Decreased striatal dopamine D1 receptor-stimulated adenylyl cyclase activity in human methamphetamine users.
OBJECTIVE
It has been assumed that some behavioral changes associated with repeated exposure to dopaminergic psychostimulant drugs might be explained by changes in activity of dopamine receptors, including the dopamine D(1) receptor, which is linked by a stimulatory G protein to the effector enzyme adenylyl cyclase. To establish whether dopamine D(1) receptor function might be altered in human methamphetamine users, the authors measured dopamine-stimulated adenylyl cyclase activity in the brain of chronic human users of the drug.


METHODS
Adenylyl cyclase activity stimulated by dopamine and by guanylyl-imidodiphosphate (to assess G protein and adenylyl cyclase coupling) was determined in the postmortem brain tissue of 16 methamphetamine users who had used the drug both recently and chronically (i.e., at least 1 year) as well as 21 matched comparison subjects.


RESULTS
A 25%-30% decrease in the maximal extent of dopamine stimulation of adenylyl cyclase activity was seen in the striatum (nucleus accumbens, caudate, and putamen) of the methamphetamine users. No changes were found in basal or guanylyl-imidodiphosphate-stimulated enzyme activity.


CONCLUSIONS
These data suggest that dopamine receptor function linked to adenylyl cyclase is partially desensitized in the striatum of human methamphetamine users. Decreased dopamine D(1) receptor function might underlie part of the known (drug withdrawal syndrome) or expected (drug tolerance) consequences of methamphetamine exposure in humans.
Human Neurochemical Pathology Laboratory, Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
Junchao
J
Tong
Brian M
BM
Ross
Gregory A
GA
Schmunk
Frank J
FJ
Peretti
Kathryn S
KS
Kalasinsky
Yoshiaki
Y
Furukawa
Lee Cyn
LC
Ang
Sally S
SS
Aiken
Dennis J
DJ
Wickham
Stephen J
SJ
Kish
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D019969:Amphetamine-Related Disorders / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D002421:Caudate Nucleus / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology*; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000494:pharmacology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D008297:Male; D008694:Methamphetamine; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology; D011699:Putamen / Q000187:drug effects / Q000201:enzymology; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology
D017447:Receptors, Dopamine D1; D006165:Guanylyl Imidodiphosphate; D008694:Methamphetamine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D004298:Dopamine