Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography.
Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys. L-[beta-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed with either a constant rate intravenous infusion of D-amphetamine aiming at plasma concentrations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [11C]N-methylspiperone was less able to sense D-amphetamine induced release of dopamine. At plasma concentrations aimed above 1 ng/ml a levelling off of the binding of [11C]raclopride at 68 +/- 8.1% of the baseline value indicated that displacement was only possible from a fraction of the binding sites. Amphetamine was observed to increase the rate constant for L-[beta-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors. L-[beta-11C]DOPA and [11C]raclopride were found suitable to indicate changes in dopamine synthesis rate and release respectively using PET and can be used to mirror drug-induced changes of brain dopaminergic function.
Hartvig
P
P
Uppsala University PET Centre, University Hospital, University of Uppsala, Sweden.
Torstenson
R
R
Tedroff
J
J
Watanabe
Y
Y
Fasth
K J
KJ
Bjurling
P
P
Långström
B
B
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003653:Decarboxylation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000378:metabolism; D008253:Macaca mulatta; D020891:Raclopride; D012457:Salicylamides / Q000378:metabolism; D013134:Spiperone / Q000031:analogs & derivatives / Q000378:metabolism; D014055:Tomography, Emission-Computed
D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D012457:Salicylamides; D020891:Raclopride; D007980:Levodopa; D013134:Spiperone; C039167:3-N-methylspiperone; D000661:Amphetamine; D004298:Dopamine