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A correlation of haloperidol-induced cognitive deficit with dysfunctional dopamine receptor activity in nonhuman primate

Authors Irene Navarro-Lobato, Mariam Masmudi-Martín, Manuel F López-Aranda, et al

Published 4 May 2010 Volume 2010:2 Pages 1—8


Review by Single-blind

Peer reviewer comments 3

Irene Navarro-Lobato1,2, Mariam Masmudi-Martín1, Manuel F López-Aranda1,2,3, Juan Félix López-Téllez1,2,3, Zafar U Khan1,2,3

1Laboratory of Neurobiology at CIMES, Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain; 2Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain; 3CIBERNED, Institute of Health Carlos III, Madrid, Spain

Abstract: Haloperidol is an antipsychotic drug that acts through blockage of dopamine D2 receptors. Chronic administration of this antipsychotic drug in nonhuman primates induces a pronounced cognitive deficit. However, receptor subtypes that are responsible for this cognitive dysfunction remain unknown. Therefore, brains of chronic haloperidol-treated young and aged monkeys were used to analyze the intricate relation of receptor activity, cognitive dysfunction, and haloperidol-mediated actions in the production of harmful effects. Taking into account the significant cognitive loss observed after haloperidol treatment, it was predicted that changes in the cognitive status that correlate with the receptor activity in the prefrontal cortex and striatum, areas implicated in the processing of haloperidol-mediated effects in brain, should be common in both young and aged animals. Based on this concept, we observed that in the prefrontal cortex, dopamine D1 and D2 receptors showed changes in receptor levels that were common in both age groups. However, this relationship was absent in GABAA, serotonin 5HT2 and muscaranic receptors. In contrast to the prefrontal cortex, in striatum, this change was restricted to the dopamine D2 receptors only. Therefore, from our results, it seems that apart from the downregulation of D1 receptor activity in the prefrontal cortex, an upregulation of D2 receptors could also contribute to the generation of the cognitive loss observed in haloperidol-treated monkeys. Additionally, reduced excitatory input due to hampered cortico-striatal D1 dopaminergic activity and stronger inhibition at the synapse of excitatory input site by upregulated striatal D2 receptor activity could promote the side effects associated with haloperidol.

Keywords: cognitive deficit, nonhuman primates, haloperidol, antipsychotic drug, receptor activity

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