Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.
Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.
Melega
William P
WP
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA. wmelega@mednet.ucla.edu
Jorgensen
Matthew J
MJ
Laćan
Goran
G
Way
Baldwin M
BM
Pham
Jamie
J
Morton
Grenvill
G
Cho
Arthur K
AK
Fairbanks
Lynn A
LA
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000097:blood; D002522:Chlorocebus aethiops; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000097:blood; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects; D020891:Raclopride / Q000493:pharmacokinetics; D012919:Social Behavior; D014316:Tritium / Q000493:pharmacokinetics
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D014316:Tritium; D020891:Raclopride; D008694:Methamphetamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine