Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity.
Acutely, methamphetamine (m-AMPH) is known to stimulate a net efflux of dopamine (DA) in the striatum while inhibiting DA uptake, thus producing high extracellular concentrations of DA. Repeated administration of m-AMPH has been shown to damage DA terminals in the striatum. However, little direct information exists about the relationship between m-AMPH-induced DA overflow and neurotoxicity. In the present study, we used in vivo microdialysis to explore this topic. Four, but not 3, injections of m-AMPH (4 mg/kg, sc, at 2 h intervals) damaged striatal DA terminals as measured by a 43-51% decrease in post mortem striatal DA content 1 week later. Striatal microdialysis in awake animals during the course of m-AMPH treatment showed that DA overflow increased after each m-AMPH injection, but that approximately 1.5 h after the fourth m-AMPH injection, a striking increase in DA overflow occurred that was significantly larger than that seen after any of the previous 3 injections. Additionally, in animals receiving 4 injections of m-AMPH, cumulative DA overflow was negatively correlated with striatal DA content 1 week later (r = -0.74, P less than 0.05), suggesting that the substantial DA overflow seen after the fourth m-AMPH injection is especially important in m-AMPH neurotoxicity.
O'Dell
S J
SJ
Department of Psychobiology, University of California, Irvine 92717.
Weihmuller
F B
FB
Marshall
J F
JF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine