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

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 cort ical neurons that express HSP70 heal shock protein. This study examined pos sible circuits and receptors that mediate this neuronal injury. Bilateral, but not unilateral, injection of dizocilpine (5, 10, 15, 20 mu g/mu L per s ide) into the anterior thalamus induced HSP-IO protein in pyramidal neurons in deep layer III of rat retrosplenial cortex 24 h later. in contrast, bil ateral dizocilpine injections (5, 10, 15, 20 mu g/mu L per side) into the r etrosplenial cortex or into the diagonal band of Broca did not induce HSP70 . Bilateral injections of muscimol (0.1, 1, 10 mu g/mu L per side), a GABA( A) (gamma-aminobutyric acid) agonist, into the anterior thalamus blocked HS P70 induction in the retrosplenial cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections of baclofen (0.1, 1, 10 mu g/mu L per side), a GABAB agonist, were ineffective. Anterograde tracer studies co nfirmed 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 G ABA neurons in the reticular nuclei of the thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and decrease activation of GAB A(A) receptors. This activates thalamic projection neurons that damage retr osplenial cortical neurons presumably via unblocked cortical glutamate alph a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate recept ors. The increases of blood flow that occur in the thalamus and retrospleni al cortex of people that have psychosis produced by NMDA antagonists could be related to thalamic excitation of the retrosplenial cortex produced by t hese drugs.