The brain is composed of numerous neurotransmitters and some of the better known ones such as dopamine, noradrenaline and serotonin regulate pleasure, mood, appetite and movement. Thus imbalances in these systems can result in depression, anxiety, irregular appetite and even addiction. The important neurochemical dopamine is produced in two main areas of the brain the substantia nigra and the ventral tegmental area (VTA) (figure 1). Neurons in these areas send thousands of dopamine connections throughout the brain. The receiving structures are involved in movement or emotional behavior. For instance the connection between the VTA and accumbens is central to the brain's reward system. Whereas the substantia nigra and striatum regulate movement. Damage to this system is a major cause of Parkinson's disease.

Dopamine binds to specific structures in the brain known as dopamine D2 receptors and activates the brain's reward system. This makes you feel good. It is established that persons addicted to alcohol, cocaine and other drugs have low levels of D2 receptors. Persons with decreased levels of these receptors need more stimulus to make them feel good. Drugs of abuse cause an increase in dopamine thus by taking these drugs people get more dopamine and therefore feel better at least for short periods of time. As most will agree eating induces feelings of gratification and pleasure. What does overeating cause in the brain? Nora Volkow director of the National Institute of Drug Abuse (NIDA) and her colleague Gene-Jack Wang, M.D suspected that obese people might have abnormalities in their brains comparable to drug addicts. They used PET scanners to look inside the brains of obese and non-obese people and found that obese people have lowered numbers of D2 receptors. In fact, Drs. Volkow and Wang's research at Brookhaven National Laboratory in New York showed that the more obese the person, the lower the number of D2 receptors. "It's possible that obese people have fewer dopamine receptors because their brains are trying to compensate for having chronically high dopamine levels, which are triggered by chronic overeating," says Wang. "However, it's also possible that these people have low numbers of dopamine receptors to begin with, making them more vulnerable to addictive behaviors including compulsive food intake."

The researchers noted that, based on this study alone, they cannot conclude whether the brain changes they've detected are a consequence or a cause of obesity. They also acknowledge that the regulation of body weight is extremely complex, involving many physiological mechanisms and neurotransmitters. But they do suggest that addressing the dopamine receptor deficiency or finding other ways to regulate dopamine in obese people might help reduce their tendency to overeat.

Even with the similarities between drug addiction and obesity in regards to the decrease in D2 receptors there are remarkable differences in the brains. Drug addiction unlike obesity causes damage to the prefrontal cortex the area responsible for judgment and impulsive behavior. Obesity does not cause such damage. This is good news since it indicates that persons who overeat have the ability to have more control over their behavior.

Not only does dopamine respond to pleasurable stimuli such as food it is also quite vulnerable to oxidative stress. Diets rich in high fat and sucrose contain an excess in calories which in turn could damage the dopamine system due to the generation of negatively charged molecular particles that cause oxidative damage in the brain. Studies are suggesting that high calorie diets may be the starting place for a number of neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's diseases (PD). Furthermore consumption of diets composed of high fats and carbohydrates can lead to metabolic syndrome which is characterized by a group of metabolic risk factors in one person. Insulin resistance, one of the consequences of consuming a high fat diet and sucrose, together with obesity are the dominant underlying factors for metabolic syndrome. Other factors associated with metabolic syndrome include elevated blood pressure and high triglycerides low HDL cholesterol and high LDL cholesterol.

Animal models of separate and combined-risk factors for metabolic syndrome are critical to advancing our understanding and treatment of this serious medical condition. Even more the fact that metabolic syndrome is considered as a risk factor for neurodegenerative disorders implies that investigations need to include the effects of these diets on brain function. This is particularly true for the dopamine system in the substantia nigra, which is quite vulnerable to oxidative stress a risk factor considered for Parkinson's disease. These investigations are novel in the sense that not much is known about the influence of excess calories on the dopamine neurons in the nigrostriatal system. Currently three rodent MS models have been identified, these are: a high fat diet, a high fructose diet and a high sucrose diet. Our research focuses on using these three models to investigate the outcome of excess calories on the nigrostriatal system. The research is currently being carried out by postgraduate students Ashton Rogers and Jaya Ramchandani under the supervision of Professors Amanda McRae, Dan Ramdath and Dr Brian Cockburn in the Departments of Preclinical Sciences and Life Sciences of the St Augustine campus.

Rats were divided into three groups : One group received a high fat diet (45 % kcal from lard, Research Diets) another one high fructose (60 % kcal from fructose, PMI Nutrition) (Figure 2) and the third 30 percent sucrose solution. Control animals were fed a standard diet (Basal Purified Diet 12% kcal fat, PMI Nutrition). At periods varying from 3 – 5 months the brains from rats maintained on high fat and fructose brains were examined for modifications in the dopamine system. The brains from rats on the sucrose solution were examined one month after treatment. The brain sections were examined with an antibody which is specific for the dopamine system. Results revealed that the dopamine system in animals on a high fat diet was not modified. However both the fructose diet and the sucrose solution caused significant decreases in dopamine in the substantia nigra. Figure 3 shows these decreases in the substantia nigra of animals on a sucrose solution.

These results suggest that diets associated with metabolic syndrome affect the nigrostriatal differently. The sucrose diet contained excess overall calories compared to the control. The custom diets (high fat and fructose) contained the same overall calories as their controls. Since the rats which were fed the sucrose had decreased dopamine in the substantia nigra just after a month, which is similar to the substantia nigra of the rats fed the high fructose diet for five months, it can be inferred that excess calories may cause the same deleterious changes in a shorter time. There is a need to further investigate whether prolonged treatment will lead to full blown dopamine degeneration, programmed cell death or impairment of the dopamine transport system.

To determine whether rats were at risk for metabolic syndrome blood samples were assayed for insulin, triglycerides, cholesterol and glucose. Rats on the high fat diet did not induce any of the characteristics of metabolic syndrome.

Rats on the fructose diet displayed impaired glucose tolerance, increase in triglyceride and total cholesterol; three risk factors for metabolic syndrome. The sucrose diet did not induce metabolic syndrome. This is interesting as it implies that sucrose affects the brain before inducing modifications in changes noted in the brain induced by sucrose precede changes in peripheral serum markers. In conclusion the high fructose diet induced metabolic syndrome whereas the other diets and feeding regimes did not.

Taken together these results suggest that high sugar intake especially in children should be carefully reviewed, as it may accelerate dysfunction of the dopamine system.

Inflammation also participates in destruction of dopamine neurons in Parkinson's disease.

Injecting an agent known as lipopolysaccharide (LPS) into the substantia nigra causes an inflammatory mediated destruction of dopamine neurons. Little is known about the influence of high calorie intake on a low-grade inflammatory reaction in the substantia nigra. To investigate this concept a group of rats received the normal dose of LPS and were maintained on water and normal diet. Another group was administered a lower dose of LPS and were maintained on a 30% sucrose solution and normal food. At one month the brains were examined for the presence of inflammatory cells known as microglia. These cells are considered to be involved with the degeneration of dopamine neurons in Parkinson's disease. Different from the group of rats administered the normal dose of LPS the sucrose group displayed a robust and intense increase in the expression of microglia. These novel results suggest that high calorie intake can exacerbate a low- grade inflammation and perpetuate microglial activation and neurodegeneration in the substantia nigra.

Thus diet in combination with a minor inflammation in the substantia nigra of early Parkinson's disease could provoke a neurodegenerative cascade of events leading to an accelerated pathological state.

How can this research be applied to human subjects? A simple answer may be exercise. Once again the dopamine system enters into play. Dopamine is also stimulated by exercise. Thus obese subjects may be able to increase dopamine through exercise thereby raising the number of dopamine receptors. Instead of accommodating for low dopamine receptors through food persons could actually satisfy this system through exercise.

Up until recently, the fact that some individuals live to be over 85 years without developing neurodegenerative disorders was probably considered as plain luck. As it turns out the lucky factor may be diet. Studies suggest that foods such as fish and a curry spice known, as curcumin, as well as a low caloric intake could be protective to the brain. On the other end of the spectrum our research shows that diets high in refined carbohydrates can damage the brain.

In conclusion our findings are tremendously important as the consumption of sugar and fructose, corn syrup, sweetened beverages and fast foods have increased dramatically in the past decades. Unless the detrimental effects of refined carbohydrates on health and the brain are incorporated into health policies a decrease in their consumption should not be expected. Further research is urgently required to better understand these effects and elucidate underlying mechanisms so that we can successfully age.

The brain can chime in and join the verse “we are what we eat” from inside to outside.