Stephen J Kohut1, Jack Bergman2, Bruce E Blough3. 1. Department of Psychiatry, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA. skohut@mclean.harvard.edu. 2. Department of Psychiatry, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA. 3. Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, Durham, NC, USA.
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.
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.
Entities:
Keywords:
Agonist therapy; Cocaine; Dopamine; Drug discrimination; Norepinephrine; Self-administration
Authors: Paul W Czoty; Chinnasamy R Ramanathan; Nicole H Mutschler; Alexandros Makriyannis; Jack Bergman Journal: J Pharmacol Exp Ther Date: 2004-07-07 Impact factor: 4.030
Authors: M T Bardo; E D Denehy; L R Hammerslag; L P Dwoskin; B E Blough; A Landavazo; J Bergman; S J Kohut Journal: Psychopharmacology (Berl) Date: 2019-07-26 Impact factor: 4.530
Authors: Stephen J Kohut; David S Jacobs; Richard B Rothman; John S Partilla; Jack Bergman; Bruce E Blough Journal: Psychopharmacology (Berl) Date: 2017-09-09 Impact factor: 4.530