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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK-801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone -and to a lesser extent haloperidol- reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2A (M100907) and α1-adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2A, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism. ; This work was supported by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (FIS Grants PI070111 and PI1001103), Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, and by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008, of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). Funding by the Generalitat de Catalunya (2009SGR220) and co-funding by the European Regional Development Fund (a way to build Europe) is also acknowledged ; Peer reviewed

El pdf del artículo es la versión pre-print.-- et al. ; Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-β peptide (Aβ) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Aβ on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Aβ {42} on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO{4}, which liberates redox active iron. Pro-oxidant conditions potentiated Aβ toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Aβ {40} and Aβ {42} or Aβ {42} alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO{4}. A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Aβ plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Aβ deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Aβ. © 2010 - IOS Press and the authors. ; This study was supported by grants SAF200613092-C02-02 from the Spanish Ministerio de Ciencia e Innovación, RD06/0013/1004 (RETICEF) from the Instituto de Salud Carlos III, 062931 from Fundació La Marató de TV3 and by the European Network of Excellence DiMI (LSHB-CT-2005-512146). S. García-Matas received a Generalitat (Autonomous Government of Catalonia) fellowship. ; Peer Reviewed