Eva Troyano-Rodriguez1, Laia Lladó-Pelfort1, Noemi Santana1, Vicent Teruel-Martí2, Pau Celada3, Francesc Artigas1. 1. Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 2. Deptartamento de Anatomia i Embriologia Humana, Facultat de Medicina, Universitat de València, Valencia, Spain. 3. Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. Electronic address: pau.celada@iibb.csic.es.
Abstract
BACKGROUND: The neurobiological basis of action of noncompetitive N-methyl-D-aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low-frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. METHODS: Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. RESULTS: PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p < .000001) and the power of LFO in RtN and PFC to ~20% of baseline (p < .001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. CONCLUSIONS: PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action.
BACKGROUND: The neurobiological basis of action of noncompetitive N-methyl-D-aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low-frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. METHODS: Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. RESULTS:PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p < .000001) and the power of LFO in RtN and PFC to ~20% of baseline (p < .001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. CONCLUSIONS:PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action.
Authors: Francesc Artigas; Esther Schenker; Pau Celada; Michael Spedding; Laia Lladó-Pelfort; Noemi Jurado; Mercedes Núñez; Noemi Santana; Eva Troyano-Rodriguez; Maurizio S Riga; Hanna van den Munkhof; Anna Castañé; Hamdy Shaban; Thérèse M Jay; Anushree Tripathi; Bill P Godsil; Claude Sebban; Jean Mariani; Philippe Faure; Samir Takkilah; Zoe A Hughes; Chester J Siok; Mihaily Hajos; Karsten Wicke; Natalia Gass; Wolfgang Weber-Fahr; Alexander Sartorius; Robert Becker; Michael Didriksen; Jesper F Bastlund; Mark Tricklebank; Céline Risterucci; Andreas Meyer-Lindenberg; Adam J Schwarz Journal: Nat Rev Drug Discov Date: 2016-11-04 Impact factor: 84.694
Authors: Anna Höflich; Andreas Hahn; Martin Küblböck; Georg S Kranz; Thomas Vanicek; Christian Windischberger; Alois Saria; Siegfried Kasper; Dietmar Winkler; Rupert Lanzenberger Journal: Int J Neuropsychopharmacol Date: 2015-04-19 Impact factor: 5.176
Authors: Mark J Hunt; Maciej Olszewski; Joanna Piasecka; Miles A Whittington; Stefan Kasicki Journal: Psychopharmacology (Berl) Date: 2015-10-08 Impact factor: 4.530