Dissertation
Neural pathways and cellular mechanisms of mercaptoacetate
Washington State University
Doctor of Philosophy (PhD), Washington State University
08/2010
DOI:
https://doi.org/10.7273/000006078
Abstract
The body senses and responds to various metabolic cues, such as the availability of glucose and free fatty acids (FFA). When there is a decrease in fatty acid oxidation, the body increases food consumption. We can artificially produce lipoprivation with the anti-metabolic drug, mercaptoacetate (MA). MA blocks fatty acid oxidation by inhibiting -oxidation. MA stimulates an increase in blood FFA and a decrease in plasma 3-hydroxybutyrate, but doesn t directly alter blood glucose. This metabolic profile makes MA a useful tool to study the lipoprivic state without being concerned about glucoprivic responses due to blood glucose changes. The feeding response to MA requires the vagus nerve. Specific regions of the brain are critical for MA induced effects; including the nucleus of the solitary tract, lateral parabrachial nucleus, central nucleus of the amygdala, and dorsal motor nucleus of the vagus. In the first set of experiments we wanted to determine if the hindbrain contained the circuitry necessary to produce the feeding response to MA stimulation. Using the decerebrate rat model, we found that the forebrain is a necessary part of the neural pathway involved in MA-induced feeding. In the second set of experiments we determined whether MA acts directly on the vagal afferents using calcium imaging techniques with isolated nodose neurons. We found that MA alone did not alter cytosolic calcium, but it did inhibit FFA induced calcium increases. Experiments with the potassium-adenosine triphosphate channel agonist, diazoxide, suggested that calcium responses induced by FFAs may not be mediated through a metabolic action. GW9508, an agonist of G-protein coupled receptor 40, also increased cytosolic calcium levels, and did so only in neurons sensitive to both FFA and capsaicin. MA significantly inhibited GW9508- and cholecystokinin (CCK)-induced calcium responses, but did not impair the calcium response to serotonin (5HT). The ability of MA to inhibit responses to both CCK and GW9508 suggests MA alters a Gprotein coupled receptor pathway leading to calcium influx. The overall conclusions from our experiments are that MA induced feeding is dependent upon forebrain structures and that MA alters FFA stimulation of the vagus nerve by a mechanism other than [beta]-oxidation.
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Details
- Title
- Neural pathways and cellular mechanisms of mercaptoacetate
- Creators
- Rebecca Anne Darling
- Contributors
- Sue Ritter (Chair)Robert C Ritter (Committee Member) - Washington State University, Department of Integrative Physiology and NeuroscienceHeiko Jansen (Committee Member) - Washington State University, Department of Integrative Physiology and NeuroscienceSteve Simasko (Committee Member) - Washington State University, Department of Integrative Physiology and Neuroscience
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 102
- Identifiers
- 99901055125701842
- Language
- English
- Resource Type
- Dissertation