The Spontaneously Diabetic Wistar B.B. Rat (SDR) is considered to be a genetically determined animal model of human Type-1 diabetes. The overall objective of this thesis was to elucidate the behavioral and neurochemical profile of the SDR. This objective was attained using various pharmacological, behavioral and neurochemical approaches. The course of the changes was followed sequentially, at discretely defined time frames (0-2, 2-8 and 8-12 months duration of diabetes), to explore and characterize the contended dysfunctions. Overall, it was found that the insulin treated SDR exhibited a significantly attenuated locomotor and rearing response to the systemically administered dopamine agonists d-amphetamine and amfonelic acid. In the case of d-amphetamine, it was found that the attenuated response was robust and chronic as it persisted across all three time frames. The attenuated response of the insulin treated SDR to amfonelic acid demonstrated that the behavioral deficit could also be elicited by a dopamine agonist with a different mechanism of action from d-amphetamine. In a nonpharmacological experiment, it was found that the insulin treated SDR manifested a significantly attenuated nocturnal locomotor and rearing response, particularly to transitional photoperiodic cues. This deficit in responding was chronic and robust as it was observed across all three time frames. The possible neurochemical substrates of the aforementioned effects were investigated. A post-mortem neurochemical analysis of the region specific basal levels of CNS catecholamines and metabolites, in the insulin maintained and deprived SDR, was undertaken. There were no significant differences between the insulin maintained SDR and non-diabetic littermates or genetically distinct controls. The cessation of insulin administration to the SDR for four consecutive days resulted in significant increases in the levels of norepinephrine in the cortex and hypothalamus, dopamine in the hippocampus, and homovanillic acid in the striatum. The neurochemical response of the insulin treated SDR was assessed following a pharmacological challenge. The SDR was exposed to a single dose of (1.0 mg/kg, i.p.) amfonelic acid. The SDR exhibited a significantly greater reduction in the post-mortem levels of dopamine in the striatum, midbrain, and olfactory bulbs as well as striatal norepinephrine. The behavioral effects elicited by d-amphetamine and amfonelic acid are believed to be dopamine mediated. Thus, it was hypothesized that one source of the observed neurochemical and behavioral deficits may be related to an impairment of dopaminergic neurotransmission. Therefore, the concomitant measurement of spontaneous nocturnal locomotor activity and levels of interstitial dopamine from the ventral striatum was measured using in vivo microdialysis. No significant differences between the insulin treated SDR and controls were found. The SDR did exhibit significantly lower levels of locomotor activity. In a different vein, the behavioral response of the insulin treated SDR was assessed following exposure to environments varying in degree of novelty. It was found that the SDR exhibited a heightened behavioral response to novelty-stress. The insulin maintained SDR manifested a greater aversion to the anxiogenic regions of the open field and elevated plus maze whilst being treated with chlordiazepoxide. The anxiolytic effects of this drug were significantly attenuated in the SDR when compared to controls. In essence, it would appear that the SDR when treated with insulin and unchallenged by: (1) withdrawal of insulin treatment, (2) pharmacological stimulation or, (3) environmental stimulation, is able to maintain relatively stable baseline levels of brain catecholamines and behavior. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/7520 |
| Date | January 1993 |
| Creators | Ahmad, Qadeer. |
| Contributors | Merali, Zul, |
| Publisher | University of Ottawa (Canada) |
| Source Sets | Université d’Ottawa |
| Detected Language | English |
| Type | Thesis |
| Format | 201 p. |
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