RATIONALE: N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. OBJECTIVES: The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. METHODS: We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. RESULTS: AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. CONCLUSIONS: These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.
RATIONALE: N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. OBJECTIVES: The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. METHODS: We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. RESULTS:AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. CONCLUSIONS: These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.
Authors: Stephen J Kohut; Takato Hiranita; Soo-Kyung Hong; Aaron L Ebbs; Valeria Tronci; Jennifer Green; Linda Garcés-Ramírez; Lauren E Chun; Maddalena Mereu; Amy H Newman; Jonathan L Katz; Gianluigi Tanda Journal: Biol Psychiatry Date: 2014-04-19 Impact factor: 13.382
Authors: Weimin C Hong; Michael J Wasko; Derek S Wilkinson; Takato Hiranita; Libin Li; Shuichiro Hayashi; David B Snell; Jeffry D Madura; Christopher K Surratt; Jonathan L Katz Journal: J Pharmacol Exp Ther Date: 2018-06-26 Impact factor: 4.030
Authors: Takato Hiranita; Stephen J Kohut; Paul L Soto; Gianluigi Tanda; Theresa A Kopajtic; Jonathan L Katz Journal: J Pharmacol Exp Ther Date: 2013-11-05 Impact factor: 4.030