Phencyclidine treatment in mice: effects on phencyclidine binding sites and glutamate uptake in cerebral cortex preparations.

Chronic treatment with phencyclidine (PCP), a psychotomimetic drug, alters glutamatergic neurotransmission in mice. After PCP administration via implanted minipumps (1 mg per mouse per day for 3 days), the binding capacity of TCP to cortical membranes increased, indicating more binding sites became available, while binding affinity remained unchanged. The actions of glutamate, its receptor agonists, and glycine were potentiated. Glutamate uptake showed changes in transport kinetics: the high-affinity component's transport constant increased and its maximal velocity increased, while the low-affinity component's maximal velocity decreased. Inhibition by structural analogues was also potentiated, suggesting modification of the glutamate transporter. These findings indicate that chronic PCP treatment, used as a psychosis model, markedly affects glutamatergic parameters.

Study at a glance

Abstract

The effects of a psychotomimetic drug, phencyclidine (PCP), on glutamatergic neurotransmission were studied in mice. The binding of tritiated N-[1-(2-thienyl)cyclohexyl]piperidine (TCP) to cerebral cortical membranes and the uptake of [3H]glutamate by cortical synaptosomal preparations were assessed after PCP treatment (1 mg/d/mouse for 3 days) with implanted minipumps. The binding capacity Bmax of TCP significantly increased but the binding constant KD remained the same after PCP exposure, indicating that more binding sites became available. The basic properties of the binding remained unaltered but the actions of glutamate, glutamate receptor agonists and glycine were potentiated in PCP-treated mice. The uptake of glutamate was saturable, consisting of both high- and low-affinity transport components. After PCP exposure the transport constant Km of the high-affinity component increased and that of the low-affinity component was not changed. The maximal velocity V of the high-affinity component increased while that of the low-affinity transport decreased. Moreover, inhibition by structural analogues was potentiated, suggesting modification of the glutamate transporter. The results show that chronic PCP treatment, used as a model of psychosis, markedly affects the studied glutamatergic parameters.