BRAIN DOPAMINE NEUROTOXICITY IN BABOONS TREATED WITH DOSES OF METHAMPHETAMINE COMPARABLE TO THOSE RECREATIONALLY ABUSED BY HUMANS - EVIDENCE FROM [C-11] WIN-35,428 POSITRON-EMISSION-TOMOGRAPHY STUDIES AND DIRECT IN-VITRO DETERMINATIONS

The present study sought to determine whether doses of methamphetamine in the range of those used recreationally by humans produce brain dop amine (DA) neurotoxicity in baboons and to ascertain whether positron emission tomography (PET) imaging with the DA transporter (DAT) ligand [C-11]WIN-35,428 ([C-11]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-t ropane) could be used to detect methamphetamine-induced DAT loss in li ving primates. Baboons were treated with saline (n = 3) or one of thre e 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 k illed for direct neurochemical determination of brain DA axonal marker s. PET-derived binding potential values, used to index striatal DAT de nsity, 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 [H-3]WIN-35,428 and [H-3]DTBZ binding determined in vitro. Decreases in DAT detected with PET were highly correlated with decreases in specific [H-3]WIN-35,428 binding d etermined in vitro in the caudate of the same animal (r = 0.77; p = 0. 042). These results indicate that methamphetamine, at doses used by so me humans, produces long-term reductions in brain DA axonal markers in baboons, and that it is possible to detect methamphetamine-induced DA T loss in living nonhuman primates by means of PET.