The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP) is used as pharmacological model of schizophrenia due to its ability to mimic schizophrenia symptoms. PCP markedly disrupts prefrontal cortex (PFC) activity, increasing pyramidal neuron discharge and attenuating low frequency cortical oscillations (LFCO, ~1 Hz). These actions may underlie PCP psychotomimetic activity and are reversed by haloperidol and clozapine.
The aim of the present study is twofold: 1) to validate the PCP-induced disruption in LFCO as a model to screen antipsychotic activity, and 2) to elucidate the pharmacological mechanisms involved in antipsychotic reversal.
Classical (chlorpromazine, haloperidol, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone) antipsychotic drugs reversed PCP-evoked loss of LFCO in rat medial PFC. Raclopride and SCH-23390 partially reversed PCP effects, suggesting that classical antipsychotic action may involve the blockade of D1-R and D2-R. 8-OH-DPAT and BAYx3702 (but not M100907) fully reversed PCP effects, suggesting that atypical drug reversal may additionally involve 5-HT1A-R activation. Pyrilamine, prazosin and citalopram were ineffective in this model.
PCP may reduce LFO by breaking the physiological balance between excitatory and inhibitory transmission in PFC, since agents enhancing GABAA-R-mediated neurotransmission, such as muscimol, diazepam and valproate were able to reverse the PCP disruption. Likewise, LY379268 (mGluR2/3 agonist), which suppresses thalamocortical excitatory inputs onto mPFC, reversed PCP effect.
Overall, these results support the validity of the present model in antipsychotic drug screening and target identification. Moreover, the results give further support to the concept that atypical antipsychotics can exert its superior therapeutic action via 5-HT1A receptor activation, reestablishing the excitatory/inhibitory balance in PFC.