Blockade of serotonin 2A receptors prevents PCP-induced attentional performance deficit and CREB phosphorylation in the dorsal striatum of DBA/2 mice
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Rational and objective
Functional opposition between N-methyl-d-aspartate and 5-HT2A receptors may be a neural mechanism supporting cognitive functions. These systems converge on an intracellular signaling pathway that involves protein kinase A-dependent phosphorylation of different proteins including cyclic adenosine monophosphate response element binding (CREB). Thus, we tested whether selective 5-HT2A receptor antagonist, M100907, might abolish phencyclidine (PCP)-induced attentional performance deficit by preventing its effects on transduction mechanisms leading to CREB phosphorylation.
Using the five-choice serial reaction time task, the ability of subcutaneous injections of 2.5 and 10 µg/kg of M100907 to abolish the effects of an intraperitoneal injection of 1.5 mg/kg PCP on attentional performance as measured by accuracy (percentage of correct responses) and anticipatory and perseverative responding was assessed in DBA/2 mice. The effects of PCP, M100907, and their combination on S133-CREB and T34-DARPP32 phosphorylation in the dorsal striatum and prefrontal cortex (PFC) of behaviorally naïve mice were examined using Western blotting technique.
PCP reduced accuracy and increased anticipatory and perseverative responses as well as it increased S133-CREB phosphorylation in the dorsal striatum but not in the PFC. Ten μg/kg M100907 abolished the PCP-induced attentional performance deficits and the increase in S133-CREB but not T34-DARPP32 phosphorylation. By itself, M100907 had no effect on attentional performance or phospho-S133-CREB and phospho-T34-DARPP32. Interestingly, the effect of PCP on phospho-S133-CREB but not on phospho-T34-DARPP32 was dependent on endogenous 5-HT.
The data indicate that blockade of 5-HT2A receptors may exert beneficial effects on cognitive deficits through a mechanism linked to striatal S133-CREB phosphorylation.
KeywordsM100907 Phencyclidine CREB DARPP32 Dorsal striatum Attention
We thank Dr. S. Kongsamut (Aventis Pharmaceutical, USA) for the generous gift of M100907. Funding for these studies was provided by the Italian Ministry for University and Research (MIUR) grant RBAU01ZS5C. Supplementary information is available at the Psychopharmacology website.
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