Title

The Role of Experience in Modulating Neurochemical and Cellular Markers of Nucleus Accumbens Neuron Activity: Food Intake and Food Reinforced Behaviors

Date of Completion

January 2011

Keywords

Biology, Neuroscience|Psychology, Behavioral

Degree

Ph.D.

Abstract

The studies in this dissertation employed three distinct neurochemical markers (microdialysis methods to measure dopamine (DA) release, immunocytochemistry of c-Fos and phosphorylated DARPP-32) to study the impact of various motivational conditions on activity in nucleus accumbens and related brain structures. The first group of experiments (chapter 2) was a pharmacological study that was undertaken to characterize the effects of an important drug of abuse (ethanol), and to provide an initial opportunity for the development of c-Fos staining methods. These experiments studied the effects of central (i.e., intraventricular, ICV) and peripheral (i.e., intraperitoneal, IP) administration of ethanol and acetaldehyde (the first metabolite of ethanol) on the expression of c-Fos protein immunoreactivity in nucleus accumbens and other brain areas that are potentially related to the behavioral activation induced by drugs The results of these experiments suggested that ethanol and acetaldehyde are pharmacologically active when administered into the brain, and that acetaldehyde may be an active metabolite that mediates some of the cellular effects of ethanol. The second series of experiments (chapter 3), which provided the main body of this dissertation, characterized the changes in neurochemical markers of accumbens activity that occurred during food intake and food-reinforced behavior and specifically investigated the role of novelty (e.g. novel food or schedule conditions) as a factor influencing the responsiveness of these markers. For the first two series of experiments (experiments 1 and 2), DA release was measured by in vivo microdialysis under different sets of behavioral conditions. In one study (experiment 1), the neurochemical correlates of feeding on a high carbohydrate diet in animals pre-exposed to this food were compared to the effects of novel exposure to the same food. It was hypothesized that food consumption in experienced animals would result in little or no increase in DA release, while exposure to the novel food would result in a modest increase. Neither the novel exposure nor the pre-exposed free-feeding group showed a significant increase in extracellular DA in nucleus accumbens. In the second experiment (experiment 2), the transition from one operant schedule (fixed ratio 1; FR1) to another schedule with a higher ratio requirement (FR5) was assessed at several stages of training (i.e. last day of FR1 training, Days 1, 2 and 3 of exposure to the FR5, and repeated training on the FR5). It was hypothesized that the initial transition from the FR1 schedule to the FR5 schedule would be characterized by large increases in accumbens DA release. During the first day of FR5 training, there was a robust and significant increase in DA release in the nucleus accumbens shell. In contrast, rats with nucleus accumbens core placements showed a significant increase in extracellular DA on the 2nd day of FR5 training. Rats with extensive FR5 training also showed increases in extracellular DA during the behavioral session, with both the shell and core placements showing significant increases. The third and forth group of studies used a different marker of neural activity (c-Fos immunohistochemistry) for assessing activity in the nucleus accumbens core and dorsomedial shell under the same behavioral conditions used in the microdialysis experiments. For the fifth and sixth group of experiments, a measure of the signal transduction cascade initiated by DA D1 receptor stimulation (i.e. DARPP-32 immunoreactivity) was employed to assess nucleus accumbens neural activity under the same behavioral conditions (i.e., food intake and operant conditioning) described above. For the operant conditioning experiments, changes in c-Fos and DARPP-32 immunoreactivity largely mimicked those seen in the microdialysis experiments (i.e., large changes in accumbens shell on the first day of FR5 training, large changes in accumbens core on the second day of FR5 training). However, unlike the microdialysis experiments, novel exposure to the high carbohydrate diet did increase c-Fos and DARPP-32 expression in nucleus accumbens core and shell. The final series of experiments in chapter 3 used immunofluorescence double-labeling methods, and demonstrated that DARPP-32 and c-Fos expression were largely limited to substance P-positive medium spiny neurons in accumbens core and shell in rats that were tested on the first day of FR5 responding. On the basis of the results from chapter 3, the experiments in chapter 4 explored the pattern of c-Fos expression in various parts of the dorsal striatum employing the same behavioral conditions used in chapter 3. It was demonstrated that, in contrast to the nucleus accumbens, neostriatal expression of c-Fos showed greater increases with extended FR5 training. (Abstract shortened by UMI.)^