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

Rational And Objective: Functional opposition between N-methyl-D-aspartate and 5-HT(2A) 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-HT(2A) receptor antagonist, M100907, might abolish phencyclidine (PCP)-induced attentional performance deficit by preventing its effects on transduction mechanisms leading to CREB phosphorylation.

Methods: Using the five-choice serial reaction time task, the ability of subcutaneous injections of 2.5 and 10 microg/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 naïve mice were examined using Western blotting technique.

Results: 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 microg/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.

Conclusions: The data indicate that blockade of 5-HT(2A) receptors may exert beneficial effects on cognitive deficits through a mechanism linked to striatal S(133)-CREB phosphorylation.