title: Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.
abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer׳s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" (CBM"SO"), CSIC/UAM, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Gomez-Sintes
authors.affiliation: Department of Neurochemistry and Neuropharmacology, IIBB - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CSIC, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Analia
authors.initials: A
authors.lastname: Bortolozzi
authors.affiliation: Department of Neurochemistry and Neuropharmacology, IIBB - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CSIC, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: fapnqi@iibb.csic.es.
authors.forename: Francesc
authors.initials: F
authors.lastname: Artigas
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" (CBM"SO"), CSIC/UAM, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: jjlucas@cbm.csic.es.
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D014446:Tyrosine 3-Monooxygenase; D038362:Glycogen Synthase Kinase 3; D006220:Haloperidol; D004298:Dopamine
keywords: Basal ganglia; Dopamine receptors; Dorsal striatum; Glycogen synthase kinase-3 (GSK-3); Schizophrenia