Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography
- 163 Downloads
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-[β-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 forl-[β-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors.l-[β-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.
KeywordsAmphetamine [11C] L-DOPA raclopride N-methylspiperone CBF PET monkeys
Unable to display preview. Download preview PDF.
- Bjurling P, Watanabe Y, Oka S, Nagasawa T, Yamada H, Långström B (1990) Multienzymatic synthesis of 11C-labelled L-tyrosine and L-dopa. Acta Chem Scand 44: 178–182Google Scholar
- Dexamphetamine (1991) In: Dollery C et al. (eds) Therapeutic drugs, vol 1. Churchill Livingstone, Edinburgh, pp D50-D55Google Scholar
- Edling C, Hellman B, Arvidsson B, Lilja A, Andersson J, Hartvig P, Valind S, Långström B (1997) Positron emission tomography studies of subjects occupationally exposed organic solvents. Evidence of increased dopamine synthesis rate. Int Arch Occup Environ Health (in press)Google Scholar
- Eriksson L, Holte S, Bohm C, Kesselberg M. Hovander B (1988) Automated blood sampling systems for positron emission tomography. IEEE Trans Nucl Sci 35: 703–704Google Scholar
- Hartvig P, Ågren H, Reibring L, Tedroff J, Bjurling P, Kihlberg T, Långström B (1991) Brain kinetics of L-[β-11C]DOPA in humans studied by positron emission tomography. J Neural Transm [GenSect] 86: 25–41Google Scholar
- Innis RB, Malison RT, Al-Tikriti M, Hoffer PB, Sybirska EH, Scibyl JP, Zoghbi SS, Baldwin RM, Lamelle M, Smith EO, Charney DS, Heninger G, Elsworrth J, Roth RR (1992) Amphetamine-stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates. Synapse 10: 177–184PubMedGoogle Scholar
- Lindner K-J, Hartvig P, Tedroff J, Ljungström A, Bjurling P, Långström B (1995) Liquid chromatography analysis of brain homogenates and microdialysates for the quantification ofl-[β-11C]DOPA and its metabolites for the validation of positron emission tomographic studies. J Pharm Biomed Anal 13(4–5): 361–367PubMedGoogle Scholar
- Logan J, Volkow ND, Fowler JS, Wang GJ, Dewey SL, Schlyer DJ, MacGregor RR (1993) The effects of change in blood flow on the distribution volume of (11C)raclopride binding. J Nucl Med 34: 200PGoogle Scholar
- McMillen B (1983) CNS stimulants: two distinct mechanisms of action of amphetamine like drugs. Trends Pharmacol Sci Oct: 429–432Google Scholar
- Tedroff J, Aquilonius SM, Hartvig P, Bjurling P, Långström B (1992) Estimation of regional cerebral utilization of [11C]-1-3,4-dihydroxyphenylalanine (DOPA) in the primate by positron emission tomography. Acta Neurol Scand 85: 215–225Google Scholar
- Torstenson R, Hartvig P, Långström B, Tedroff J (1997) Differential effect of levodopa infusion in early and advanced Parkinson's disease. Ann Neurol (in press)Google Scholar