title: CM156, a sigma receptor ligand, reverses cocaine-induced place conditioning and transcriptional responses in the brain.
abstract: Repeated exposure to cocaine induces neuroadaptations which contribute to the rewarding properties of cocaine. Using cocaine-induced conditioned place preference (CPP) as an animal model of reward, earlier studies have shown that sigma (σ) receptor ligands can attenuate the acquisition, expression and reactivation of CPP. However, the underlying molecular mechanisms that are associated with these changes are not yet understood. In the present study, CM156, a novel antagonist with high selectivity and affinity for σ receptors was used to attenuate the expression of cocaine-induced CPP in mice. Immediately following the behavioral evaluations, mouse brain tissues were collected and alterations in gene expression in half brain samples were profiled by cDNA microarray analysis. Microarray data was analyzed by three distinct normalization methods and four genes were consistently found to be upregulated by cocaine when compared to saline controls. Each of these gene changes were found by more than one normalization method to be reversed by at least one dose of CM156. Quantitative real time PCR confirmed that a single administration of CM156 was able to reverse the cocaine-induced increases in three of these four genes: metastasis associated lung adenocarcinoma transcript 1 (malat1), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (ywhaz), and transthyretin (ttr). These genes are involved in processes related to neuroplasticity and RNA editing. The data presented herein provides evidence that pharmacological intervention with a putative σ receptor antagonist reverses alterations in gene expression that are associated with cocaine-induced reward.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Yan-Tong
authors.initials: YT
authors.lastname: Xu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.forename: Wioletta
authors.initials: W
authors.lastname: Szeszel-Fedorowicz
authors.forename: Divyen
authors.initials: D
authors.lastname: Patel
authors.forename: Robert
authors.initials: R
authors.lastname: Rooney
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011228:Prealbumin / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012201:Reward; D012640:Seizures / Q000139:chemically induced; D013457:Sulfur Compounds / Q000494:pharmacology*
chemical_list: D048948:14-3-3 Proteins; D003042:Cocaine; D018076:DNA, Complementary; D010879:Piperazines; D011228:Prealbumin; D012313:RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D017480:Receptors, sigma; D013457:Sulfur Compounds; C000590975:Ywhaz protein, mouse; C549191:3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo(d)thiazole-2(3H)-thione; C557040:Malat1 long non-coding RNA, mouse