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Eur Neuropsychopharmacol. 2014 Sep;24(9):1524-33. doi: 10.1016/j.euroneuro.2014.07.004. Epub 2014 Jul 21.

Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.

Author information

1
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.
2
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.
3
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.
4
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.

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.

KEYWORDS:

Basal ganglia; Dopamine receptors; Dorsal striatum; Glycogen synthase kinase-3 (GSK-3); Schizophrenia

PMID:
25088904
DOI:
10.1016/j.euroneuro.2014.07.004
[Indexed for MEDLINE]

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