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Methamphetamine-induced neurotoxicity in BALB/c, DBA/2N and C57BL/6N mice
1Department of Pharmacology, Nara Medical University, Kashihara, Japan. tkita@nmu-gw.cc.naramed-u.ac.jp
Abstract:
Repeated administration of methamphetamine (METH; 2 and 4 mg/kg, s.c. four times every 2 h) caused hyperthermia and a dose-dependent depletion of striatal dopamine levels 3 days after the METH-treatment in both BALB/cAnNCrj (BALB) and DBA/2NCrj (DBA) mice, but these responses were lower in C57BL/6NCrj (C57BL) mice. An acute decrease of striatal dopamine levels 30 min after the last injection of METH (4 mg/kg) was observed in both BALB and DBA mice, while an increase in dopamine was observed in C57BL mice. Striatal 3-methoxytyramine levels were drastically increased in both DBA and C57BL mice after this same treatment. Moreover, pretreatment with the superoxide dismutase inhibitor, diethyldithiocarbamate (200 mg/kg, i.p.) exacerbated the METH (4 mg/kg)-induced striatal dopamine-depletion in BALB mice. In addition, pretreatment with an inhibitor of poly(ADP-ribose) polymerase, benzamide (160 mg/kg, s.c.), significantly attenuated the METH (4 mg/kg)-induced striatal dopamine depletion in both BALB and DBA mice. These results suggest that both BALB and DBA mice possess a higher sensitivity to the METH-induced striatal dopaminergic neurotoxicity compared to C57BL mice. In addition, the striatal dopaminergic neurons of BALB mice may be more vulnerable to METH-induced oxidative stress as compared to that in C57BL mice.
Insights
Methamphetamine (METH) causes neurotoxicity in mice, with BALB and DBA strains showing higher sensitivity than C57BL mice. Oxidative stress plays a role in METH-induced dopamine depletion, particularly in BALB mice.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (METH) is a potent psychostimulant with known neurotoxic effects.
- Understanding strain-specific differences in METH neurotoxicity is crucial for developing targeted interventions.
- Dopaminergic pathways are primary targets of METH-induced damage.
Purpose of the Study:
- To investigate the differential neurotoxic effects of repeated methamphetamine administration in BALB, DBA, and C57BL mouse strains.
- To explore the role of oxidative stress and poly(ADP-ribose) polymerase in METH-induced dopaminergic neurotoxicity.
Main Methods:
- Repeated administration of methamphetamine (METH) at varying doses to BALB, DBA, and C57BL mice.
- Measurement of striatal dopamine levels and 3-methoxytyramine.
- Assessment of METH neurotoxicity following pretreatment with a superoxide dismutase inhibitor and a poly(ADP-ribose) polymerase inhibitor.
Main Results:
- BALB and DBA mice exhibited greater hyperthermia and striatal dopamine depletion post-METH compared to C57BL mice.
- Acute METH administration decreased striatal dopamine in BALB/DBA mice but increased it in C57BL mice.
- Superoxide dismutase inhibition exacerbated METH-induced dopamine depletion in BALB mice, while poly(ADP-ribose) polymerase inhibition attenuated it in BALB/DBA mice.
Conclusions:
- BALB and DBA mice are more susceptible to METH-induced striatal dopaminergic neurotoxicity than C57BL mice.
- Oxidative stress contributes significantly to METH neurotoxicity, particularly in BALB mice.
- Poly(ADP-ribose) polymerase activity may be a protective factor against METH-induced dopaminergic neurotoxicity.