Neuroleptics ameliorate phencyclidine-induced impairments of short-term memory

Phencyclidine (PCP), a non-competitive NMDA-receptor antagonist, is able to induce schizophrenia-like symptoms in animals and in humans. It is known that schizophrenic patients have deficits in memory processes. Therefore, it was investigated whether subchronic pulsatile or continuous application of 5.0 mg kg−1 PCP over 5 days induce short-term memory deficits in holeboard learning and the action of two different neuroleptics on this behavioural test. First, an impairment in the holeboard task was described when the animals were tested 24 h after the last application but not after 15 min or 1 h after the last injection. Secondly, the influence of haloperidol and risperidone on the PCP-induced short-term memory changes was tested. The combined application of PCP and risperidone led to a complete antagonism of the short-term deficits, but the combined treatment with haloperidol was accompanied by a partial abolishment of the PCP-induced deficits. PCP led to an upregulation of the glutamate binding sites in striatum and nucleus accumbens whereas the D2 binding sites were reduced in striatum. The D1 binding sites seem to be unchanged. The receptor protein expression of glutamate receptors mGluR1, GluR2, GluR5/7 and NMDAR1 were not modified in response to PCP treatment. The determination of a subpopulation of GABAergic interneurons shows a decrease of the cells within the CA3 of the hippocampal formation. These findings indicate that PCP induced impairments in short term memory can be detected by holeboard learning and may provide an interesting tool for the search of new neuroleptics. British Journal of Pharmacology (2000) 130, 33–40; doi:10.1038/sj.bjp.0703171