Linking Midbrain Dopamine Neurotransmission and Dietary Obesity
Emmanuel Pothos, PhD, recently joined the faculty of the Department of Pharmacology and Experimental Therapeutics at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences. After earning his doctorate in neuroscience from Princeton University, Pothos worked in the departments of psychiatry and neurology at Columbia University. He studies neurotransmission, which is the passage of signals from a nerve cell to its target via chemical neurotransmitters. Abnormalities in neurotransmission have been implicated in drug addiction, schizophrenia, depression, eating disorders, and Parkinson's disease. A major project in the Pothos laboratory involves neurotransmission and dietary obesity.
“The obesity project is exciting to the whole team,” says Pothos. “Neurobiology research on the subject so far has focused on mechanisms that consider the regulation of body weight as a homeostatic mechanism: that is, you remove something, something else is added to compensate; you add something, something else is removed to compensate. According to this mechanism, body weight is set and the organism’s function is to try to defend against changes. Of course, epidemiology shows that close to 80% of the population is not defending body weight successfully.”
Research from the 1950s and 60s suggested that regulation of body weight involved the hypothalamus, a portion of the brain that helps control body temperature, blood sugar, and fat metabolism. “With the overabundance of high-energy diets, it became crystal clear that these [hypothalamic] mechanisms can be overcome,” says Pothos. “There is some more dynamic control of food intake and it seems to be coming from centers that do not regulate body weight per se but that regulate food reward. That puts a change in emphasis further up in the brain, in the midbrain, where most centers that mediate motivation and reward are located.”
Pothos’s obesity research focuses on dopamine, a catecholamine neurotransmitter. Dopamine in some ways can be thought of as a "feel good" messenger in that it stimulates reward centers of the brain. A hungry animal releases dopamine in the projections of the midbrain when it eats, and tastier foods will cause more dopamine to be released. Pothos’s research group is investigating the basic effects of obesity on dopamine neurotransmission and will explore the cellular mechanisms involved. Using strains of rats inbred to be prone (or resistant) to obesity, the group is asking questions such as "Is the dopamine system of the obesity-prone animal different very early in life from that of the obesity-resistant animal?" and "How does a high-energy, tasty diet affect the dopamine system?"
Preliminary studies revealed that obesity-prone animals have a very depressed dopamine system – at least 60% less dopamine is released from the midbrain of obesity-prone animals in comparison with normal animals. This depressed dopamine release in obesity-prone animals led the Pothos group to propose a theory of compensation, which suggests that food has a diminished reward value for obesity-prone animals. The animals have to eat more to feel the same level of compensation or satisfaction that obesity-resistant animals feel.
Cell culture studies demonstrated that the number of dopamine molecules released from midbrain neurons is much lower in obesity-prone animals. Inside the neuron, dopamine molecules are sequestered in vesicles, little membranous organelles. When the neuron is stimulated to release dopamine, the vesicles merge with the cell membrane and release their neurotransmitter molecules into the extracellular space, a controlled secretory process known as exocytosis. “In neuroscience we identify quantal size as the number of neurotransmitter molecules released by a single vesicle during exocytosis,” says Pothos. For decades, neuroscientists have thought that quantal size was fixed and invariant, but recent measurements with improved techniques have demonstrated that quantal size can be plastic and variable. In support of this view, Pothos’s group found that the quantal sizes of vesicles in neurons from obesity-prone animals were smaller than those from obesity-resistant animals. An interesting finding that they are investigating further was that vesicles sometimes close before releasing all their dopamine, suggesting that regulation of vesicle closing may also be involved in the amount of dopamine released.
Although a dopamine-related predisposition to obesity appears to be “pre-wired” in the midbrain of obesity-prone animals, Pothos believes it is not necessarily “hard-wired” and may be susceptible to intervention. It appears that dietary intervention can change the dopamine release status of obesity-prone animals. The Pothos group took newborn pups from an obesity-prone mother and allowed them to nurse from an obesity-resistant mother, and they took newborn pups from an obesity-resistant mother and allowed them to nurse from an obesity-prone mother. Control groups of pups did not switch mothers. A significant number of the switched pups developed the predisposition toward obesity of their adoptive mother rather than the resistance of their genetic mother. “So that means that at least in mother’s milk in the rat there may be some crucial components that can change this pre-wiring, that it is not hard-wired,” says Pothos. This opens the possibility of regulating appetite through the midbrain dopamine system by pharmacological or pharmaceutical interventions.
Pothos would like to find a collaborator who studies the hypothalamus in relation to homeostasis of body weight in order to look at differences in metabolism and correlate them with dopamine research. “There is a separate, independent dopamine system in the hypothalamus. We’re very much interested in seeing what it’s doing in terms of dietary obesity – if we have any differences from the main systems of the midbrain – or if it regulates the signals in the hypothalamus in any way,” says Pothos. He would also like to collaborate with researchers who study leptin, a protein secreted by fat tissue that is thought to reduce food intake and increase energy expenditure, and ghrelin, a protein that is thought to regulate appetite by countering the signal of leptin. “We would like to see how the hypothalamus makes this decision in connection with the midbrain,” says Pothos, “how the midbrain responds to these signals, because receptors for leptin and ghrelin apparently exist in the midbrain too.”
Pothos would also like to collaborate with a neuroanatomist who would be interested in mapping neuronal connections between the hypothalamus and the midbrain, and with a molecular biologist who would be interested in studying mRNA in these tissues. Besides his project on the regulation of quantal neurotransmission and his dopamine/obesity project, Pothos studies Parkinson’s disease through a collaboration with neurology researchers affiliated with Harvard. He welcomes other Parkinson’s researchers to contact him about collaborating.
For more information, please go to http://www.tufts.edu/sackler/pharmacology/faculty/pothos.html