title: d-Cycloserine enhanced extinction of cocaine-induced conditioned place preference is attenuated in serotonin transporter knockout rats.
abstract: d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT-/-compared with 5-HTT+/+rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT-/-rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT+/+rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT-/-rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5-HTT-/-ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5-HTT genotype.
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Karel
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Universita'degli Studi di Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Universita'degli Studi di Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Riva
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Universita'degli Studi di Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brivio
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Van der Veen
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Homberg
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003523:Cycloserine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D054333:Drug Partial Agonism; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D055786:Gene Knockout Techniques; D005838:Genotype; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D000071184:Pharmacogenomic Variants; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
chemical_list: D018765:Dopamine Uptake Inhibitors; C483820:Fosb protein, rat; C409466:NR1 NMDA receptor; C432823:NR2C NMDA receptor; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D003523:Cycloserine; D003042:Cocaine
keywords: NMDA; addiction; cocaine; d-cycloserine; serotonin transporter; ∆FosB