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


OBJECTIVE
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.
Ferragud
Antonio
A
Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE), University of Valencia-General Foundation & Red de Trastornos Adictivos (RETICS), Polígono de la Coma s/n, Paterna, 46980, Valencia, Spain.
Velázquez-Sánchez
Clara
C
Hernández-Rabaza
Vicente
V
Nácher
Amparo
A
Merino
Virginia
V
Cardá
Miguel
M
Murga
Juan
J
Canales
Juan J
JJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001590:Benztropine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
D018765:Dopamine Uptake Inhibitors; C464560:N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane; D001590:Benztropine; D013395:Sucrose; D003042:Cocaine