Phencyclidine-induced disruption of oscillatory activity in prefrontal cortex: Effects of antipsychotic drugs and receptor ligands

Jan 20, 2016European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

Phencyclidine disrupts brain rhythms in thinking areas: Effects of antipsychotic drugs and receptor-targeting compounds

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Abstract

Classical and atypical antipsychotic drugs countered the PCP-evoked fall of low frequency oscillations in the medial prefrontal cortex of anesthetized rats.

PCP disrupts thalamocortical activity by increasing excitatory neuron discharge and reducing low frequency oscillations.
Classical antipsychotics (e.g., haloperidol, chlorpromazine) and atypical antipsychotics (e.g., clozapine, olanzapine) were effective against PCP-induced changes, while the antidepressant citalopram was not.
D2 and D1 receptor blockade may contribute to the effects of classical antipsychotics in reversing PCP actions.
Atypical antipsychotics may also involve activation of the 5-HT1A receptor to counter PCP effects, unlike the 5-HT2A receptor.
Enhancing GABA receptor activity and decreasing excitatory neurotransmission partially or completely countered PCP effects.

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The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP) markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO, <4Hz) that temporarily group neuronal discharge. These actions are mainly driven by PCP interaction with NMDA-R in GABAergic neurons of the thalamic reticular nucleus and likely underlie PCP psychotomimetic activity. Here we report that classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripripazole) antipsychotic drugs--but not the antidepressant citalopram--countered PCP-evoked fall of LFO in the medial prefrontal cortex (mPFC) of anesthetized rats. PCP reduces LFO by breaking the physiological balance between excitatory and inhibitory transmission. Next, we examined the role of different neurotransmitter receptors to reverse PCP actions. D2-R and D1-R blockade may account for classical antipsychotic action since raclopride and SCH-23390 partially reversed PCP effects. Atypical antipsychotic reversal may additionally involve 5-HT1A-R activation (but not 5-HT2A-R blockade) since 8-OH-DPAT and BAYx3702 (but not M100907) fully countered PCP effects. Blockade of histamine H1-R (pyrilamine) and α1-adrenoceptors (prazosin) was without effect. However, the enhancement of GABAA-R-mediated neurotransmission (using muscimol, diazepam or valproate) and the reduction of excitatory neurotransmission (using the mGluR2/3 agonist LY379268 and the preferential kainite/AMPA antagonist CNQX--but not the preferential AMPA/kainate antagonist NBQX) partially or totally countered PCP effects. Overall, these results shed new light on the neurobiological mechanisms used by antipsychotic drugs to reverse NMDA-R antagonist actions and suggest that agents restoring the physiological excitatory/inhibitory balance altered by PCP may be new targets in antipsychotic drug development.

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Phencyclidine-induced disruption of oscillatory activity in prefrontal cortex: Effects of antipsychotic drugs and receptor ligands

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