title: Phencyclidine-induced disruption of oscillatory activity in prefrontal cortex: Effects of antipsychotic drugs and receptor ligands.
abstract: 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.
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Lladó-Pelfort
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Troyano-Rodriguez
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: H E
authors.initials: HE
authors.lastname: van den Munkhof
authors.affiliation: Departament d׳Anatomia i Embriologia Humana, Facultat de Medicina, Universitat de València, València, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cervera-Ferri
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Jurado
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Núñez-Calvet
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Artigas
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC) (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: pau.celada@iibb.csic.es.
authors.forename: P
authors.initials: P
authors.lastname: Celada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005583:Fourier Analysis; D018494:Histamine Agents / Q000494:pharmacology; D008297:Male; D010622:Phencyclidine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018490:Serotonin Agents / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D018494:Histamine Agents; D018490:Serotonin Agents; D010622:Phencyclidine
keywords: Antipsychotic drugs; NMDA receptor antagonists; Oscillations; Phencyclidine; Prefrontal cortex; Schizophrenia