Substituting a long-acting dopamine uptake inhibitor for cocaine prevents relapse to cocaine seeking Clara Velázquez-Sánchez 1 , Antonio Ferragud 1 , Alfredo Ramos-Miguel 2 , Jesús A. García-Sevilla 2 & Juan J. Canales 1 Behavioural Neuroscience, Department of Psychology, University of Canterbury, New Zealand 1 and Laboratory of Neuropharmacology, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands, and Redes Temáticas de Investigación Cooperativa en Salud–Red de Trastornos Adictivos (RETICS-RTA), Spain 2 ABSTRACT The treatment of cocaine addiction remains a challenge. The dopamine replacement approach in cocaine addiction involves the use of a competing dopaminergic agonist that might suppress withdrawal and drug craving in abstinent individuals. Although it has long been postulated that such an approach may be therapeutically successful, preclinical or clinical evidence showing its effectiveness to prevent relapse is scant. We used in rats a procedure that involved substitution of the N-substituted benztropine analog 3a-[bis(4′-fluorophenyl)methoxy]-tropane (AHN-1055), a long- acting dopamine uptake inhibitor (DUI), for cocaine. Maintenance treatment was self-administered. After extinction, reinstatement of drug seeking was induced by cocaine priming. We measured the contents of brain-derived neu- rotrophic factor (BDNF), c-Fos and Fas-associated death domain (FADD) proteins in the medial prefrontal cortex (mPFC) following reinstatement. DUI, but not amphetamine, substitution led to extinction of active lever presses, as did saline substitution. DUI substitution significantly reduced cocaine-induced reinstatement of drug-seeking behavior, which was strongly elicited after saline substitution. Rats passively yoked to DUI also showed reduced cocaine-primed reinstatement. Reductions in drug seeking during reinstatement were matched by downward shifts in the contents of BDNF, c-Fos and FADD proteins in the mPFC, which were elevated in relapsing rats. These data indicate that DUI substitution not only leads to extinction of self-administration behavior but also prevents reinstatement of drug seeking induced by cocaine re-exposure. Thus, DUI substitution therapy using compounds with low abuse potential, even if received passively in the context previously paired with drug taking, may provide an effective treatment for stimulant addiction. Keywords Addiction, cocaine, dopamine uptake blocker, relapse, therapy. Correspondence to: Juan J. Canales, Department of Psychology,The University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand. E-mail: juan.canales@canterbury.ac.nz INTRODUCTION Relapse to drug use is the most significant clinical problem in the treatment of drug addiction. In addition to conditioned drug-related cues and stressors, a major cause of relapse is re-exposure to the drug itself (Kalivas & McFarland 2003; Shaham et al. 2003). In detoxified human addicts, re-experiencing the effects of the drug that was once abused often evokes or intensifies craving and precipitates relapse, even after prolonged periods of drug abstinence (Mahoney et al. 2007). In laboratory animals, priming injection of the drug self-administered previously produces reinstatement of extinguished drug-seeking behavior and, typically, reinstatement can be elicited after extended (weeks-to-months) drug-free periods (Bossert et al. 2005). The model of reinstatement has been used extensively to evaluate behavioral and pharmacological interventions to prevent relapse (Epstein et al. 2006). The treatment and prevention of cocaine addiction is especially challenging. Strong experimental evidence indicates that withdrawal from several drugs of abuse, including cocaine, decreases the activity of the mesolim- bic dopamine system (Rossetti, Hmaidan & Gessa 1992; Weiss et al. 1992). Compromised dopamine function during critical phases of the addiction cycle, such as withdrawal, might fuel anhedonia and dysphoria and decreased motivation for non-drug-related stimuli, in ORIGINAL ARTICLE Addiction Biology doi:10.1111/j.1369-1600.2012.00458.x © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction Addiction Biology