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L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats;
Shuangteng He1, Kenneth Grasing
1Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA.
Abstract:
Selegiline is an inhibitor of type B monoamine oxidase (MAO) with psychostimulant effects that can decrease morphine-reinforced and non-reinforced responding. The present study was undertaken to compare the effects of MAO inhibition and treatment with L-methamphetamine, the major psychostimulant metabolite of selegiline, on these behaviors. After rats acquired a stable pattern of morphine self-administration under a progressive ratio schedule, chronic treatment was initiated with vehicle, L-methamphetamine, clorgyline (a selective inhibitor of MAO-A), or rasagiline (a selective inhibitor of MAO-B); with both MAO inhibitors administered at a dose selective for one MAO isoform and a higher dose that inhibited both isoforms. Rats were evaluated for up to four cycles of opiate dependence maintained by morphine self-administration and withdrawal during which extinction responding was recorded. Most behavioral measures (92.4%) did not differ in animals evaluated during an initial and subsequent cycles of dependence and withdrawal. All active treatments attenuated non-reinforced responding during extinction. Morphine reinforcement was also decreased by each of the three active treatments, but greater and more prolonged effects were observed following inhibition of MAO-B with rasagiline. Responding during either cue- or morphine-induced reinstatement was attenuated by either clorgyline or rasagiline administered at nonselective doses, but not by either compound administered at selective dose levels. Treatment with L-methamphetamine did not produce significant effects on cue-induced reinstatement, but decreased non-reinforced responding during morphine-induced reinstatement. These findings indicate that morphine reinforcement and different non-reinforced behaviors differ greatly in their susceptibility to modification by psychostimulant treatment or MAO inhibition.
Insights
Monoamine oxidase (MAO) inhibition and L-methamphetamine treatment differentially affect morphine reinforcement and non-reinforced behaviors. MAO-B inhibition with rasagiline showed the most prolonged decrease in morphine reinforcement.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Selegiline, a monoamine oxidase (MAO) inhibitor, exhibits psychostimulant properties and can reduce behaviors reinforced by morphine.
- Understanding the distinct effects of MAO inhibition versus its psychostimulant metabolite, L-methamphetamine, is crucial for elucidating their impact on drug-seeking behaviors.
Purpose of the Study:
- To compare the effects of MAO inhibition and L-methamphetamine on morphine-reinforced and non-reinforced behaviors in a rat model.
- To investigate the specific roles of MAO-A and MAO-B inhibition in modulating opiate dependence and reinstatement.
Main Methods:
- Rats self-administered morphine under a progressive ratio schedule to establish dependence.
- Chronic treatments included vehicle, L-methamphetamine, clorgyline (MAO-A inhibitor), and rasagiline (MAO-B inhibitor) at selective and non-selective doses.
- Behavioral responses during withdrawal, extinction, and reinstatement (cue- or morphine-induced) were recorded across multiple cycles.
Main Results:
- Most behavioral measures remained consistent across initial and subsequent cycles of dependence and withdrawal.
- All tested treatments (L-methamphetamine, clorgyline, rasagiline) reduced non-reinforced responding during extinction.
- Morphine reinforcement was decreased by all active treatments, with rasagiline (MAO-B inhibition) demonstrating more potent and sustained effects.
- Non-selective doses of clorgyline and rasagiline attenuated cue- and morphine-induced reinstatement, while selective doses did not.
- L-methamphetamine affected cue-induced reinstatement minimally but reduced non-reinforced responding during morphine-induced reinstatement.
Conclusions:
- Morphine reinforcement and various non-reinforced behaviors exhibit differential sensitivity to psychostimulant treatment and MAO inhibition.
- MAO-B inhibition appears particularly effective in reducing morphine reinforcement and associated behaviors.
- The findings highlight the complex interplay between MAO inhibition, psychostimulant effects, and opiate dependence, suggesting distinct mechanisms underlying different behavioral responses.
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