Effect of monoamine oxidase inhibition on amphetamine-evoked changes in dopamine receptor availability in the living pig: a dual tracer PET study with [11C]harmine and [11C]raclopride.
The activity of both isozymes of monoamine oxidase (MAO) is reduced by 50% in the brain of human smokers. We hypothesized that this is not an epiphenomenon, but should bring about potentiation of the action of psychostimulant drugs. To test this hypothesis, we carried out serial positron emission tomography (PET) studies in Göttingen miniature pigs to measure the binding of the MAO-A ligand [11C]harmine and to measure the changes in [11C]raclopride binding evoked by a low dose of amphetamine (0.7 mg/kg as free base, i.v.), first in a baseline condition, and, one month later, after acute treatment with pargyline (2 x 3 mg/kg as free base, i.m.). In the baseline, the distribution volume of [11C]harmine relative to the arterial input (V(d), ml g(-1)) ranged from 74 ml g(-1) in cerebellum to 139 ml g(-1) in the medial hypothalamus. Pargyline treatment reduced the magnitude of V(d) globally to 34-54 ml g(-1). Nearly complete displacement of [11C]harmine binding was detected in neocortex and striatum, but there was evidence for pargyline-resistant binding in the pituitary gland and diencephalon. In the baseline condition, the low dose of amphetamine evoked a 14% decline in the binding potential (BP) (pB) of [11C]raclopride in striatum (P = 0.026). After pargyline treatment, the amphetamine effect was of similar magnitude (-11%), although not statistically significant (P = 0.054). However, the second amphetamine challenge evoked a 24% reduction in [11C]raclopride pB relative to the original baseline condition (P = 0.018). Present results do not strongly support our hypothesis that MAO inhibition should potentiate the amphetamine-evoked dopamine release as measured in the [11C]raclopride competition paradigm.
PET Centre, Aarhus University Hospital, Nørrebrogade 44, Aarhus C, Denmark 8000.
Svend Borup
SB
Jensen
Aage Kristian
AK
Olsen
Kasper
K
Pedersen
Paul
P
Cumming
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism*; D005260:Female; D006247:Harmine / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013552:Swine
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D008996:Monoamine Oxidase Inhibitors; D011954:Receptors, Dopamine; D020891:Raclopride; D006247:Harmine; D010293:Pargyline; D000661:Amphetamine; D008995:Monoamine Oxidase