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.

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

“…In previous studies, donepezil has been found to reverse sub-chronic PCP-induced (McLean et al, 2011a;Kunitachi et al, 2009;Le Cozannet et al, 2010) and scopolamineinduced deficits (Lenz et al, 2012) in rodents. In support of our data in a model of delayinduced deficits, donepezil (0.1-3 mg/kg) alleviates object recognition deficits following a 4 hour inter-trial interval (Kendall et al, 2011).…”

Animal models of schizophrenia

“…In contrast, many of the PCP‐induced cognitive deficits appear to be reversed by several atypical antipsychotics. However, acute clozapine failed to reverse a subchronic PCP‐induced impairment in episodic memory (Le Cozannet et al ., 2010), and only sertindole, but not risperidone, restored performance in the extra‐dimensional shift of the attentional set‐shifting task (Goetghebeur and Dias, 2009). Few studies have evaluated the effect of repeated or chronic antipsychotic drug treatment on cognitive impairment in PCP models.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The deficit was reversed by acute treatments with atypical antipsychotic compounds ziprasidone, olanzapine, and clozapine. PCP withdrawal impaired performance in object-placecontext task in rats, which was reversed by donepezil but not by clozapine (Le Cozannet et al, 2010). Subchronic PCP treatment induced a persistent deficit in novel object recognition that was attenuated by lurasidone (a potent 5-HT 1A partial agonist, 5-HT 2A antagonist), tandospirone (weak D 2 antagonist), and F15599 (selective postsynaptic 5-HT 1A agonist), and interaction studies with these various ligands showed that 5-HT 1A agonism was adequate to attenuate the PCP-induced effects (Horiguchi and Meltzer, 2012).…”