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The Journal of Neuroscience, August 15, 2007, 27(33):8816-8825; doi:10.1523/JNEUROSCI.1067-07.2007

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Behavioral/Systems/Cognitive
Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Heather A. Boger,¹ Lawrence D. Middaugh,^1,2 Kennerly S. Patrick,³ Sammanda Ramamoorthy,¹ Emily D. Denehy,¹ Haojie Zhu,³ Alejandra M. Pacchioni,¹ Ann-Charlotte Granholm,¹ and Jacqueline F. McGinty^1,2

¹Department of Neurosciences and Center on Aging, and ²Departments of Psychiatry and Behavioral Sciences, and ³Pharmaceutical Sciences, Medical University of South Carolina, South Carolina 29425

Correspondence should be addressed to Jacqueline F. McGinty, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Basic Science Building Suite 403, Charleston, SC 29425. Email: mcginty{at}musc.edu

Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 x 10 mg/kg, i.p., at 2 h intervals), GDNF^+/– mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF^+/– mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF^+/– mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging.

Key words: aging; GDNF; methamphetamine; mice; neurotoxicity; Parkinsonism

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Received Aug. 11, 2006; revised June 11, 2007; accepted June 27, 2007.

Correspondence should be addressed to Jacqueline F. McGinty, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Basic Science Building Suite 403, Charleston, SC 29425. Email: mcginty{at}musc.edu

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