Blockade of serotonin 2A receptors prevents PCP-induced attentional performance deficit and CREB phosphorylation in the dorsal striatum of DBA/2 mice.
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.
Pozzi
Laura
L
Laboratory of Neurochemistry and Behavior, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri", via Giuseppe La Masa 19, 20156 Milan, Italy.
Greco
Barbara
B
Sacchetti
Giuseppina
G
Leoni
Giampaolo
G
Invernizzi
Roberto W
RW
Carli
Mirjana
M
D000818:Animals; D001288:Attention / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010622:Phencyclidine / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012691:Serial Learning / Q000187:drug effects; D058830:Serotonin 5-HT2 Receptor Antagonists
D017362:Cyclic AMP Response Element-Binding Protein; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; C079049:volinanserin; D010622:Phencyclidine