title: Activation of extracellular signal-regulated kinase is critical for the discriminative stimulus effects induced by U-50,488H.
abstract: We previously demonstrated that the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H were associated with its aversive effects in rats. However, its molecular signaling mechanisms are not fully understood. The aim of this study was to investigate the intracellular signaling that plays a role in mediating the discriminative stimulus effect induced by U-50,488H. To better understand the involvement of molecular signaling mechanisms in the discriminative stimulus effects of U-50,488H, rats were subjected to a drug discrimination paradigm, and levels of immunoreactivity and mRNA expression were determined in these rats. Although U-50,488H-trained rats did not show changes in the mRNA expression of typical dopamine (DA) receptors, NMDA receptor subunits, or transcriptional activators, there were remarkable changes in the levels of immunoreactivity of several phosphorylated protein kinases. The levels of immunoreactivity of phosphorylated p38 MAPK and phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) were significantly increased in the nucleus accumbens and amygdala in lever-press, yoked and discrimination groups compared to a naive group. Furthermore, the level of phosphorylated cAMP response element-binding protein was also increased in both the discrimination and yoked groups. In contrast, the immunoreactivity of phosphorylated extracellular signaling-regulated kinase (ERK 1/2) was specifically increased in the discrimination group. These results suggest that the ERK signaling pathway in the nucleus accumbens and amygdala may be critical for the expression of the discriminative stimulus effects of U-50,488H.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Mai
authors.initials: M
authors.lastname: Saeki
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Kana
authors.initials: K
authors.lastname: Isotani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000679:Amygdala / Q000187:drug effects* / Q000201:enzymology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D017362:Cyclic AMP Response Element-Binding Protein; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1