Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain

Abstract

The prevention by six reversible and selective monoamine oxidase-A (MAO-A) inhibitors (alpha-ethyl-tryptamine, harmaline, 4-methoxyamphetamine, amiflamine [FLA 336(+)], N-desmethylamiflamine [FLA 788(+)] and N,N-desmethylamiflamine [FLA 668(+)] of the phenelzine-induced irreversible MAO inhibition in the rat brain was examined. By using crude synaptosome preparations of hypothalamus and striatum incubated with low substrate concentrations of 14C-serotonin (1 X 10(-7) M), 14C-noradrenaline (2.5 X 10(-7) M) and 14C-dopamine (2.5 X 10(-7) M) in the absence and presence of selective amine uptake inhibitors (alaproclate, maprotiline and amfonelic acid, respectively), it was possible to determine the deaminating activities inside and outside the specific aminergic synaptosomes. Thus, with this technique the protection of MAO by the reversible inhibitors administered orally 1 h prior to the subcutaneous injection of phenelzine against the phenelzine effect could be determined inside and outside the specific aminergic neurons. It was found that alpha-ethyltryptamine, 4-methoxyamphetamine and particularly amiflamine and FLA 788(+) were more potent inside than outside the serotonergic neurons. FLA 668(+) was a selective inhibitor of noradrenergic MAO, to which also 4-methoxyamphetamine, amiflamine and FLA 788(+), but not alpha-ethyltryptamine had some preference. Harmaline had no certain preference for MAO in any of the aminergic neurons. At high doses of FLA 668(+) a preference for dopaminergic MAO was observed. Since pretreatment of the rats with norzimeldine or desipramine antagonized the preferences for serotonergic or noradrenergic MAO, it is plausible to conclude that the compounds showing these preferences are accumulated in the neurons by the membranal uptake systems.

Inhibition of monoamine oxidase in 5‐ hydroxytryptaminergic neurones by substituted p‐aminophenylalkylamines

“…The inhibition of rat brain mitochondrial MAO in vitro was determined as described by Ask et al (1982b) The deamination of ['4C]-5-HT by the synaptosomal preparation was determined as described previously (Ask et al, 1983) with some modifications. Fifty microlitres of the synaptosomal preparation, corresponding to 2.5 mg wet weight of tissue, was added to glass-stoppered centrifuge tubes containing 925 gi of Krebs-Henseleits buffer, pH 7.4, equilibrated with 93.5% 02 and 6.5% CO2, and containing glucose 5.6 mM, ascorbic acid 1.1 mM, Na2 EDTA 0.…”

“…Neuronal selectivity was regarded to occur ifat (Ask et al, 1983;. Most of the compounds examined showed sig- Figure 1 Inhibition of monoamine oxidase (MAO) within (continuous lines) and outside (broken lines) 5-hydroxytryptaminergic nerve terminals in the rat hypothalamus in vivo.…”

“…In previous studies we have observed that some reversible MAO-A inhibitors protect MAO within the aminergic neurones in the rat brain against phenelzine at lower doses than required to protect MAO outside these neurones (Ask et al, 1983;. Of particular interest were the findings that amiflamine and Ndesmethylamiflamine ((+ )-FLA 788) showed significant preference for MAO inside 5-hydroxytryptaminergic and noradrenergic nerve terminals in the rat hypothalamus whereas N,N-didesmethylamiflamine (( + )-FLA 668) was a very selective inhibitor of MAO in noradrenergic nerve terminals (Ask et al, 1983;.…”

“…Of particular interest were the findings that amiflamine and Ndesmethylamiflamine ((+ )-FLA 788) showed significant preference for MAO inside 5-hydroxytryptaminergic and noradrenergic nerve terminals in the rat hypothalamus whereas N,N-didesmethylamiflamine (( + )-FLA 668) was a very selective inhibitor of MAO in noradrenergic nerve terminals (Ask et al, 1983;. Since pretreatment of the rats with norzimeldine or desipramine which are selective inhibitors of 5-hydroxytryptamine (5-HT) and noradrenaline uptake respectively, antagonized the preference for MAO of these monoaminergic nerves, the neuronal selectivity appears to be due to accumulation of the inhibitors within the aminergic nerve terminals via the membranous uptake mechanisms.…”

Increased total activity in the rat after L‐tryptophan plus the monoamine oxidase‐A inhibitor amiflamine but not after L‐tryptophan plus clorgyline

“…This is found in rats with an ED50 of 0.4mgkg-' given orally, whereas MAO-A localised elsewhere (such as within noradrenergic neurones or extra-neuronally) is inhibited with an ED50 of > 1.4mgkg-' orally (Ask et al, 1983). At doses of amiflamine of ca 3.5 mg kg-' orally and higher, there appears to be a concomitant release of 5-HT from the neurones (Ogren et al, 1981;Renyi, 1984).…”