Blockade of serotonin 2A receptors prevents PCP-induced attentional performance deficit and CREB phosphorylation in the dorsal striatum of DBA/2 mice

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 A mu g/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 S-133-CREB and T-34-DARPP32 phosphorylation in the dorsal striatum and prefrontal cortex (PFC) of behaviorally na < ve mice were examined using Western blotting technique. PCP reduced accuracy and increased anticipatory and perseverative responses as well as it increased S-133-CREB phosphorylation in the dorsal striatum but not in the PFC. Ten mu g/kg M100907 abolished the PCP-induced attentional performance deficits and the increase in S-133-CREB but not T-34-DARPP32 phosphorylation. By itself, M100907 had no effect on attentional performance or phospho-S-133-CREB and phospho-T-34-DARPP32. Interestingly, the effect of PCP on phospho-S-133-CREB but not on phospho-T-34-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 S-133-CREB phosphorylation.