Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb.
BACKGROUND
Methamphetamine (METH) is an addictive drug that can cause neurological and psychiatric disorders. In the rodent brain, toxic doses of METH cause damage of dopaminergic terminals and apoptosis of nondopaminergic neurons. The olfactory bulb (OB) is a brain region that is rich with dopaminergic neurons and terminals.


METHODS
Rats were given a single injection of METH (40 mg/kg) and sacrificed at various time points afterward. The toxic effects of this injection on the OB were assessed by measuring monoamine levels, tyrosine hydroxylase (TH) immunocytochemistry, terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL) histochemistry, and caspase-3 immunochemistry.


RESULTS
Methamphetamine administration caused marked decreases in dopamine (DA) levels and TH-like immunostaining in the mouse OB. The drug also caused increases in TUNEL-labeled OB neurons, some of which were also positive for TH expression. Moreover, there was METH-induced expression of activated caspase-3 in TH-positive cells. Finally, the METH injection was associated with increased expression of the proapoptotic proteins, Bax and Bid, but with decreased expression of the antideath protein, Bcl2.


CONCLUSIONS
These observations show, for the first time, that METH can cause loss of OB DA terminals and death of DA neurons, in part, via mechanisms that are akin to an apoptotic process.
Deng
Xiaolin
X
Molecular Neuropsychiatry Branch, Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA.
Ladenheim
Bruce
B
Jayanthi
Subramaniam
S
Cadet
Jean Lud
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives; D004298:Dopamine / Q000502:physiology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009830:Olfactory Bulb / Q000166:cytology / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; C079213:RTI 121; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine