title: STEP signaling pathway mediates psychomotor stimulation and morphine withdrawal symptoms, but not for reward, analgesia and tolerance.
abstract: Striatal-enriched protein tyrosine phosphatase (STEP) is abundantly expressed in the striatum, which strongly expresses dopamine and opioid receptors and mediates the effects of many drugs of abuse. However, little is known about the role of STEP in opioid receptor function. In the present study, we generated STEP-targeted mice carrying a nonsense mutation (C230X) in the kinase interaction domain of STEP by screening the N-ethyl-N-nitrosourea (ENU)-driven mutant mouse genomic DNA library and subsequent in vitro fertilization. It was confirmed that the C230X nonsense mutation completely abolished functional STEP protein expression in the brain. STEP(C230X-/-) mice showed attenuated acute morphine-induced psychomotor activity and withdrawal symptoms, whereas morphine-induced analgesia, tolerance and reward behaviors were unaffected. STEP(C230X-/-) mice displayed reduced hyperlocomotion in response to intrastriatal injection of the μ-opioid receptor agonist DAMGO, but the behavioral responses to δ- and κ-opioid receptor agonists remained intact. These results suggest that STEP has a key role in the regulation of psychomotor action and physical dependency to morphine. These data suggest that STEP inhibition may be a critical target for the treatment of withdrawal symptoms associated with morphine.
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Yoon-Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Park
authors.affiliation: Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Lee
authors.affiliation: University of Science and Technology, Daejeon, Republic of Korea.|Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Murata
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Yoichi
authors.identifier: http://orcid.org/0000-0003-2184-6489
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: College of Biosciences and Biotechnology, Chung-Nam National University, Daejeon, Republic of Korea.
authors.forename: Myungchull
authors.initials: M
authors.lastname: Rhee
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea.|Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.affiliation: University of Science and Technology, Daejeon, Republic of Korea.|BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D011595:Psychomotor Agitation / Q000209:etiology*; D011957:Receptors, Opioid / Q000378:metabolism; D012201:Reward; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D009020:Morphine; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse