title: Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization and Activation of Ras-ERK-∆FosB Pathway in the Caudate Putamen.
abstract: Addiction is a debilitating, chronic psychiatric disorder that is difficult to cure completely owing to the high rate of relapse. Behavioral sensitization is considered to may underlie behavioral changes, such as relapse, caused by chronic abuse of psychomotor stimulants. Thus, its animal models have been widely used to explore the etiology of addiction. Recently, increasing evidence has demonstrated that N-methyl-D-aspartate receptors (NMDARs) play an important role in addiction to psychomotor stimulants. However, the role of GluN2B-containing receptors and their downstream signaling pathway(s) in behavioral sensitization induced by methamphetamine (METH) have not been investigated yet. In this study, we used different doses of ifenprodil (2.5, 5, 10 mg/kg), a selective antagonist of the GluN2B subunit, to investigate the role of GluN2B-containing NMDARs in METH-induced behavioral sensitization. We then examined changes in the levels of Ras, phosphorylated extracellular signal-regulated kinase (pERK)/ERK, and ∆FosB in the caudate putamen (CPu) by western blot. We found that 2.5 or 10 mg/kg ifenprodil significantly attenuated METH-induced behavioral sensitization, whereas the mice treated with a moderate dose of ifenprodil (5 mg/kg) displayed no significant changes. Further results of western blot experiments showed that repeated administration of METH caused the increases in the levels of Ras, pERK/ERK and ∆FosB in the CPu, and these changes were inhibited by only the 2.5 mg/kg dose of ifenprodil. In conclusion, these results demonstrated that 2.5 mg/kg ifenprodil could attenuate METH-induced behavioral sensitization. Moreover, GluN2B-containing NMDARs and their downstream Ras-ERK-∆FosB signaling pathway in the CPu might be involved in METH-induced behavioral sensitization.
authors.affiliation: School of Forensic Science and Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Forensic Science and Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China. lxins@xjtu.edu.cn.|The Key Laboratory of Health Ministry for Forensic Science and Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China. lxins@xjtu.edu.cn.
authors.forename: Xinshe
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Forensic Science and Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
authors.forename: Chuchu
authors.initials: C
authors.lastname: Qiao
authors.affiliation: School of Forensic Science and Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: School of Forensic Science and Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China. litao050428@xjtu.edu.cn.|The Key Laboratory of Health Ministry for Forensic Science and Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China. litao050428@xjtu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D011905:Genes, ras / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000378:metabolism; D011699:Putamen / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; C483819:Fosb protein, mouse; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine; D048049:Extracellular Signal-Regulated MAP Kinases; C010739:ifenprodil
keywords: Behavioral sensitization; Caudate putamen; Ifenprodil; Methamphetamine; N-Methyl-D-aspartate receptor