Phencyclidine withdrawal disrupts episodic-like memory in rats: reversal by donepezil but not clozapine

Abstract

Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder. However, in contrast to humans, PCP and PCP withdrawal-induced memory deficits in rodents are reversed by antipsychotic drugs such as clozapine. One possible explanation is that the memory tasks used in animal studies do not simultaneously test the What? Where? When? components that characterize episodic memory in human tasks. We investigated whether subchronic PCP withdrawal disrupts memory in rats in a task that requires simultaneous integration of memory for object, place and context. Rats learn to discriminate objects under specific spatial and contextual conditions analogous to the What? Where? When? components of human episodic memory. We found that PCP withdrawal impaired performance on this task and that the atypical antipsychotic drug clozapine did not reverse this impairment. However the acetylcholinesterase inhibitor (AChEI) donepezil, which has been shown to improve episodic memory in humans did reverse the effect of PCP. This suggests that PCP withdrawal disruption of object-place-context recognition in rats may prove to be a useful model to investigate episodic memory impairment in schizophrenia and supports the suggestion that AChEIs could prove to be a useful pharmacological strategy to specifically treat episodic memory problems in schizophrenia.

Fig. 1

(a) Shows the drug treatment and behavioural testing protocol. (b) Shows the experimental design of the object–place–context (OPC) recognition task. Rats explored two contexts with two different objects in alternating locations. After a 5- or 10-min delay, they were tested in one of the contexts (first one encountered) with two similar objects. Only one object (‘what’) was located in a new place (‘where’) depending on the context (‘which–when’).

Fig. 2

Phencyclidine (PCP) disrupts object–place–context memory in rats. (a) Object exploration (time in seconds) decreased similarly in both groups during the sample phase and did not differ between groups. (b) Mean discrimination index (DI). At 5-min delay, only the saline group was significantly greater than zero (^§ p < 0.05) and was significantly different from the PCP group (* p < 0.05). Error bars represent ± s.e.m.

Fig. 3

Clozapine does not reverse phencyclidine (PCP)-induced object–place–context memory deficit in rats. (a) During the sample phase, clozapine-treated rats showed reduced exploration compared to saline (p < 0.01). (b) Mean discrimination index. At 5-min delay, both saline–saline and saline–clozapine (Clz) groups showed performance significantly greater than zero (^§ p < 0.05). * Indicates p < 0.05 significant difference from saline–saline group at 5-min delay. Errors bars represent ± s.e.m.

Fig. 4

Donepezil reverses phencyclidine (PCP)-induced object–place–context memory deficit in rats. (a) Exploration decreased over days during sample phase but there was no difference between drug groups. (b) Mean discrimination index (DI). At 5-min delay, only the PCP–saline group DI was not significantly greater than zero (^§ p < 0.05) and there was a significant difference between scores from the PCP–saline group with drug groups (* p < 0.05). At 10-min delay, the saline–donepezil-treated rats’ DI was significantly greater than zero (^§ p < 0.05). Errors bars represent ± s.e.m.