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Effects of d-methamphetamine on monkey brain monoamine oxidase, in vivo and in vitro
T Egashira1, T Yamamoto, Y Yamanaka
1Department of Pharmacology, Medical College of Oita, Japan.
Abstract:
A and B form MAO activities in mitochondria and synaptosome were measured in the brain of monkeys administered d-methamphetamine (d-MP) 2 mg/kg, i.m., daily for 7 days. When mitochondria were used as an enzyme preparation, the Km and Vmax values decreased with 5-HT (serotonin for A-form MAO substrate) and beta-phenylethylamine (beta-PEA for B-form MAO substrate), while in the synaptosome, a significant increase of the Km and Vmax values was observed with 5-HT and dopamine as substrates. The mitochondrial MAO treated with d-MP was inhibited strongly by clorgyline and deprenyl with beta-PEA as a substrate, while synaptosomal MAO was highly sensitive to these MAO inhibitors with 5-HT as a substrate. MP and amphetamine (AP) were found in brain mitochondrial and synaptosomal preparations of monkeys administered 2 mg/kg d-MP, i.m. daily for 7 days; MP and AP contents were 5.05 +/- 0.22 pg/mg protein and 37.3 +/- 3.8 ng/mg protein in mitochondria and 2.35 +/- 0.35 pg/mg protein and 46.4 +/- 1.5 ng/mg protein in synaptosomes, respectively. MAO was inhibited by MP and its metabolites, AP p-hydroxymethamphetamine (OH-MP) and p-hydroxyamphetamine (OH-AP), with 5-HT, beta-PEA and dopamine as substrates, in vitro. MP and its metabolites were more potent inhibitors of A-form MAO than B-form MAO.
Insights
d-methamphetamine administration alters monoamine oxidase (MAO) activity and enzyme kinetics in primate brain mitochondria and synaptosomes. MAO inhibition by d-methamphetamine and its metabolites preferentially affects the A-form.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Monoamine oxidase (MAO) enzymes are crucial for neurotransmitter metabolism.
- d-methamphetamine (d-MP) is a psychoactive substance with known effects on monoamine systems.
- Understanding MAO activity alterations is vital for neurotoxicity and drug action research.
Purpose of the Study:
- To investigate the effects of chronic d-methamphetamine administration on MAO-A and MAO-B activities in primate brain.
- To characterize the changes in enzyme kinetics (Km and Vmax) and inhibitor sensitivity of MAO in different subcellular fractions.
- To determine the presence and inhibitory potential of d-MP and its metabolites on MAO activity.
Main Methods:
- Monkeys were administered d-methamphetamine (2 mg/kg, i.m.) daily for 7 days.
- MAO-A and MAO-B activities were measured in isolated brain mitochondria and synaptosomes using specific substrates (5-HT, beta-PEA, dopamine).
- Enzyme kinetic parameters (Km, Vmax) and inhibition patterns with clorgyline and deprenyl were analyzed. d-MP and its metabolites were quantified and tested for in vitro MAO inhibition.
Main Results:
- Chronic d-MP administration altered MAO kinetics differently in mitochondria and synaptosomes.
- Mitochondrial MAO showed decreased Km and Vmax with 5-HT and beta-PEA, while synaptosomal MAO exhibited increased Km and Vmax with 5-HT and dopamine.
- d-MP and its metabolites (AP, OH-MP, OH-AP) were detected in brain preparations and acted as potent inhibitors, particularly of MAO-A.
Conclusions:
- Chronic d-methamphetamine exposure significantly modifies MAO enzyme activity and kinetics in primate brain subcellular fractions.
- The observed changes suggest complex neuroadaptive responses to d-MP.
- d-MP and its metabolites are potent MAO inhibitors, with a stronger effect on MAO-A, contributing to their neuropharmacological profile.