Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice.
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.
Boger
Heather A
HA
Department of Neurosciences and Center on Aging, Medical University of South Carolina, South Carolina 29425, USA.
Middaugh
Lawrence D
LD
Patrick
Kennerly S
KS
Ramamoorthy
Sammanda
S
Denehy
Emily D
ED
Zhu
Haojie
H
Pacchioni
Alejandra M
AM
Granholm
Ann-Charlotte
AC
McGinty
Jacqueline F
JF
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000097:blood / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency / Q000502:physiology*; D008694:Methamphetamine / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012701:Serotonin; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
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