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Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb
Xiaolin Deng1, Bruce Ladenheim, Subramaniam Jayanthi
1Molecular Neuropsychiatry Branch, Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA.
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.
Insights
Methamphetamine (METH) causes damage to dopamine (DA) terminals and neuron death in the olfactory bulb (OB) through apoptosis. This study reveals METH-induced apoptotic mechanisms in OB dopaminergic neurons.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Methamphetamine (METH) is an addictive substance linked to neurological and psychiatric disorders.
- Toxic METH doses induce dopaminergic terminal damage and neuronal apoptosis in rodent brains.
- The olfactory bulb (OB) is a brain region densely populated with dopaminergic neurons and terminals.
Purpose of the Study:
- To investigate the toxic effects of methamphetamine on the olfactory bulb.
- To determine if METH-induced neuronal death in the OB involves apoptotic pathways.
Main Methods:
- Rats received a single METH injection (40 mg/kg).
- OB tissues were analyzed at various time points post-injection.
- Assays included monoamine level measurement, tyrosine hydroxylase (TH) immunocytochemistry, TUNEL histochemistry, and caspase-3 immunochemistry.
Main Results:
- METH significantly reduced dopamine levels and TH-like immunostaining in the OB.
- Increased TUNEL-labeled neurons, some TH-positive, were observed post-METH.
- METH induced activated caspase-3 in TH-positive cells, alongside altered expression of pro- and anti-apoptotic proteins (Bax, Bid, Bcl2).
Conclusions:
- METH causes loss of OB dopaminergic terminals.
- METH induces death of dopaminergic neurons in the OB.
- These neuronal losses occur, at least partly, via apoptotic mechanisms.
