Brain vesicular acetylcholine transporter in human users of drugs of abuse.
Limited animal data suggest that the dopaminergic neurotoxin methamphetamine is not toxic to brain (striatal) cholinergic neurons. However, we previously reported that activity of choline acetyltransferase (ChAT), the cholinergic marker synthetic enzyme, can be very low in brain of some human high-dose methamphetamine users. We measured, by quantitative immunoblotting, concentrations of a second cholinergic marker, the vesicular acetylcholine transporter (VAChT), considered to be a "stable" marker of cholinergic neurons, in autopsied brain (caudate, hippocampus) of chronic users of methamphetamine and, for comparison, in brain of users of cocaine, heroin, and matched controls. Western blot analyses showed normal levels of VAChT immunoreactivity in hippocampus of all drug user groups, whereas in the dopamine-rich caudate VAChT levels were selectively elevated (+48%) in the methamphetamine group, including the three high-dose methamphetamine users who had severely reduced ChAT activity. To the extent that cholinergic neuron integrity can be inferred from VAChT concentration, our data suggest that methamphetamine does not cause loss of striatal cholinergic neurons, but might damage/downregulate brain ChAT in some high-dose users. However, the finding of increased VAChT levels suggests that brain VAChT concentration might be subject to up- and downregulation as part of a compensatory process to maintain homeostasis of neuronal cholinergic activity. This possibility should be taken into account when utilizing VAChT as a neuroimaging outcome marker for cholinergic neuron number in human studies.
Siegal
Deborah
D
Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Erickson
Jeffrey
J
Varoqui
Helene
H
Ang
Lee
L
Kalasinsky
Kathryn S
KS
Peretti
Frank J
FJ
Aiken
Sally S
SS
Wickham
Dennis J
DJ
Kish
Stephen J
SJ
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000032:analysis / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D003932:Heroin / Q000633:toxicity; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000032:analysis / Q000633:toxicity*; D009294:Narcotics / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019966:Substance-Related Disorders / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D026901:Membrane Transport Proteins; D009294:Narcotics; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D008694:Methamphetamine; D003932:Heroin; D002795:Choline O-Acetyltransferase; D003042:Cocaine