title: The dopamine uptake inhibitor 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward.
abstract: Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing marginal decreases at low and moderate doses (1, 3 mg/kg) in both dorsal and ventral striatum. Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment, but not by treatment with D-amphetamine. Such reduced ability did not result from an increase in stereotyped behavior. Another dopamine uptake inhibitor, nomifensine, decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies. Remarkably, the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone, and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum. These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties, including attenuation of cocaine-induced striatal c-Fos expression, locomotor stimulation, and CPP, support its candidacy, and that of structurally related molecules, as possible pharmacotherapies in cocaine addiction.
authors.affiliation: Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE), University of Valencia-FGUV & Red de Trastornos Adictivos-RETICS, Paterna, Valencia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Velázquez-Sánchez
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferragud
authors.forename: Vicente
authors.initials: V
authors.lastname: Hernández-Rabaza
authors.forename: Amparo
authors.initials: A
authors.lastname: Nácher
authors.forename: Virginia
authors.initials: V
authors.lastname: Merino
authors.forename: Miguel
authors.initials: M
authors.lastname: Cardá
authors.forename: Juan
authors.initials: J
authors.lastname: Murga
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Canales
mesh_terms: D000818:Animals; D001590:Benztropine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003214:Conditioning, Classical / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009627:Nomifensine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012201:Reward; D013028:Space Perception / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D018765:Dopamine Uptake Inhibitors; C464560:N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane; D016760:Proto-Oncogene Proteins c-fos; D009627:Nomifensine; D001590:Benztropine; D003042:Cocaine