Background Combining extinction training with cognitive-enhancing pharmacotherapy represents a novel strategy for improving the efficacy of exposure therapy for drug relapse prevention. were conducted under conditions that precluded explicit extinction of cocaine-conditioned responses. Results Compared to vehicle 30 and 45 mg/kg RO4543338 significantly decreased responding early in extinction training and during subsequent reacquisition sessions. The latter effect persisted for at least five sessions. In control studies reacquisition of cocaine-seeking behavior was not altered when RO4543338 was administered either prior to weekly self-administration control sessions or prior to weekly control sessions in which cocaine and cues were omitted and the levers retracted. Conclusions As the GlyT-1 inhibitor facilitated cocaine-cue extinction learning and attenuated subsequent reacquisition of cocaine-seeking behavior this class of compounds may have utility as a pharmacological adjunct to cocaine-cue exposure therapy in addicts. Keywords: Cocaine-seeking behavior Cognitive enhancer Glycine transporter-1 inhibitor Extinction training Relapse 1 Introduction Drug addiction is a brain disease thought PD0325901 to represent pathological usurpation of the mechanisms of reward-related learning and memory (Hyman 2007 Through the process of associative learning environmental stimuli (cues) paired with drugs of abuse gain enhanced salience to exert long-lasting influences over behavior of addicts (Volkow et al. 2004 Extinguishing such abnormally strengthened learned responses remains a key problem for treating drug addiction. Exposure-based behavioral therapy makes use of an extinction strategy in which individuals are confronted with cues in a controlled setting and without access to drug in an effort to reduce craving and forestall relapse to drug-seeking behavior. Exposure therapy however is not effective consistently as a stand-alone treatment for drug addiction (Conklin and Tiffany 2002 which may be due in part to drug-induced deficits in memory systems important for extinction learning (c.f. Kantak and Nic Dhonnchadha 2011 Combining extinction training with cognitive-enhancing pharmacotherapy has been proposed as a novel strategy for improving the efficacy PD0325901 of exposure therapy for drug relapse prevention (c.f. Nic Dhonnchadha and Kantak 2011 Activation of N-methyl-D-aspartate (NMDA) receptors induces long-term potentiation and/or depression which are mechanisms of synaptic plasticity associated with learning and memory formation (Kemp and Manahan-Vaughan 2007 as well as its extinction (Quirk 2006 Dalton et al. 2008 D-cycloserine (DCS) is a partial agonist at the glycine site of NMDA receptors that enhances glutamate neurotransmission (Bowery 1987 Hood et al. 1989 Studies showing facilitative effects of DCS on extinction learning have focused mainly on conditioned fear in animals and anxiety disorders in humans (Davis et al. 2006 However recent studies have shown a facilitative effect of DCS on extinction of cocaine-conditioned responses in animals (Botreau et al. 2006 Paolone PD0325901 et al. 2009 Torregrossa et al. 2010 Yang et al. 2010 A previous study that used an extinction procedure conceptually similar to exposure therapy in humans showed that prior DCS treatment significantly attenuated reacquisition of cocaine-seeking behavior in both rodents and monkeys by augmenting consolidation of cocaine-cue extinction learning (Nic Dhonnchadha et al. 2010 Recent work has replicated our findings in rats (Thanos et al. 2011 These preclinical findings encourage CD248 continued development of strategies and drug targets for facilitating extinction of cocaine-conditioned responses and preventing relapse. One such drug target is glycine transporter-1 (GlyT-1) which regulates the synaptic levels of glycine (Aragon and Lopez-Corcuera 2005 GlyT-1 sites are located on glia and on postsynaptic glutamatergic neurons in close proximity to NMDA receptors (Cubelos et al. 2005 Raiteri and Raiteri 2010). Pharmacological blockade or genetic deletion of GlyT-1 has been shown to increase glycine levels PD0325901 in glutamatergic synapses and consequently to augment NMDA-receptor transmission (Berger et al. 1998 Bergeron et al. 1998 Kinney et al. 2003 Depoortere et al. 2005 Dubroqua et al. 2010 Rodent studies have shown improvements in cognitive function after treatment with GlyT-1.