRM1 increases activity in the opioid neuronal circuits. Carriers of this variant have greater risk for drug addiction and heightened sensitivity towards both physical and emotional pain. Despite showing a preference for sweet and fatty foods, these people are less likely to gain weight than non-carriers, possibly due to their heightened satisfaction. About 38% of Asians, 16% of Caucasians, and 1% of Africans carry this variant (Table 1).

Surprisingly, it is the combination of the above OPRM1 variant and the normal DRD2 gene (not the DRD2 variant leading to reduced dopamine function) that results in a dramatically increased risk for binge eating disorder. This combination represents the highest sensitivity toward palatable foods. People carrying this combination are less likely to gain weight. But when they eat palatable foods too often, they are very likely to develop “addition” to the foods by the same mechanism that account for addiction to abusive substances. At a point when the addiction of palatable food is out of control, binge eating occurs. So does the rapid weight gain and dramatically increased risk for obesity associated with binge eating. About 11% Caucasians and 14% Asians have this combination (118G + Taq1A2A2 in Table 1) while very few Africans (less than 0.4%) have it.

Table 1. Frequency of the risk variants and the risk combination of the DRD2 gene and OPRM1 gene in major ethnic groups.

Gene Risk Variant Minor allele frequency
Caucasians Africans Asians
DRD2 Taq1A1 18% 38% 39%
OPRM1 118G 16% 1% 38%
DRD2-OPRM1 118G + Taq1(A2A2) 11% 0.4% 14%

However, just having these gene variants or combination does not automatically make an emotional eater or a binger eater. Only when you have had the experience of enjoying a particular food do emotional cues interact with your genes to create cravings for that food, also known as a trigger food. A general strategy for emotional eating is trigger food control.

You can remove trigger foods from visible place to create an “out of sight is out of mind” mentality. You can also substitute the “high sugar” and “high fat” foods with the diet versions that give you the same palatability but no much calories. After all, it is the palatability, not the calorie of the foods that modulate the reward system. Naturally available palatable foods happen to be the ones mostly loaded with calories. During human evolution, our ancestors developed the preference for palatable foods because of the calories supported survival in times of food shortage. Today, in the land of food abundance, we retained the genes that made us preferring to palatable foods. But we don’t want the calories anymore. This is how the diet versions of every food are created.

GB HealthWatch scientists have worked out detailed techniques for trigger food control and for smart food choices that can help you cope with cravings. Log in now to see our tips.

[Read More]

The dopamine and opioid neuronal circuits locate in several brain areas including the hypothalamus, prefrontal cortex, amygdala, and hippocampus. These areas of the brain are critical to attention, judgment, decision making, learning, memory, and behavior control. They all have roles in the brain reward system when dealing with food.

The hypothalamus processes information related to the taste, hedonic valuation (liking), and motivational (wanting) properties of foods. The orbitofrontal cortex and amygdala encode information related to the reward value, such as how much risk you are willing to take for getting the reward, of food. And the hippocampus is responsible for reward memories such as whether one ate, what environment was associated, where the foods are located, and how to pleasurable the foods were (Fig. 1).

The dopamine and opioid neuronal circuits also extend to spinal cord and peripheral systems to receive and send signals for physiological processes in the lung, blood vessels, the kidney and the gastric intestinal tract. Through these connections, the hunger hormone ghrelin and the satiety hormone leptin influence the reward effect of the food. The dopamine and opioid neuronal circuits overlap and interact with each other, and interact with many other neuronal systems, such as the cannabinoids and serotonin systems to determine the overall outcome of the rewards system. For example, activation of the opioid neurons inhibit the release of the neurotransmitter GABA while increase the release of dopamine.

Areas of the Human Brain Activated in Response to Palatable Food or Food-Associated Cues

Figure 1. Areas of the Human Brain Activated in Response to Palatable Food or Food-Associated Cues. The orbitofrontal cortex and amygdala encode information related to the reward value of food. The insula processes information related to the taste of food and its hedonic valuation. The nucleus accumbens and dorsal striatum, which receive dopaminergic input from the ventral tegmental area and substantia nigra, regulate the motivational and incentive properties of food. The lateral hypothalamus may regulate rewarding responses to palatable food and drive food-seeking behaviors. These brain structures act in a concerted manner to regulate learning about the hedonic properties of food, shifting attention and effort toward obtaining food rewards and regulating the incentive value of environmental stimuli that predict availability of food rewards (Kenny 2013).

Dopamine and Dopamine receptors

Dopamine is a “feel good” neurotransmitter that makes you not only feeling good about yourself but also have good feelings toward others. Low levels are often associated with lack of motivation and depression. Reduced dopamine levels are known as a risk factor for addiction disorders. Addictive substances, palatable foods included, cause the euphoric sensation by increasing dopamine levels in the brain.

Dopamine is synthesized in the hypothalamus areas of the midbrain called substantia nigra and ventral tegmental area (Fig. 1) and is transmitted to other parts of the nervous system through the neuron networks called dopaminergic pathways. There are many dopaminergic pathways in human body functioning in a variety of physiological processes. Dysfunctions of these pathways are accounted for schizophrenia, bipolar disorder, Parkinson’s disease, attention deficit/hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD) etc. Many medicines target the dopaminergic pathways in one way or another. For example, MOA inhibitors for depression treatment and COMT inhibitors for Parkinson’s disease target enzymes that break down dopamine; bupropion for quitting smoking targets the dopamine reuptake; and the antipsychotic medicine aripiprazole used for treating schizophrenia and bipolar disorder partially function through the dopamine D2 receptor.

Dopamine functions through five dopamine receptors: D1 through D5. These receptors belong to a class of G-protein coupled receptors distributed in the central nervous system. Activities of these receptors are responsible for many processes such as motivation, pleasure, cognition, memory, learning, and fine motor control.

DRD2 gene polymorphism and obesity risk

Dopamine plays a critical role in food reward through the dopamine D2 receptor in the hypothalamus of midbrain area called dorsal striatum (Fig. 1). Transgenic mouse that unable to synthesize dopamine die of starvation due to lack of motivation to eat. Restoring dopamine in the dorsal stratum rescues these mice, whereas restoring dopamine in another area such in the nucleus accumbens (Fig.1) does not.

The dopamine D2 receptor is encoded by the DRD2 gene. A single nucleotide polymorphism (SNP) known as the Taq1A polymorphism (SNP# rs1800497) is the most studied genetic variation related to the DRD2 gene. This SNP does not reside in DRD2, but in a neighboring gene called Ankyrin Containing Kinase 1 (Neville et al., 2004). It is characterized by the reaction to the restriction enzyme Taq1 cutting. The variant that is resistant to the cutting is designated as Taq1A1 allele (which corresponds to the minor allele A at this SNP) and the variant that is cut by Taq1 is designated as Taq1A2 (corresponding to the major allele G).

The TaqA1 allele has a 30–40% reduction in D2 receptor density in the dorsal striatum (Jönsson et al., 1999). As the result, individuals carrying the Taq1A1 allele have a reduced brain dopamine function and a decreased activity to experience natural reward compared to those with the A2A2 genotype. The decreased dopamine function renders the A1 allele carriers an increased risk for addiction disorders such as alcoholism, drug (cocaine, nicotine and opioid) dependence, and pathological gambling (Noble, 2003).

Decreased D2 receptor availability correlates with increased risk for overweight and obesity. In obese people the dopamine D2 receptor is reduced when compared to lean individuals. It is hypothesized that the reduced dopamine D2 receptor fosters eating as the compensatory means for the decreased dopamine activity (Wang et al., 2001). Since the A1 allele of the TaqlA1 gene is associated with reduced dopamine D2 receptors, it is not surprising to see its association with increased BMI and obesity risk (Stice et al., 2008).

Using brain image technology, Stice and colleagues studied activation of the dorsal striatum in response to eating palatable chocolate milkshake in female college students. They found a reverse correlation: a greater BMI correlates a less activated dorsal striatum. And this inverse correlation is amplified by the presence of the TaqIA A1 allele.  One year later, individuals with the A1 allele who recorded lower dorsal striatum activation gained more weight than those who recorded higher activation. A follow-up study found that it was the activity of dorsal stratum after seeing, not actually eating the chocolate milkshake that correlated with weight gain in the A1 allele carriers (Stice et al., 2008; 2010). These findings suggest that lower dopamine function in response to the motivation of the reward, as indicated by the lower response to seeing the palatable chocolate milkshake in female college students, is the root cause of weight gain for the A1 allele carriers.

Opioid systems

The major players of the opioid system are opioids and opioid receptors. Opioids are molecules that activate the neurons by binding to the opioid receptors distributed in the brain, spinal cord and peripheral neuronal systems. There are two types of opioids: endogenous and exogenous.

Endogenous opioids are small peptides that are produced by human body as neurotransmitters. Levels of these peptides control neurological processes involved in pain, reward, appetite, and mood. The major groups of endogenous opioids include endorphins, endormorphins, dynorphins, eukephalins, and noceteptin. Endorphins are credited with the “runner’s high”, the euphoria and happiness feeling generated by strenuous exercise.
Exogenous opioids are chemicals that activate the opioid system when introduced into human body. There are many of them. The most common exogenous opioids are pain killer medicines such as hydrocodone, oxycodone, morphine, codeine, etc. Many abusive drugs such as heroin and methadone are exogenous opioids.

Opioid antagonists are the chemicals that binds opioid receptors but do not activate them. They are often used as medicines for treating drug addiction. Naloxone and natrexone are the two most common opioid antagonists.

All opioids and opioid antagonists function through three types of opioid receptors: mu (µ), delta (δ) and kappa (κ). Activation or suppression of these receptors leads to increased or decreased pain, euphoria, appetite, anxiety, depression, or respiratory depression. The µ-opioid receptors are the major ones involved in brain reward systems and addictive behaviors. They are also involved in the pain relieve by morphine.

OPRM1 gene polymorphism and food preference

The opioid system modulates how much people eat according to the palatability of the foods. This modulation functions through the µ-opioid receptor. Administration of µ-opioid receptor agonists in animals can induce binge eating of fat, but cannot induce binge eating of foods lacking fat and sugar, whereas antagonist such as naloxone decreases intake of a palatable food but not a bland one (Will et al., 2004; Olszewski & Levine, 2007).

The µ-opioid receptor is encodes by the OPRM1 gene. OPRM1 gene knock out mouse abolished the response to the painkiller morphine (Matthes et al., 1996). Mouse pups with this gene knocked out lost attachment to their mother (Moles et al., 2004). Otherwise the knockout mice seem normal.
A variation in the OPRM1 gene, the SNP A118G (rs1799971), is caused by a structural change of the receptor. The A to G nucleotide substitution changed the amino acid from asparagine (Asn) to aspartic acid (Asp) at position 40 of the protein, resulting in an about 3-times greater affinity for endorphin and morphine. Therefore, it represents a “gain-of-function” variation, which mimics the administration of OPRM1 agonists in the aspect of increased activity.

People carrying the G allele show a greater tendency to alcohol craving and drug abuse in general (Ray & Hutchinson, 2004; van den Wildenberg et al., 2007; Filbey et al., 2008) and a greater sensitivity toward pains inflicted by physical pain (Branford et al., 2012) as well by social rejection (Way et al., 2009). A study in Uyghurs population showed that the G-allele was also associated with decreased BMI (Xu et al, 2009).

Study by Davis et al (2011) showed the G-allele homozygous genotype carriers prefer fatty and sweet foods more that the heterozygous or AA genotype carriers do. It seems that GG individuals are innately prone to assigning a higher reward value, which in turn promotes a strong appetitive response to highly palatable food (Davis et al., 2011). Nevertheless, the G-allele carriers have a lower risk for overweight and obesity.

DRD2, OPRM1 and Binge Eating Disorders

A higher risk for weight gain associated with the Taq1A1 allele of the DRD2 gene means a lower risk for weight gain associated with the A2A2 genotype. One would then expect the combination of the G-allele of the OPRM1 gene, which is also associated with lower risk of weight gain, and the A2A2 genotype of the DRD2 gene represent the lowest risk for obesity. It turned out to be true according to the report by Davis et al (2009).

In a study of obese populations, the combination of the A2A2 genotype of the DRD2 gene and the G-allele of the OPRM1 gene (A-/G+ in Fig. 2) was the least frequent allele combination in the obese control group, defined by those who are obese but not binge eaters.  However, this combination was also the most frequent one in the group characterized by obese and binge eating (BED group in Fig. 2). These data suggest that the A1-/G+ combination is the cause of binge eating. Since the A1- is associated with a higher dopamine D2 receptors and the G allele is associated with an increased opioid activation, the A1−/G+ combination reflects a hedonic-enhanced genotype combination, one that increase the risk for binge eating.

The fact that the majority (80%) of the A1−/G+ genotype were in the binge eating group while most of the A1+/G− genotype (65%) were in obese controls (Fig. 2) suggests that obesity and binge eating are two different traits. The underling mechanisms for each of them are distinct. Bing eating can lead to obesity whereas obesity can be cause by many other factors other than binge eating.

Figure 2. Percentage of obese participants with and without binge eating in each of the four gene–gene combination groups formed by the Taq1A and A118G SNPs. Here A1+ refers to A1A1 or A1A2 genotypes while A1- refers to A2A2 genotype; G+ refers to GG or GA genotypes while G- refers to AA genotype (Davis et al, 2009).

Interventions

The function of foods in the reward system is independent of their calorie content (Wang et al, 2004). It is the palatability, not the calorie of the foods that modulate the reward system. In this sense, the effect of palatable foods is very similar to that of the abusive drugs such as cocaine or nicotine, which are devoid of calorie or nutrient value. Palatable foods just happen to be mostly loaded with calories. Therefore, one of the options to weight control is switching to diet foods that replace sugar with saccharin or other artificial sweeteners.

Emotional eating is a behavior that can be triggered by emotions as well as palatable food.  While overcome the underline emotions may require social support or even professional help, a variety of techniques can help you reduce emotional eating by dealing with the trigger food. Log in now to see these tips designed specifically to help you minimize the impact of trigger foods.

Those who are suffering a binge eating disorder need to seek help from medical professionals or clinic psychologists for treatment.

References

1. Berridge KC. 2007. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 191(3):391-431. PMID:17072591
2. Branford R, Droney J, Ross JR. 2012. Opioid genetics: the key to personalized pain control? Clin Genet. 2012 Oct;82(4):301-10. doi: 10.1111/j.1399-0004.2012.01923.x. Epub 2012 Jul 27. Review. PMID:22780883.
3. Davis CA, Levitan RD, Reid C, Carter JC, Kaplan AS, Patte KA, King N, Curtis C, Kennedy JL. 2009. Dopamine for “Wanting” and Opioids for “Liking”: A Comparison of Obese Adults With and Without Binge Eating. Obesity, 17(6):1220-5. PMID:19282821
4. Epstein LH, Temple JL, Neaderhiser BJ, Salis RJ, Erbe RW, Leddy JJ. 2007. Food reinforcement, the dopamine D2 receptor genotype, and energy intake in obese and nonobese humans.Behav Neurosci. 121(5):877-86. PMID:17907820
5. Jönsson EG, Nöthen MM, Grünhage F, Farde L, Nakashima Y, Propping P, Sedvall GC.1999. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry. 4(3):290-6. PMID:10395223
6. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dollé P, Tzavara E, Hanoune J, Roques BP, Kieffer BL. 1996. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature. 1996 Oct 31;383(6603):819-23. PMID:8893006
7. Moles A, Kieffer BL, D'Amato FR. 2004. Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science. 304(5679):1983-6. PMID:15218152
8. Neville MJ, Johnstone EC, Walton RT. 2004. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 23:540–545. PMID:15146457
9. Noble EP. 2003. D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotype. Am J Med Genet B Neuropsychiatr Genet;116B:103–125. PMID:12497624
10. Olszewski PK, Levine AS. 2007. Central opioids and consumption of sweet tastants: when reward outweighs homeostasis. Physiol Behav. 15;91(5):506-12. Epub 2007 Jan 30. Review. PMID:17316713
11. Ray LA, Hutchison KE.2004. A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res. 2004 Dec;28(12):1789-95.PMID:15608594
12. Stice E, Spoor S, Bohon C, Small DM. 2008. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science 322, 449–452. PMID:18927395
13. Stice E, Yokum S, Bohon C, Marti N, Smolen A. 2010. Reward circuitry responsivity to food predicts future increases in body mass: Moderating effects of DRD2 and DRD4. Neuroimage 50, 1618–1625. PMID:20116437
14. van den Wildenberg E, Wiers RW, Dessers J, Janssen RG, Lambrichs EH, Smeets HJ, van Breukelen GJ. 2007. A functional polymorphism of the mu-opioid receptor gene (OPRM1) influences cue-induced craving for alcohol in male heavy drinkers. Alcohol Clin Exp Res. 31(1):1-10. PMID:17207095
15. Volkow ND, Wang GJ, Baler RD. 2011. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 15(1):37-46. doi: 10.1016/j.tics.2010.11.001. PMID: 21109477
16. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. 2001. Brain dopamine and obesity. Lancet. 357:354–357. PMID:11210998
17. Wang GJ, Volkow ND, Thanos PK, Fowler JS. (2004). Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. J. Addict. Dis. 23, 39–53. PMID:15256343
18. Way BM, Taylor SE, Eisenberger NI. 2009. Variation in the m-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection. Proc Natl Acad Sci;106: 15079–15084. PMID:19706472
19. Will MJ, Franzblau EB, Kelley AE. 2004. The amygdala is critical for opioid mediated binge eating of fat. Neuroreport 15:1857–1860. PMID:15305124
20. Xu L, Zhang F, Zhang DD, Chen XD, Lu M, Lin RY, Wen H, Jin L, Wang XF. 2009. OPRM1 gene is associated with BMI in Uyghur population.Obesity (Silver Spring). 17(1):121-5. doi: 10.1038/oby.2008.504. PMID:19008867



copyright © 2013 gbhealthwatch.com All rights reserved.