Rapid cortico-limbic alterations in AMPA receptor densities after administration of PCP: implications for schizophrenia.
Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4 h after a single injection of PCP. We used receptor autoradiography and [3H]MK801, [3H]AMPA, [3H]pirenzepine and [3H]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F = 14.5, d.f. = 1, p < 0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿16%), hippocampus CA2 (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿25%), dentate gyrus (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿27%), parietal cortex layers IIIÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿VI (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿19%), central nucleus of the amygdala (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿40%), and basolateral amygdala (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions.