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, 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: Antonio Ferragud, Clara Velázquez-Sánchez, Vicente Hernández-Rabaza, Amparo Nácher, Virginia Merino, Miguel Cardá, Juan Murga, Juan J Canales
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 207 Issue 2 Pg. 281-9 (Dec 2009) ISSN: 1432-2072 [Electronic] Germany
• PMID: 19756525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Uptake Inhibitors
• N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane
• Benztropine
• Sucrose
• Cocaine

Topics

• Animals
• Behavior, Animal (drug effects)
• Benztropine (administration & dosage, analogs & derivatives, pharmacology)
• Cocaine (administration & dosage)
• Cocaine-Related Disorders (drug therapy)
• Dopamine Uptake Inhibitors (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Male
• Motor Activity (drug effects)
• Rats
• Rats, Long-Evans
• Reinforcement Schedule
• Reward
• Self Administration
• Sucrose (administration & dosage)