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MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated
F B Weihmuller1, S J O'Dell, J F Marshall
1Department of Psychobiology, University of California, Irvine 92717.
Abstract:
Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Blocking N-methyl-D-aspartate (NMDA) receptors with MK-801 prevents methamphetamine-induced dopamine terminal damage by reducing dopamine overflow. This suggests dopamine overflow is key to methamphetamine neurotoxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Neurotoxicology
Background:
- Repeated methamphetamine (m-AMPH) administration causes dopamine (DA) terminal damage in the striatum.
- N-methyl-D-aspartate (NMDA) receptor blockade previously showed neuroprotective effects against m-AMPH, but the mechanism was unclear.
Purpose of the Study:
- To investigate the role of NMDA receptor blockade with MK-801 in modulating m-AMPH-induced striatal DA overflow.
- To determine the relationship between DA overflow and subsequent DA terminal damage.
Main Methods:
- In vivo microdialysis was used to measure extracellular striatal DA levels.
- Animals received repeated administrations of m-AMPH and/or MK-801.
- Striatal DA tissue content was assessed one week after m-AMPH treatment.
Main Results:
- MK-801 alone did not alter basal extracellular DA levels.
- m-AMPH significantly increased striatal DA overflow, leading to a 40% reduction in DA tissue content one week later.
- MK-801 administration before m-AMPH attenuated DA overflow and completely protected against DA depletions.
Conclusions:
- The extensive dopamine overflow during m-AMPH neurotoxicity is a critical factor in the subsequent damage.
- NMDA receptor antagonism, specifically with MK-801, mitigates m-AMPH neurotoxicity by reducing DA overflow.