Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK‐801) injures pyramidal neurons in rat retrosplenial cortex

Abstract

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine, phencyclidine (PCP) and dizocilpine (MK-801), produce psychosis in people. In rodents they produce cytoplasmic vacuoles in injured retrosplenial cortical neurons that express HSP70 heat shock protein. This study examined possible circuits and receptors that mediate this neuronal injury. Bilateral, but not unilateral, injection of dizocilpine (5, 10, 15, 20 microg/microL per side) into the anterior thalamus induced HSP70 protein in pyramidal neurons in deep layer III of rat retrosplenial cortex 24 h later. In contrast, bilateral dizocilpine injections (5, 10, 15, 20 microg/microL per side) into the retrosplenial cortex or into the diagonal band of Broca did not induce HSP70. Bilateral injections of muscimol (0.1, 1, 10 microg/microL per side), a GABAA (gamma-aminobutyric acid) agonist, into the anterior thalamus blocked HSP70 induction in the retrosplenial cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections of baclofen (0.1, 1, 10 microg/microL per side), a GABAB agonist, were ineffective. Anterograde tracer studies confirmed that neurons in the anterior thalamus project to superficial layer III of the retrosplenial cortex where the dendrites of HSP70-immunostained neurons in deep layer III reside. Bilateral blockade of NMDA receptors on GABA neurons in the reticular nuclei of the thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and decrease activation of GABAA receptors. This activates thalamic projection neurons that damage retrosplenial cortical neurons presumably via unblocked cortical glutamate alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate receptors. The increases of blood flow that occur in the thalamus and retrosplenial cortex of people that have psychosis produced by NMDA antagonists could be related to thalamic excitation of the retrosplenial cortex produced by these drugs.

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…In accordance with these findings, it has been shown that the local application of PCP into the hippocampus increases locomotion and the firing of pyramidal neurons of the mPFC in freely moving rats (Jodo et al, 2005). Furthermore, Sharp and coworkers have described that the blockade of NMDA receptors in the anterior thalamus by MK-801 resulted in injury of cortical pyramidal neurons measured by an increased synthesis of heat-shock protein 70 (HSP-70) in limbic cortex (Tomitaka et al, 2000;Sharp et al, 2001). Thus, all these findings suggest that NMDA receptor antagonists would attenuate the tonic activation of inhibitory (GABA) neurons (possibly, though not exclusively, in the hippocampus and/or the thalamus), which would result in a disinhibition of glutamatergic input to the mPFC (Olney and Farber, 1995;Moghaddam et al, 1997;Krystal et al, 2003).…”

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

“…Animal studies using the MK-801 injury model used here have identified regions, circuits and receptors that interact to produce injury in limbic cortex via activation of thalamus and basal forebrain (Tomitaka et al, 2000b;Sharp et al, 2001;Farber et al, 2002Farber et al, , 2003. Although the current study does not address mechanisms and sites of action of the atypical antipsychotic drugs, it is likely the atypical antipsychotics protect retrosplenial cortex by blocking dopamine D2 and other receptors associated with thalamic, midbrain, and basal forebrain projections to limbic cortex (Farber et al, 2003;Sharp et al, 2001).…”

“…Cell counts were performed as previously described (Tomitaka et al, 2000b). Counts were performed at  100 magnification within a 0.1 mm 2 area centered over layer III in the retrosplenial cortices using a microcomputer-imaging device (MCID, London, Canada).…”

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

“…This hyper-excitation has been related to an increase in thalamo-cortical glutamatergic excitation of downstream cortical regions such as the anterior cingulate and retrosplenial cortices (Tomitaka et al, 2000;Holcomb et al, 2005). PET scan studies have shown that schizophrenic subjects respond to ketamine with higher hypermetabolism than normal subjects.…”