To investigate the possible changes in pyruvate oxidation during the rapid growth period in an animal model, the oxidation of radioactive labeled pyruvate was measured in mitochondria isolated from the gastrocnemius muscle of Sprague--Dawley rats between 4 and 16 weeks of age. The influence of the fatty acid derivative palmitylcarnitine, as an inhibitor of pyruvate oxidation, was also tested.The gastrocnemius muscle was removed from anesthesized animals at 4, 8 and 16 weeks of age. Isolated mitochondria from the muscle samples were incubated with C1--14C] pyruvate and E1-14C] pyruvate + palmitylcarnitine in a KC1 medium. The decarboxylation of pyruvate was measured by the evolution of radioactive labeled carbon dioxide. Pyruvate oxidation significantly (p .; 0.0001) increased from ages 4 to 16 weeks. The initial low rate of pyruvate oxidation was attributed to the residual metabolic effects of the pre-weaned animal' high-fat diet. The subsequent increase in the capacity of pyruvate oxidation was then explained by the shift in the animaldiet to high-carbohydrate lab chow. These results may also be attributed to the maturation of the hindlimb muscle fibers during this period: the differentiation of predominately red, oxidative fibers to an increase in the percentage of white, glycolytic fibers, common in the adult hindlimb. The fatty acid derivative, palmitylcarnitine, failed to inhibitpyruvate oxidation at the level of decarboxylation. This finding supports the proposal that fatty acids do not inhibit glucose oxidation directly, but instead suppress glycogen breakdown. Thus, the findings indicate an increase in the capacity for- pyruvate oxidation during the rapid growth period without inhibition by the fatty acid derivative, palmitylc_arnitine. / Department of Biology

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N-methyl-D-aspartate (NMDA) receptor activation is believed necessary for certain types of learning. The present experiments investigated the effects of the NMDA antagonist, MK-801, on spatial learning and memory in rats. Experiment 1 tested the effects of MK-801 on the acquisition and retention of a water maze task. MK-801 produced a performance, but not a spatial learning deficit. Experiment 2 tested the effects of MK-801 on the acquisition and retention of a radial arm maze task (RAM). MK-801 had no effect on initial acquisition and retention, but impaired subsequent reversal learning when the pattern of rewarded and unrewarded arms was reversed. Experiment 3 investigated the effects of MK-801 on RAM reversal learning in rats previously trained on the initial task in the absence of drugs. MK-801 produced a dose dependent impairment on reversal learning. These results are consistent with one interpretation that MK-801 impairs the ability to suppress interference from previously learned information.

The objective of this investigation was to determine whether lesions to the region of the mammillary bodies of rats impair performance on various learning and memory tasks. It was demonstrated that such lesions are sufficient to impair performance on tasks that require memory for spatial information. Deficits were found in both working and reference memory paradigms, with more severe impairments in the former. Ability to discriminate spatial location was not affected when delay was minimal, but retention was progressively impaired as delay was increased. A dissociation in the effect of the lesions on performance of analogous spatial and nonspatial tasks was observed. The lesions did not impair the learning of a visual discrimination/reversal, or a conditioned taste aversion. It is concluded that lesions to the region of the mammillary bodies have a selective effect on spatial learning and memory. The relevance of these findings to Korsakoff's psychosis is discussed.

Declarative learning entails the internalization of facts and events. This type of learning depends on the integrity of the hippocampal system. In rodents, spatial learning is studied as a model of declarative learning. In this thesis, electrophysiological and behavioral experiments assessed the role of NMDA receptors in synaptic plasticity and rats' spatial learning and memory. Primed burst potentiation (PBP), a form of synaptic strengthening, was studied in freely-behaving rats treated with NMDA receptor antagonists. The impairments caused by the antagonists correlated with those observed in behavioral studies. The results support the idea that NMDA receptors in the hippocampal system mediate the internalization of the contents and organization of new environmental information, and show that the receptors are not relevant for spatial working memory or performance once a representation of the environment is stable. The results also suggest that stable spatial representations resemble multiple relations of events and do not correspond to topographical maps of an environment. As learning proceeds, representations are activated by smaller subsets of environmental cues, which eventually become sufficient for effective navigation. The representations thus are encoded as relationships of stimuli that share similarities or that are unique to a particular event. The organization of novel information is given through NMDA receptor-mediated synaptic plasticity. This plasticity mechanism could resemble a process similar to the synaptic changes observed during PBP.

This series of studies was designed to investigate the residual erectile capacity of paraplegic rats. Results from human studies suggest that erectile capacity in paraplegic men may be maintained following psychogenic, but not reflexogenic, stimulation. Using an animal model to overcome methodological difficulties associated with human studies, reflexogenic stimulation was defined as local stimulation of the genitals, and psychogenic stimulation as stimulation of a key central structure. Results from higher CNS stimulation showed that electrical stimulation of the medial preoptic area of the hypothalamus reliably triggers penile responses in rats and elicits penile responses as a post-stimulation effect. Optimal stimulation parameters were identified and used to maximize the effect on spinal animals. The effect of central stimulation was then compared to that of local stimulation to examine whether truly sexual responses were elicited. Results demonstrated that central stimulation elicits primarily erectile responses with a few urine-marking responses. The two stimulation sources were then used to test the residual erectile capacity of paraplegic rats whose lesions interrupted the L6-S1 fibers. Results showed that a high proportion of animals (85%) indeed maintain erectile responses to central stimulation but lose reflex activity from the genital area. These results support the hypothesis under study and are discussed in terms of the neural substrates of erection and their implication at the human level.

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In this study a standardized 46 week chronic drinking water toxicity protocol was used to elucidate the toxic potential of Sutherlandia frutescens (S. frutescens) using histopathologic, morphometric and transmission electron microscopic analysis. The histopathologic changes in the duodenum, heart, kidney, liver, lung, pancreas and spleen of male Wistar rats were evaluated. Fifty-four rats were randomly divided into four groups: Group 1 – Normal diet control (ND control), n=7, Group 2 – Normal diet + plant extract (ND + p), n=9, Group 3 – High fat diet control (HFD control), n=19Group 4 – High fat diet + p (HFD + p), n=19In the high fat group male Wistar rats were fed ±55 g/day of a specialised high fat diet over a 46 week period to induce obesity and an insulin resistant state. The treatment groups (groups 2 and 4) received a dose concentration of a tea extract of the S. frutescens plant in their drinking water daily. This study showed that the consumption of S. frutescens significantly reduces weight gain in male Wistar rats on a chronic high fat diet (p≤0.001 vs. HFD control group). S. frutescens appears to propagate periportal and centrilobular glycogen storage in rat hepatocytes in the experimental groups as exemplified by a significantly (p≤0.0001 vs. control groups) increased incidences of Periodic Acid Schiff (PAS) positive staining S. frutescens also reduced intracellular lipid accumulation as made evident by the significantly lower incidence of epicardial adipose tissue (EAT), hepatic steatosis and pancreatic interstitial fat. Obesity was associated with increased fibrotic lesions such as myocardial perivascular fibrosis, centrilobular hepatic fibrosis and pancreatic periductal fibrosis. Obesity associated hypertension contributed to the widespread and significant increase in the average lesion severity of arterial congestion in all organs in the HFD control group. Pulmonary infection was equally prevalent in all rats. Despite the complex histopathology in all groups, differences in the control groups, such as, the presence of a conservative polymorphonuclear leukocyte (PMNL) infiltration, substantial intra-alveolar oedema and focal arterial wall hypertrophy in the control groups was highly suggestive of Sendai viral infection. However histopathologic evidence, in the treatment groups, suggested chronic recurrent viral infection with superimposed Mycoplasma pulmonis (M. pulmonis) bacterial infection. The impact of advanced suppurative pulmonary infection was widespread and exemplified by increased lesion incidences of spontaneous murine progressive cardiomyopathy (MCP) and spontaneous chronic progressive nephropathy (CPN) among others. In conclusion S. frutescens administered for 46 weeks to male Wistar rats significantly lowered intracellular lipid accumulation and obesity associated myocardial, renal, hepatobiliary, pulmonary and pancreatic histopathology. Moreover, duodenal, cardiovascular, hepatobiliary, pulmonary, renal, pancreatic and splenic tissue did not show histopathologic evidence of direct plant extract associated toxicity or carcinogenicity.

Pyridoxine-deficient rats are known to exhibit little, if any, weight gain; they also have decreased fat stores in comparison with their pair-fed controls. The defect in energy metabolism responsible for this phenomenon is not well understood at present. This study was undertaken to investigate some aspects of glycogenesis and glycogenolysis in order to add to the present information on energy metabolism in the pyridoxine deficiency state. Meal-fed animals were used, in order to eliminate differences due to the mode of feeding between the experimental and the pair-fed control animals. Male weanling rats were fed a pyridoxine-deficient diet in one 2-hour daily meal, while the controls were pair-fed. This eliminated differences due to feeding frequency when these groups were compared with each other. Aspartate amino-transferase and alanine aminotransferase activities were assayed in liver and erythrocytes in order to verify the presence of a pyridoxine deficiency state under the conditions used in this laboratory. The activities of glycogen phosphorylase, the rate-limiting enxyme in glycogenolysis, and glycogen UDP-glucosyltransferase were assayed in liver and muscle. Glycogen storage in these tissues was also measured. Finally, the incorporation of labelled carbon atoms into blood glucose and liver glycogen following intraperitoneal injection of L-alanine-¹⁴C was assayed. Glycogen phosphorylase activity was reduced in pyridoxine-deficient animals. This defect was not accompanied by a concomitant increase in the deposition of glycogen. There was, therefore, the possibility of a decreased ability to form glycogen. Glycogen UDP-glucosyltransferase activity was normal in muscle and elevated in liver indicating, if anything, an unimpaired ability to synethesize glycogen from UDPG. A trend towards a lesser incorporation of labelled carbon atoms into the blood glucose by the pyridoxine-deficient group appeared when the results were expressed as a percent of administered dose per ml. This became statistically significant when the data was expressed in terms of the circulating glucose pool. Although not at a statistically significant level, there was a greater incorporation of labelled carbon atoms into the liver glycogen of the pyridoxine-deficient group. It appeared from these findings that the defect in energy metabolism in pyridoxine deficiency may be the result of a reduced availability of carbon skeletons and occurred prior to the formation of glycogen. Further study in this area is necessary to reveal the exact point at which energy loss occurred. / Land and Food Systems, Faculty of / Graduate