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: Clara Velázquez-Sánchez, Antonio Ferragud, Vicente Hernández-Rabaza, Amparo Nácher, Virginia Merino, Miguel Cardá, Juan Murga, Juan J Canales
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 34 Issue 12 Pg. 2497-507 (Nov 2009) ISSN: 1740-634X [Electronic] England
• PMID: 19606084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Uptake Inhibitors
• N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane
• Proto-Oncogene Proteins c-fos
• Nomifensine
• Benztropine
• Cocaine

Topics

• Animals
• Benztropine (administration & dosage, analogs & derivatives, pharmacology)
• Brain (drug effects, metabolism)
• Cocaine (pharmacology)
• Cocaine-Related Disorders (drug therapy)
• Conditioning, Classical (drug effects)
• Dopamine Uptake Inhibitors (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Male
• Mice
• Motor Activity (drug effects)
• Nomifensine (pharmacology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Reward
• Space Perception (drug effects)
• Stereotyped Behavior (drug effects)