Effects of repeated treatment of phencyclidine on cognition and gene expression in C57BL/6 mice

Abstract

A number of studies indicate that glutamatergic N-methyl-D-aspartate (NMDA) neurotransmission is disturbed in schizophrenia partly based on the findings that NMDA receptor antagonists such as phencyclidine (PCP) can reproduce a schizophrenia-like syndrome in both humans and rodents. This study investigated whether repeated administration of low doses of PCP can induce cognitive dysfunctions in mice at doses which produce no sensorimotor disturbances. In addition, the effects on cognition were related to the expression of two genes, Arc and spinophilin, which have been related to neuronal plasticity and learning. Adult male C57Bl/6J mice received daily s.c. doses of PCP (0.5-2.0 mg/kg) or saline for 7 d. Testing was performed 24 h after the last day of treatment. Only the 2.0 mg/kg PCP dose produced a consistent impairment in spatial learning and working memory performed in the water-maze task without any apparent sensorimotor deficits. Importantly, the 2.0 mg/kg PCP dose produced no impairment in a non-spatial learning paradigm in the water-maze task. PCP treatment altered Arc mRNA levels in the hippocampus and retrosplenial agranular cortex while leaving the striatum and prefrontal cortex unaffected. The mRNA expression of spinophilin was down-regulated in striatum by repeated PCP treatment. These results demonstrate that repeated treatment with low doses of PCP in mice can produce specific cognitive deficits which are associated with alterations in gene expression in brain regions that appear to play a role in the pathophysiology of schizophrenia. These results suggest that the low-dose PCP model may have significant potential in characterizing the behavioural and molecular mechanisms underlying cognitive deficits seen in schizophrenia patients.

Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia

“…PCP disrupts performance in the water maze when administered during acquisition and recall (Didriksen et al, 2007; Podhorna and Didriksen, 2005; Wass et al, 2006) but does not interfere with consolidation in C57BL/6J mice and Wistar rats (Podhorna and Didriksen, 2005). Subchronic PCP (2 mg/kg, 7 days, 24 h washout) produced specific deficits in spatial learning and memory in C57 mice while not affecting performance in the visible platform variations, ruling out general effects on sensorimotor function (Beraki et al, 2008a). A similar regimen of MDMA (b.i.d., 4 days; 72 h washout) also impaired learning and memory in the water maze (Camarasa et al, 2008).…”

Mouse pharmacological models of cognitive disruption relevant to schizophrenia

“…Repeated clozapine treatment blocked the PCP-induced impairment, while haloperidol did not (Beraki et al, 2008). In a separate study, subchronic PCP (0.5-2 mg/kg for 7 days) impaired learning the MWM 24 hour after PCP cessation (Beraki et al, 2009). This effect of PCP was measured as altered latencies to find the platform, however, while the path length taken by the mice did not differ.…”

Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms

“…Other laboratories have also shown cognitive deficits following sub-chronic PCP treatment in several tasks, e.g. working memory in the water maze in rats and mice (Beraki et al 2009) and in novel object recognition (NOR) in mice (Hashimoto et al 2008) and in a test of conditional discrimination in rats (Dunn and Kilcross 2006). In the reversal learning test, the main aim was to incorporate an element of task switching, which demands cognitive flexibility and the suppression of previously learned responses.…”