Effects of selective calcium-permeable AMPA receptor blockade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse.
Diminished glutamate neurotransmission via the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of D-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because D-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- (tricyclo3.3.1.1