Date of Award

Spring 5-2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Pharmacology and Neuroscience

Department

Graduate School of Biomedical Sciences

First Advisor

Dr. Michael Forster

Abstract

Frequent abuse of psychostimulants is known to induce changes in brain neurochemistry that are most profound in dopaminergic neurons. These changes could both impair dopamine neurotransmission and adversely affect psychomotor and cognitive functions. One hypothesized cause of these impairments is the adverse effects of psychostimulant-induced increases in oxidative stress. The current studies addressed the general hypothesis that chronic administration of cocaine and methamphetamine would create a change in neurochemistry in dopaminergic neurons and, as a consequence, increase oxidative damage. This would result in decreases in dopaminergic functions specifically in the nigrostriatal region and cause impairments in psychomotor functions.

To test this hypothesis we utilized an in vivo rodent model involving continuous chronic administration of cocaine or methamphetamine. Separate groups of mice were exposed to a 30-day treatment, involving continuous infusion of saline, 40 mg/kg of cocaine, or 2 mg/kg of methamphetamine. After discontinuation of the drug treatment, separate groups of the mice were tested for cognitive and psychomotor function at 11, 14, or 16 months of age i.e., 1 week, 3 months, or 5 months after treatment. The test used in this study included spatial learning and memory (swim maze), coordinated running ability (accelerating rotorod), muscle and grip strength (wire suspension) and balance and coordination (bridge walking). Following completion of the behavioral tests brain regions were dissected. The regions we analyzed were the cortex, striatum, cerebellum, hippocampus, midbrain, and hindbrain. These regions were analyzed for carbonyl and thiobarbituric acid reactive substances concentrations to measure levels of protein and lipid oxidation, and Western blotting procedures to address dopaminergic protein expression.

Overall, both chronic administration of cocaine and methamphetamine resulted in significant impairments to psychomotor functions. These impairments were evident for both groups on wire hanging tests, bridge walking, and rotating rod tests, both initially following the treatment phase and throughout the age ranges that were analyzed. In addition, the cocaine treatment administered led to profound impairments on cognitive function in the 14-month-old age groups. This impairment was most evident on the reversal phase of the spatial swim maze tests.

The biochemical tests revealed that chronic cocaine and methamphetamine administration induced significant increases in protein oxidative damage in the striatum initially following the treatment phase. Psychostimulant-induced lipid oxidative damage was evident in the striatum in both the 14 and 16 month old age groups. Age related declines were evident in the midbrain, cortex and striatum. Overall neither treatment had any effect on the expression of the dopaminergic proteins that were analyzed.

The results from these studies warrant the conclusion that chronic cocaine and methamphetamine administration causes an increase in intracellular oxidative damage in the nigrostriatal neurons which decrease dopamine-mediated psychomotor functions. Overall there was not enough evidence to conclude that chronic abuse of these drugs induce impairments that would increase during senescence.

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