TY - JOUR T1 - Involvement of a Dysfunctional Dopamine-D1/<em>N</em>-Methyl-<span class="sc">d</span>-aspartate-NR1 and Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1598 LP - 1609 DO - 10.1124/mol.106.032961 VL - 71 IS - 6 AU - Akihiro Mouri AU - Yukihiro Noda AU - Akihiro Noda AU - Tomonobu Nakamura AU - Takanobu Tokura AU - Yoshimitsu Yura AU - Atsumi Nitta AU - Hiroshi Furukawa AU - Toshitaka Nabeshima Y1 - 2007/06/01 UR - http://molpharm.aspetjournals.org/content/71/6/1598.abstract N2 - Continuous ingestion of phencyclidine (PCP) in humans produces long-lasting schizophrenic-like cognitive dysfunction. Although a malfunction of dopaminergic and/or glutamatergic neurotransmission is implicated in the etiology of schizophrenia, involvement of the dopaminergic-glutamatergic neurotransmission in the cognitive dysfunction induced by repeated PCP treatment is minor. We demonstrated that mice treated with PCP (10 mg/kg/day s.c.) for 14 days displayed an impairment of latent learning in a water-finding task and of learning-associated phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and NR1 in the prefrontal cortex even after drug withdrawal. The infusion of a CaMKII inhibitor and NR1 antisense oligonucleotide into the prefrontal cortex produced an impairment of latent learning and decrease of learning-associated phosphorylation of CaMKII, which were observed in the PCP-treated mice. Exogenous NMDA-induced CaMKII activation was not observed in slices of the prefrontal cortex prepared from mice treated repeatedly with PCP. The potentiation of NMDA receptor function by the infusion of glycine into the prefrontal cortex ameliorated these impairments in mice treated repeatedly with PCP. The high potassium-stimulated release of dopamine from the prefrontal cortex was less extensive in the PCP-treated than saline-treated mice. The infusion of a dopamine-D1 receptor agonist into the prefrontal cortex attenuated the impairment of latent learning and decrease of learning-associated NR1 phosphorylation in the PCP-treated mice, suggesting a functional linkage between glutamatergic and dopaminergic signaling. These findings indicate that repeated PCP treatment impairs latent learning through a prefrontal cortical dysfunction of NMDA-CaMKII signaling, which is associated with dopaminergic hypofunction. The American Society for Pharmacology and Experimental Therapeutics ER -