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Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain
Abstract:
Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.
Insights
Repeated D-methylamphetamine (MA) injections in monkeys depleted dopamine (DA) and serotonin (5-HT) in the brain. This correlated with reduced homovanillic acid (HVA) in both brain tissue and cerebrospinal fluid.
Area of Science:
- Neuroscience
- Pharmacology
- Neurochemistry
Background:
- Repeated D-methylamphetamine (MA) administration is known to cause long-lasting depletion of key neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), across various brain regions and species.
- Understanding the precise neurochemical consequences of MA exposure is crucial for assessing its neurotoxic potential and developing therapeutic strategies.
Purpose of the Study:
- To establish a reliable, short-term subcutaneous (s.c.) injection regimen for inducing MA-related neuronal alterations.
- To assess the efficacy of this new regimen in causing norepinephrine (NE) depletions.
- To investigate whether central neurochemical changes induced by MA are mirrored by alterations in cerebrospinal fluid (CSF) monoamine metabolite concentrations.
Main Methods:
- Rhesus monkeys were administered high doses of MA via subcutaneous injection over a 2-week period.
- Neurotransmitter levels (DA, NE, 5-HT) were measured in various brain regions.
- Dopamine (DA) uptake sites, homovanillic acid (HVA) levels, and DA turnover were assessed in the caudate nucleus.
- Cerebrospinal fluid (CSF) concentrations of monoamine metabolites, including HVA, were analyzed.
Main Results:
- Subcutaneous MA administration over 2 weeks resulted in significant decreases in dopamine (DA) and serotonin (5-HT) levels in multiple brain regions, but did not affect norepinephrine (NE) levels.
- A notable decrease in caudate DA levels was observed, accompanied by a reduction in DA uptake sites and homovanillic acid (HVA) levels, alongside an increase in DA turnover.
- The observed decrease in brain DA was strongly correlated with a reduction in HVA concentration within the cerebrospinal fluid (CSF).
Conclusions:
- The established 2-week subcutaneous MA injection regimen effectively induces significant depletions in brain dopamine (DA) and serotonin (5-HT) in rhesus monkeys.
- MA-induced changes in central dopaminergic systems, including decreased DA levels and altered turnover, are reflected in peripheral CSF metabolite concentrations, specifically HVA.
- This study highlights the utility of CSF HVA as a potential biomarker for central dopaminergic alterations following MA exposure.