title: Involvement of dopamine D2 receptor signal transduction in the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats.
abstract: We have reported previously that the inhibition of both dopaminergic and psychotomimetic/hallucinogenic components plays a role in the discriminative stimulus effects of U-50,488H. However, the mechanisms that underlie the discriminative stimulus effects of U-50,488H, and especially the component that plays a significant role, have not yet been clarified. The present study was designed to further investigate the mechanism(s) of the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats that had been trained to discriminate between 3.0 mg/kg U-50,488H and saline. The dopamine D2 receptor antagonist sulpiride, but not the D1 receptor antagonist SCH23390, generalized to the discriminative stimulus effects of U-50,488H. The mood-stabilizing agents lithium chloride and valproic acid, which have attenuating effects on the Akt/GSK3 pathway, also partially generalized to the discriminative stimulus effects of U-50,488H. In contrast, the 5-HT-related compound racemic 3,4-methylenedioxymethamphetamine, the cannabinoid receptor agonist WIN55,212-2, and the μ-opioid receptor agonist morphine failed to generalize to the discriminative stimulus effects of U-50,488H. These results suggest that the inhibition of the dopaminergic activity mediated by the postsynaptic D2 receptor, followed by suppression of the Akt/GSK3 pathway may be critical for the induction of the discriminative stimulus effects induced by U-50,488H.
authors.affiliation: Departments of Toxicology, Tokyo University of Science, Faculty of Pharmaceutical Sciences, Chiba, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Tamami
authors.initials: T
authors.lastname: Ueno
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishiwaki
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
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*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018712:Analgesics, Non-Narcotic; D018692:Antimanic Agents; D015259:Dopamine Agents; D009294:Narcotics; D017448:Receptors, Dopamine D2; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D018021:Lithium Chloride; D018817:N-Methyl-3,4-methylenedioxyamphetamine