Sigma-1 receptor ligand PD144418 and sigma-2 receptor ligand YUN-252 attenuate the stimulant effects of methamphetamine in mice

• Published in: Psychopharmacology 2019-11, Vol.236 (11), p.3147-3158
• Main Authors: Tapia, Melissa A., Lever, John R., Lever, Susan Z., Will, Matthew J., Park, Eric S., Miller, Dennis K.
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Attention-deficit hyperactivity disorder; Biomedical and Life Sciences; Biomedicine; Central Nervous System Stimulants - antagonists & inhibitors; Central Nervous System Stimulants - pharmacology; Cocaine; Drug abuse; Hyperactivity; Isoxazoles - metabolism; Isoxazoles - pharmacology; Ligands; Locomotion - drug effects; Locomotion - physiology; Male; Methamphetamine; Methamphetamine - pharmacology; Mice; Narcotics; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Pyridines - metabolism; Pyridines - pharmacology; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; Reinforcement, Psychology; Sigma-1 Receptor; Stimulants; Withdrawal
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-019-05268-2

Rationale Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported. Objectives The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment. Methods Mice ( n  = 8–14/group) were injected with PD144418 (3.16, 10, or 31.6 μmol/kg), YUN-252 (0.316, 3.16, 31.6 μmol/kg), or saline. After 15 min, mice injected with 2.69 μmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice ( n  = 8–14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period. Results Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 μmol/kg or 31.6 μmol/kg of PD144418 and 31 μmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 μmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression. Conclusions Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical.