Francis Gregory R Samonte*
College of Public Health Manila, University of the Philippines Manila, Philippines
Received Date: May 24, 2017; Accepted Date: June 01, 2017; Published Date: June 06, 2017
Citation: Samonte FGR. The Epigenetic of Dopamine Reward in Obesity and Drug Addiction: A Philippine Perspective. J Clin Epigenet. 2017, 3:2. doi: 10.21767/2472-1158.100051
The enormous challenges of developing countries in the world have brought changes not only in traditional lifestyle but also in the inherent cultural and behavioral norms. The changes in their diet have led to the current understanding of global nutrition transition, a developmental disease epidemic brought about by changes in the dietary habits in many developing countries. This dietary shift from traditional diet to processed food products have led to the increase prevalence of obesity and overnutrition. On top of the global nutrition transition, the epidemic of drug addiction is no longer attributed to high income countries but in low to middle income countries as well. Recent studies in developing countries have shown that the increase prevalence of obesity and overnutrition precedes the development of increase prevalence in drug addiction. Current understanding into the behavioral plasticity in obesity and drug addiction points to the dopaminereward system as a fundamental substrate into the developmental programming of these diseases. This paper examines the neural axis reward mechanism and the epigenetic implications which governs the development of obesity and drug addiction, a seemingly unrelated phenomenon and yet interrelated and connected by the same substrate mechanism based on a reward mechanism.
Drug addiction; Dopamine reward; Epigenetic; Behavior; Nutrition transition; Obesity
The global nutrition transition and substance abuse problems in developing countries
The global pandemic of obesity has led to significant public health issues that threaten to inundate institutions in many developing countries. The epidemiological change from infectious disease to Non-communicable Disease (NCD) etiology in these countries coincides with changes in their traditional diet. This shift in diet towards processed foods coupled by sedentary lifestyles has led to a profound increased in non-communicable diseases and related morbidities. In the past the level of understanding that obesity is primarily a disease of higher income countries and urban areas has changed to what is now a global disease burden and metabolic patterns that has important implications for the distribution of health inequalities especially in developing economies.
In Asia, the rapid shift of diet into increased consumption of high fat and sugar content in conjunction with decrease consumption of traditional high fiber and organic products has caused an increased prevalence of obesity, diabetes, and cardiovascular diseases. The dominant factor besides the shift in diet that contributes to the development of obesity in developing countries includes decreased physical activity and the increased accessibility to poor nutritional food products. In the Philippines, recent economic development has similarly led to the rapid rise of obesity and non-communicable diseases both in the urban and rural settings, where accessed to processed food has gained enormous market shares. In 2010, Philippine Health Statistics  data revealed that cardiovascular and metabolic diseases have replaced the position of infectious disease (tuberculosis) etiology as top-most common causes of death.
There have been few cross sectional studies available that examines the correlation between income and the association of overweight growth. Cross sectional data analysis from studies involving low and middle income countries have revealed that the association between country level income and increase in overweight prevalence has a direct correlation effect . The study revealed that in 73% of developing countries examined, the increase prevalence of overweight was positively related to a country’s increased GDP. Among countries with a higher GDP, lower income inequality was associated with faster overweight growth among the poor .
Drug addiction is considered as a chronic relapsing, behavioral disorder that should be treated like any other chronic illnesses. Globally, it is regarded as a major medical and social problem. Addiction to drugs and alcohol is increasingly becoming a worldwide trend in lifestyle that is prevalent in rich and poor countries alike. Addiction to alcohol, drugs and cigarette smoking is now regarded as a major public health problem .
The problem of drug addiction can lead to acute toxicity and long term health problem. The effects of acute toxicity from a single exposure like cocaine can lead to euphoria, reduced fatigue, and increased mental acuity at low doses. Heroin has been found to cause analgesia, euphoria, relaxation and sleep, reduced sex drive, drying of secretions and decreased blood pressure . These results reveal physiological physical functions that appear to be similar in obesogenic state; findings that are mediated by the dopamine-reward system.
At a chronic stage, the prolonged use of addictive drugs can lead to cognitive and psycho-behavioral impairment. The dependence is attributed to both physiological and emotional attachment. For instance the problems of attention, impulsivity, depression, mood, and schizophreniform disorders are encountered following marijuana use; while delusion, anxiety and perception disorders are more common from abuse of hallucinogens, methamphetamine, and cocaine .
The increased prevalence of overweight and obesity is a global health problem that requires a multidisciplinary approach. Recent estimates (2014) revealed that more than 1.9 billion adults were overweight, defined as individuals with Body Mass Index (BMI) of 25 kg/m2 or higher. Of these adults, over 600 million were classified as obese or with a BMI of 30 kg/m2 or higher as per World Health Organization (WHO) cut-offs . Other data suggests that by 2030 globally an estimated 2.16 billion adults will be overweight, and 1.12 billion will be obese . Developing countries in Asia, Africa and Latin America the burden is greater in magnitude due to inherent differences in the body composition, fat patterning, and the cardio-metabolic effects of BMI [6,7] these populations have a higher predilection to development of metabolic diseases. The results provide a staggering burden in the overall trends particularly in productivity and health care costs.
While the problem of under nutrition remains higher compared to overweight, current projections support a more rapid rise in overweight that will likely surpass under nutrition. In the Philippines prevalence of overweight children below five years old has become rampant. Recent studies conducted by UNICEF revealed that the problem of overnutrition in children increased by 4.3% from 2008 to 2012 . Government figures revealed the rise of overweight/obesity among adults from 1993 increased from 16.6% to 31.1% in 2013. The increase in the prevalence of overnutrition was further supported by increase in both waist circumference and waist hip ratio for adults, which serves as proxy indicators of overnutrition .
The problem of substance abuse is a global problem represented by approximately 246 million people whose age ranged from 15 years old to 64 years old . This study in 2013 was notable due to a 3-million higher figure compared to the previous year’s estimated number of drug users. Attributing for the increase in population, the prevalence remains stable at 5.2% from 2011 to 2013. However, bigger concern is given to problem users, those who are suffering from drug use disorders or exhibiting drug dependence. In addition, health-seeking behavior of drug users also poses a significant problem since only a small portion seeks treatment especially for women. However in Asia, Amphetamine Type Stimulants (ATS) usage has been reported to be high. This is due to the relatively low price and high production in the region .
In the Philippines, approximately 4 to 7 million Filipinos have used drugs at least once [11,12]. It has been reported that 47% of the barangays or local government units are drug affected with the national prevalence of 1.8% for 2016. This is relatively lower compared to the global prevalence reported. Lifetime drug users have been reported to have a prevalence proportion of 6.1% .
Main drugs of abuse in the country are crystalline methamphetamine and cannabis. Crystalline methamphetamine is a stimulant type of drug which is locally produced and relatively cheaper than the other drugs available. It is popularly called as shabu, basura, or crystal by the locals. Approximately 78.97% of rehab patients used shabu in 2012 . It has been reported that, in 2013, 7,555 or 17.98% of 42,024 barangays/communities are drug affected with the possibility of having at least one of the following: a drug laboratory, known pushers, and users. The second most common drug of abuse is cannabis or marijuana with approximately 34.04% usage for rehab patients in 2012.
The role of dopamine in obesity and drug use
The problem of obesity and substance abuse can be traced on the behavioral and cognitive developmental programming of the reward mechanism found in both humans and animals. Various research models using animals and humans have implicated the dopamine reward system as an intrinsic system that can be modified through environmental perturbations, such as food and illegal drugs. The dopamine reward system plays an important role in understanding the problem of obesity. Generally, food that tastes good is eaten while those that taste bland are not. Studies involving human brain imaging have revealed that the cortico-limbic and meso-accumbens brain circuits implicated in reward– Orbito-frontal Cortex (OFC), insula, amygdala, hypothalamus, striatum, midbrain, Ventral Tegmental Area (VTA) and Substantia Nigra (SN) can be activated by environmental factors as well as food–related visual or olfactory cues.
Observational studies involving the administration of dopamine receptor agonists in patients with Parkinson’s Disease (PD) revealed adverse reaction, marked by compulsive behaviour of increase consumption of palatable food. In animal models, ingestion of palatable sucrose solutions stimulated dopamine transmission in the Nucleus Accumbens (NAc) [13,14]. This represents an important framework that reveals how behaviour is modified through environmental (food) consumption. The role of environmental cues has been correlated in causing a positive predictive effect and lead to induction of dopamine transmission in the NAc. In this case the use of sucrose as en environmental cue and reward leads to increase expression of the dopamine reward system . The neural pathways in the dopamine reward system can be influenced in various capacities depending on the glucose level. For instance, the level of dopamine release from the SN has proportional stimulatory response on the striatum depending on the amount of glucose provided [16,17]. The striatum is a critical component in the dopaminergic reward and motor response which coordinate cognitive function, including motivation and reward perception. In obesity this neural pathway reveals increase activation with proportional response depending on the amount of environmental cues (food, glucose) present in the system. The correlation of BMI (body mass index) with the dopamine reward system reveals proportionate response to food and food associated cues. Lean and overweight controls (BMI>25 but <30) were found to have increase activation of the brain reward circuitries in response to food, while obese women (BMI>30) were found to have diminished baseline sensitivity to the dopamine reward system [13,18]. The diminished sensitivity to dopaminergic reward system in obese individuals coincides with the lack of appropriate behavioural control resulting in increased necessity for food intake as a substrate to increase the release of dopamine into the system. These findings involving the dopaminergic reward system in obesity is similarly noted in problems related to illicit substance abuse and drugs. The results implicate the direct activation of the dopaminergic neurons leading to over excitation of the brain reward circuitry . Dopamine (DA) was implicated in almost all stages of drug addiction, from induction to maintenance, and even stages of relapsed following a period of abstinence. Animal (rats and primates) and human model studies suggest that highly addictive drugs lead to an increase extracellular DA preferentially in the ventral striatum (nucleus accumbens, NAc), and preferentially increase dopamine concentration in the NAc shell rather in the core . In rat models acute administration of Tetrahydrocannabinol (THC), a highly addictive agent, suggests that the reward thresholds can be decreased following stimulatory processed .
The dopamine reward mechanism in both obesity and illicit substance abuse are interrelated through neural pathways and mechanisms where the increase release of dopamine neurotransmitter leads to an intrinsic behavioral plasticity and later modification that provides an increased pleasurable, physiologic response. The behavioral plasticity is shaped upon by the environmental cues of food and illegal drugs. The phenotypical behavioral response of heightened pleasure and gratification (hedonistic mechanism) from the reward mechanism results in deeper acquiescence of stimulatory environmental perturbations. Over time, the extrinsic environmental exposure from food or drugs can lead to phenotypical behavioral modification and related psychological expressions.
Epigenetics is the inheritance of information based on gene expression levels rather than on gene sequence. Modifications brought about by epigenetic mechanisms are responsible for closely regulated tissue and cell-type specific gene expression patterns. There are several epigenetic modifications that have been identified over the years: DNA methylation, DNA hydroxymethylation, histone tail modifications, chromatin remodeling and micro RNA- (mRNA) gene interaction. Of all the identified epigenetic modifications, DNA methylation is by far the most widely-studied. DNA methylation is mediated by DNA Methyltransferases (DNMTs) by an addition of a methyl group (from S-adenosylmethionine, an intermediate product of the onecarbon pathway) to a cytosine in the 5' position, resulting into a 5-methylcytosine (5-mC). The occurrence of DNA methylation is predominantly found in the cytosine-guanine (CpG) residues of the DNA promoter regions called "islands". Methylation of DNA, especially in the CpG islands, results in the repression or silencing of downstream genes.
Epigenetic modifications and the dopamine reward system
The inter-relation of epigenetic modification and changes in transcription factors as it relates to dopaminergic reward system has been suggested in previous studies. For instance, the total cellular levels of histone acetylation for H3 and H4 in the nucleus accumbens (NAc) after chronic exposure to cocaine led to increased transcription and reduction in the total cellular levels of H3 lysine demethylation (H3K9me2) . Conversely during the early phase of cocaine withdrawal a decrease in DNMT3a (an enzyme that catalyzes the transfer of methyl groups) expression was noted in NAc and the dorsal striatum. Similar epigenetic modifications have been observed in diet induced environmental factor. Animal mice studies found changes in promoter methylation of two important enzymes, Tyrosine Hydroxylase (TH) and Dopamine transporter (DA) following diet-induced obesity. Other observations revealed that that mRNA copies from the enzymes corroborated the changes in promoter methylation, wherein the hypermethylation of the promoters led to decreased mRNA copies while the hypomethylation process led to increased mRNA copies. These studies suggest crucial implications linking the behavioural actions of increase food intake during obesity and illicit drug use as factors that can lead to epigenetic modification of the dopamine reward system. The Reward Deficiency Syndrome (RDS)  suggest the concept that a “genetic commonality exists between dopamine-activating substances like opiates and even glucose”. This in part provides a conceptual bridge in linking the actions of obesogenic substances and drug use in the brain reward system .
The emergence of Non-communicable Diseases (NCD) following the global nutrition transition in developing countries such as the Philippines has led to an epidemic of metabolic diseases from obesity to diabetes. In these countries the problem of overnutrition and obesity has strained the inadequate resources with institutions overwhelmed by the increasing number. In the Philippines, these challenges are not adequately being addressed and as a result the problems of obesity and overnutrition have surpassed infectious diseases at the top of the most common causes of morbidity and mortality. With no immediate solution, the prevalence and burden of obesity is expected to further complicate the present state of inadequacy which leads to increase number of new cases.
In addition the growing problem of drug addiction and substance abuse in the Philippines has become the second public health related burden that further threatens the stability of institutions and government structure in the country. Even though government estimates on drug users vary, the prevalence of drug abuse is expected to rise and bring into focus the limited availability of expertise and resources.
The problems of obesity and drug abuse is interrelated and conjugated through the dopaminergic reward mechanism. This reward mechanism provides a possible biomedical framework as a means to elucidate and provide understanding into the interrelatedness of obesity and drug abuse in much of the developing countries. The release of dopamine, an excitatory neurotransmitter, is predicated by environmental cues and stimulatory effects. In this case obesity and illegal drugs act as environmental agents which can cause the release of dopamine to the neural axis and create a sense of indulgence. Over time the chronic stimulation modulated by these environmental agents can lead to craving and search for continuous, repeated dopamine release.
The difficulty in mitigating the problems of obesity and drug abuse can be explained through epigenetic modification. With the chronic exposure to dopamine release subsequently a behavioral modification takes place which results in a different personality, character and behavior on the individual affected. This behavioral modification can be traced to epigenetic modification by altering the morphology of dopamine reward system. This epigenetic modification will result in the silencing of transcription factors involved in decreasing the release of dopamine resulting in continuous release of the neurotransmitter. In obesity the role of epigenetic modification in the constant stimulation of the reward mechanism leads to further increase in food intake. Similarly drug abuse can also lead to epigenetic modification which leads to increase susceptibility of the individual to develop behavioral modification and subsequent drug dependence to achieve constant dopaminergic stimulatory response.
The increased prevalence of obesity and drug abuse in developing economies presents a double burden of public health issues with no clear solution given the general lack of infrastructure, financial resources, and possibly interests. Governments in developing economies may not have the appropriate and necessary expertise to address this problem of epidemic proportions. Rebalancing limited resources may not be sufficed in mitigating the spread of these burdens, and yet responsible public health initiatives should remain the focus and goal of these nations in the foreseeable future. These public health initiatives should be focused towards education of the general public through campaign and seminars of the various stakeholders including but not limited to educators, allied health personnel, and local government units engaged in public health management. The need for adequate and well guided public health policy in addressing drug addiction provides a more relevant approach in managing and mitigating the adverse effects of addiction. The Sweden’s national drug policy [23,24], for instance, is viewed as part welfare and social policy bringing together a concerted effort from legislative advocacy to prosecutorial discretion giving an individual a renewed start, thereby making their rehabilitation more successful.
In addition the application of public health genomics  has become an important framework in improving the prevention and management of metabolic diseases including obesity. Rebalancing policy areas that incorporates the design and function of physical activity environments including urban planning policies, transport policies and organizational policies on the provision of facilities for physical activity has been generally more effective intervention and ultimately leads to a successful management. Potential policy areas in the future should also be transmitted from the public environment to home environment, a crossover policy channel meant to provide a broader policy level of socioeconomic environments. In addition, a greater sense of urgency should be focused in advancing our understanding into biomolecular physiology by looking at the specific roles between epigenetic and dopaminergic mechanisms. Further research through animal models should focus into this dynamic interrelationship in hopes of possibly providing a more definitive plan in addressing the burdens of obesity and drug abuse.
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