title: The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization.
abstract: The discovery and evaluation of high affinity dopamine transport inhibitors with low abuse liability is an important step toward the development of efficacious medications for cocaine addiction. We examined in mice the behavioural effects of (N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (JHW 007), a benztropine (BZT) analogue that blocks dopamine uptake, and assessed its potential to influence the actions of cocaine in clinically-relevant models of cocaine addiction. In the conditioned place preference (CPP) paradigm, JHW 007 exposure did not produce place conditioning within an ample dose range but effectively blocked the CPP induced by cocaine administration. Similarly, in the CPP apparatus JHW 007 treatment failed to stimulate locomotor activity at any dose but dose-dependently suppressed the hyperactivity evoked by cocaine treatment. In locomotor sensitization assays performed in the open field, JHW 007 did not produce sensitized locomotor behaviour when given alone, but it prevented the sensitized component of the locomotor response elicited by subchronic (8-day) cocaine exposure. In the elevated plus maze (EPM), acute treatment with JHW 007, cocaine and combinations of the BZT analogue and cocaine produced an anxiogenic-like profile. Re-test in the EPM following subchronic (8-day) exposure enhanced the anxiogenic-like effect of the same drug treatments. The present findings indicate that JHW 007 exposure counteracts some critical behavioural correlates of cocaine treatment, including conditioned reward, locomotor stimulation and sensitization, and lend support to the further development of BZT analogues as potential replacement medications in cocaine addiction.
authors.affiliation: Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE), University of Valencia-FGUV, Valencia, Spain. juan.canales@uv.es
authors.forename: C
authors.initials: C
authors.lastname: Velázquez-Sánchez
authors.forename: A
authors.initials: A
authors.lastname: Ferragud
authors.forename: J
authors.initials: J
authors.lastname: Murga
authors.forename: M
authors.initials: M
authors.lastname: Cardá
authors.forename: J J
authors.initials: JJ
authors.lastname: Canales
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001590:Benztropine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D012201:Reward
chemical_list: D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C504726:N-(n-butyl)-(bis-fluorophenyl)methoxytropane; D001590:Benztropine; D003042:Cocaine