Abstract
Rationale
Monoamine releasers with prominent dopaminergic actions, e.g., d-methamphetamine (d-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, D-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder.
Objectives
The l-isomer of methamphetamine (l-MA), unlike d-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether l-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration.
Methods
Separate groups (N = 4–5) of rhesus monkeys were studied to determine whether l-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement.
Results
l-MA, like d-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5–10-day treatments with continuously infused l-MA (0.032–0.32 mg/kg/h, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding.
Conclusions
These results indicate that l-MA both shares discriminative stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. l-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.
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Acknowledgments
This work was supported by grants R01-DA002519 and K01-DA039306 from the National Institute on Drug Abuse, National Institute of Health. We thank Claire Barkin, Nathanial Osiris, and Olga Smirnova for excellent technical assistance.
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Kohut, S.J., Bergman, J. & Blough, B.E. Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys. Psychopharmacology 233, 1067–1075 (2016). https://doi.org/10.1007/s00213-015-4186-5
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DOI: https://doi.org/10.1007/s00213-015-4186-5