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

Abstract

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.

Specific binding of [18F]fluoroethyl‐harmol to monoamine oxidase A in rat brain cryostat sections, and compartmental analysis of binding in living brain

“…); only the locus coeruleus and interpeduncular nucleus had higher MAO‐A binding in that study; we have earlier discerned [ 11 C]harmine binding in the locus coeruleus of living pigs (Jensen et al . ), but this was not evident in the present [ 18 F]FEH study, presumably because of greater effects of partial volume with μPET. The rank order and magnitude of present autoradiographic findings in vitro in cerebellum, striatum, and cerebral cortex match closely the results obtained earlier with [ 14 C]clorgyline, the irreversible ligand.…”

“…); in brain of living pigs, this tracer had a V D close to 40 mL/g and a BP ND as high as three (Jensen et al . ). Recent clinical research PET studies with [ 11 C]harmine have revealed an association between MAO‐A and depression (Chiuccariello et al .…”

“…We have used [ 11 C]harmine‐PET to verify blockade of MAO‐A in pargyline‐treated Göttingen minipigs, toward testing an hypothesis that MAO blockade should potentiate the amphetamine‐evoked release of dopamine in striatum (Jensen et al . ). Clinical PET studies with [ 11 C]harmine show increased uptake in the brain of patients with major depression (Chiuccariello et al .…”

Serotonin and molecular neuroimaging in humans using PET

“…The most successful ligands which have been validated in humans are [ 11 C]harmine (e.g., Bergström et al 1997;Ginovart et al 2006;Jensen et al 2006;Soliman et al 2011), [ 11 C]clorgyline and [ 11 C]clorgyline-D2 (Fowler et al 1987Logan et al 2002) and [ 11 C]befloxatone (Bottlaender et al 2003;Leroy et al 2009). Another promising carbonlabeled PET ligand, …”

Synthesis and in vitro evaluation of 18F‐β‐carboline alkaloids as PET ligands

“…11 C]Harmine has as well been used in a dual tracer positron emission tomography (PET) study together with [ 11 C]raclopride in pig 10 and its biodistribution and radiation dosimetry evaluated in baboons. 11 Recently we observed that the high expression of MAO-A could be exploited for characterization of neuroendocrine gastroenteropancreatic tumours by using [ 11 C]harmine as a tracer.…”