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 DirectIn VitroDeterminations

Abstract

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]2beta-carbomethoxy-3beta-(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.

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

“…1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces parkinsonism in both humans [4] and non-human primates [5] with the cognitive, biochemical, histological and classical behavioral changes that occur in PD [6] . Therefore, Increasing evidence has suggested that single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can be used to sensitively and objectively evaluate the integrity of the nigrostriatal dopaminergic system and may be useful tools for providing diagnostic information on PD [7][8][9][10] . There are numerous SPECT and PET imaging tracers for monitoring the integrity of dopaminergic neurons.…”

Modeling Human Methamphetamine Exposure in Nonhuman Primates: Chronic Dosing in the Rhesus Macaque Leads to Behavioral and Physiological Abnormalities

“…To date, most studies involving METH administration and the consequent CNS pathology have focused on neurotoxicity in the striatal dopamine projections (Ricaurte et al, 1984;Cadet et al, 1998;Villemagne et al, 1998;Harvey et al, 2000b). However, the applicability of these studies to human METH abuse has been questioned due to differences between the pattern of drug-abuse dosage/frequency in human users and those used in animal studies.…”

“…In rodents, one of the most common acute high dose METH administration protocols used is 10 mg/kg injected four to five times over the course of a single day at 2 h intervals (Broening et al, 1997;Chapman et al, 2001;Gluck et al, 2001), although doses as high as 40 mg/kg are also administered (Sabol et al, 2001). Short-term protocols are often utilized as well in nonhuman primate studies, with METH doses ranging from 0.5 to 2 mg/kg given for just 1-5 days, two to four times each day (Melega et al, 1997;Villemagne et al, 1998;Harvey et al, 2000a, b). However, such dosing can lead to severe symptoms of METH toxicity resulting in the stoppage of the scheduled dosing regimen or even death of experimental animals.…”

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

“…In the PET study with [ 18 F] FCT in the cocaine self-administration model with monkeys, the laterality of DAT function was changed even before enough cocaine was consumed to produce significant overall changes in receptor and transporter availability [58] . has also revealed a reduction of the DAT in MA abusers and in baboons after MA injection [63][64][65][66] .Methylphenidate ( d-threo-MP to the DAT, suggesting that it is a useful PET tracer for imaging presynaptic dopaminergic neurons [67] . A PET imaging study using pretreatment with MP showed a marked decrease of [ 11 C] d-threo-MP binding in the human brain [68] .…”