Activation of Thalamocortical Networks by the N -methyl-D-aspartate Receptor Antagonist Phencyclidine: Reversal by Clozapine

• Published in: Biological psychiatry (1969) 2011-05, Vol.69 (10), p.918-927
• Main Authors: Santana, Noemí, Troyano-Rodriguez, Eva, Mengod, Guadalupe, Celada, Pau, Artigas, Francesc
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Antipsychotic Agents - pharmacology; Antipsychotics; Brain Mapping; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Clozapine - pharmacology; delta oscillations; Drug Interactions; Evoked Potentials - drug effects; Excitatory Amino Acid Antagonists - pharmacology; GABAergic interneurons; Gene Expression Regulation - drug effects; glutamate; Male; Neural Pathways - drug effects; Neural Pathways - physiology; Neurons - drug effects; Phencyclidine - pharmacology; prefrontal cortex; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Psychiatry; pyramidal neurons; Rats; RNA, Messenger - metabolism; thalamus; Thalamus - cytology; Thalamus - drug effects; Thalamus - metabolism; Vesicular Glutamate Transport Protein 1 - genetics; Vesicular Glutamate Transport Protein 1 - metabolism
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2010.10.030

Background Noncompetitive N -methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area. Methods We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings ( n = 50 neurons from 35 Wistar rats) and c-fos expression. Results Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15–4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c- fos expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c- fos expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c- fos expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c- fos expression. Conclusions Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks.