Long-Lasting Impairment of Associative Learning Is Correlated with a Dysfunction of N-Methyl-d-aspartate-Extracellular Signaling-Regulated Kinase Signaling in Mice after Withdrawal from Repeated Administration of Phencyclidine

Abstract

In humans, the administration of phencyclidine causes schizophrenic-like symptoms that persist for several weeks after withdrawal from phencyclidine use. We demonstrated here that mice pretreated with phencyclidine (10 mg/kg/day s.c. for 14 days) showed an enduring impairment of associative in a Pavlovian fear conditioning 8 days after cessation of phencyclidine treatment. Extracellular signaling-regulated kinase (ERK) was transiently activated in the amygdalae and hippocampi of saline-treated mice after conditioning. In the phencyclidine-treated mice, the basal level of ERK activation was elevated in the hippocampus, whereas the activation was impaired in the amygdala and hippocampus after conditioning. Exogenous N-methyl-D-aspartate (NMDA), glycine, and spermidine-induced ERK activation was not observed in slices of hippocampus and amygdala prepared from phencyclidine-treated mice. Repeated olanzapine (3 mg/kg/day p.o. for 7 days), but not haloperidol (1 mg/kg/day p.o. for 7 days), treatment reversed the impairment of associative learning and of fear conditioning-induced ERK activation in repeated phencyclidine-treated mice. Our findings suggest an involvement of abnormal ERK signaling via NMDA receptors in repeated phencyclidine treatment-induced cognitive dysfunction. Furthermore, our phencyclidine-treated mice would be a useful model for studying the effect of antipsychotics on cognitive dysfunction in schizophrenia.

Nobiletin, a Citrus Flavonoid, Reverses Learning Impairment Associated withN-Methyl-D-aspartate Receptor Antagonism by Activation of Extracellular Signal-Regulated Kinase Signaling

“…Thus, NMDA receptor antagonists, such as phencyclidine, MK-801, and ketamine, induce psychotic states in normal human volunteers and exacerbate symptoms in patients with schizophrenia (Javitt and Zukin, 1991;Olney et al, 1999). Based on the results of the present study and the previously reported finding that the phencyclidine-treated animal, a useful model of schizophrenia, induces a long-lasting impairment of associative learning accompanied by a decrease in learning-associated NMDA-ERK signaling (Enomoto et al, 2005), nobiletin might improve the cognitive impairment associated with schizophrenia through activation of ERK signaling. Furthermore, it is necessary to investigate the beneficial effects of nobiletin on schizophrenia-like positive and negative symptoms in animal models of schizophrenia in the future study.…”

“…Reversely, in vivo blockade of NMDA receptors or inhibition of ERK signaling results in impairment of associative learning (Kim et al, 1991;Atkins et al, 1998). Furthermore, long-lasting impairment of associative learning after repeated administration of phencyclidine, a noncompetitive NMDA receptor antagonist, is correlated with a dysfunction of ERK signaling (Enomoto et al, 2005). Accordingly, it is plausible that control of ERK signaling is a potential target for treatment of neurological disorders exhibiting cognitive dysfunction.…”

The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Ameliorates the Cognitive Dysfunction in Beta Amyloid25–35 I.c.v.-Injected Mice: Involvement of Dopaminergic Systems

“…The cued and contextual fear-conditioning tasks were carried out on the days 9-10 after Ab 25À35 infusion according to a previous report (Enomoto et al, 2005) with a minor modification. For measuring basal levels of freezing response (preconditioning phase), on the day 9, mice were individually placed in a neutral cage (23 Â 23 Â 12 cm) for 1 min and then in the conditioning cage (25 Â 31 Â 11 cm) for 2 min.…”

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Accordingly, rodents and nonhuman primates treated with non-competitive NMDAR antagonists display behavioral features consistent with many symptoms of schizophrenia . Repeated dosing with these drugs may provide greater validity than acute administration, as such regimens induce neurochemical changes similar to those seen in schizophrenic patients (Cochran et al, 2003;Enomoto et al, 2005;Reynolds et al, 2004), as well as lasting cognitive deficits that can be observed when animals are tested in a drug-free state (Jentsch and Roth, 1999).…”