Date of Award

2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Ann-Charlotte Granholm

Second Advisor

Jacqueline F. McGinty

Fourth Advisor

Peter Kalivas

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Studies have shown that GDNF levels decrease in the substantia nigra (SN) and striatum during normal aging and in patients with Parkinson's disease. Furthermore, exogenous GDNF infusion protects DA neurons against injury induced by 6-hydroxydopamine, MPTP, and methamphetamine (METH). A heterozygous mouse model was created to assess whether a chronic reduction in this neurotrophic factor impacts motor function and the nigrostriatal DA system during the aging process. In this dissertation, two models of dopaminergic loss and motor dysfunction were characterized. First, a partial loss of GDNF demonstrated a slow, progressive loss of SN DAergic neurons as well as motor dysfunction with aging. Secondly, a possible model for a dual-hit hypothesis for dopamine neurodegeneration was described. In this model, mice with a partial loss of GDNF displayed an increase vulnerability to the neurotoxic effects of METH. To determine if the damage caused by these two factors was primarily by inflammatory processes, minocycline, a second-derivative tetracycline with anti-inflammatory and neuroprotective properties, was administered. Treatment with minocycline was able to reduce substantia nigra microglial activation and phosphorylated p38 MAPK in all groups. Although minocycline treatment was able to partially restore the lower levels of tyrosine hydroxylase seen in GDNF+/- mice, the antibiotic was unable to reverse the damage associated with METH treatment. Thus, increased age-related vulnerability of the DA system is seen when a genetic predisposition (GDNF depletion) is combined with a post-natal neurotoxic exposure (METH binge). This dual-hit model may be useful for studies of neuroprotective treatments.

Rights

All rights reserved. Copyright is held by the author.

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