Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain

© 2014 Society of Biological Psychiatry. 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.This work was supported by Innovative Medicines Initiative (IMI) Joint Undertaking Grant115008 (Newmeds). IMI is a public-private partnership between the European Union and European Federation of Pharmaceutical Industries and Associations; by Grant PI12/00156 (PN de I+D+I 2008-2011) from the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, co-financed by the European Union “A Way to build Europe”; by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental; and by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya (PC)Peer Reviewe