A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat

Abstract

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, 3α-[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.