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The Journal of Neuroscience, January 1, 1998, 18(1):419-427
Brain Dopamine Neurotoxicity in Baboons Treated with Doses of
Methamphetamine Comparable to Those Recreationally Abused by Humans:
Evidence from [11C]WIN-35,428 Positron Emission
Tomography Studies and Direct In Vitro Determinations
Victor
Villemagne1,
Jie
Yuan2,
Dean F.
Wong1,
Robert F.
Dannals1,
George
Hatzidimitriou2,
William B.
Mathews1,
Hayden T.
Ravert1,
J.
Musachio1,
Una D.
McCann3, and
George A.
Ricaurte2
1 Department of Radiology, Division of Nuclear Medicine
and 2 Department of Neurology, The Johns Hopkins Medical
Institutions, Baltimore, Maryland 21205, and 3 Unit on
Anxiety Disorders, Biological Psychiatry Branch, National Institute of
Mental Health, Intramural Research Program, Bethesda, Maryland 20892
The present study sought to determine whether doses of
methamphetamine in the range of those used recreationally by humans produce brain dopamine (DA) neurotoxicity in baboons and to ascertain whether positron emission tomography (PET) imaging with the DA transporter (DAT) ligand [11C]WIN-35,428
([11C]2 -carbomethoxy-3-(4-fluorophenyl)-tropane)
could be used to detect methamphetamine-induced DAT loss in living
primates. Baboons were treated with saline (n = 3)
or one of three doses of methamphetamine [0.5 mg/kg
(n = 2); 1 mg/kg (n = 2); and 2 mg/kg (n = 3)], each of which was given
intramuscularly four times at 2 hr intervals. PET studies were
performed before and 2-3 weeks after methamphetamine treatment. After
the final PET studies, animals were killed for direct neurochemical
determination of brain DA axonal markers. PET-derived binding potential
values, used to index striatal DAT density, were significantly
decreased after methamphetamine, with larger decreases occurring after
higher methamphetamine doses. Reductions in striatal DAT documented by
PET were associated with decreases in DA, dihydroxyphenylacetic acid,
and specific [3H]WIN-35,428 and
[3H]DTBZ binding determined in
vitro. Decreases in DAT detected with PET were highly
correlated with decreases in specific
[3H]WIN-35,428 binding determined in
vitro in the caudate of the same animal (r = 0.77; p = 0.042). These results indicate that methamphetamine, at doses used by some humans, produces long-term reductions in brain DA axonal markers in baboons, and that it is
possible to detect methamphetamine-induced DAT loss in living nonhuman
primates by means of PET.
Key words:
methamphetamine; dopamine; neurotoxicity; PET; primates; WIN-35,428
Copyright © 1998 Society for Neuroscience 0270-6474/98/181419-09$05.00/0
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