期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 24, 期 9, 页码 1524-1533出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2014.07.004
关键词
Basal ganglia; Dopamine receptors; Dorsal striatum; Glycogen synthase kinase-3 (GSK-3); Schizophrenia
资金
- Instituto de Salud Carlos III [PI10/00290]
- Centro de Investigacion Biomedica en Red de Salud Mental [P91C]
- Ministerio de Ciencia (MICINN, MINECO) [SAF2012-35183]
- Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de Salud Carlos III)
- Ministerio de Ciencia (MEC, MICINN) [SAF2009-08233, SAF2012-34177]
- Fundacion Ramon Areces
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. (C) 2014 Elsevier B.V. and ECNP. All rights reserved.
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