Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous systems.

1. Experiments were conducted in vitro on isolated spinal cords of frogs and immature rats and in vivo on cat spinal neurones. 2. The concept of two major types of excitatory amino acid receptors present in these preparations is summarized, one type (NMDA receptors) being activated specifically by N-methyl-D-aspartate (NMDA) and blocked by specific antagonists such as D(-)-2-amino-5-phosphonovalerate (APV), and a second type (non-NMDA receptors) characterized by insensitivity to specific NMDA antagonists. This second type may be comprised of two sub-types activated selectively by the agonists quisqualate and kainate. The putative transmitters L-glutamate and L-aspartate have mixed action on both NMDA and non-NMDA receptors. The major action of both transmitter candidates is considered to be on non-NMDA receptors, but the proportion of the composite responses mediated by NMDA receptors (at least for spinal neurones) appears to be greater for L-aspartate than for L-glutamate. 3. The preference of NMDA and non-NMDA receptors for a range of agonists is discussed. Some newer agonists are considered, in addition to several known agonists not previously discussed in terms of NMDA- and non-NMDA-receptor preference. Structure-activity relations of agonists are discussed. 4. The actions of some new amino acid antagonists are reported. Some of these have useful kainate and quisqualate blocking activity, in addition to their ability to block NMDA induced responses. 5. Evidence is presented suggesting that excitatory amino acid receptors are involved in both polysynaptic and monosynaptic excitation in the spinal cord, NMDA receptors mediating polysynaptic excitation and non-NMDA receptors monosynaptic excitation. 6. The unusual effect is reported of L-2-amino-4-phosphonobutyrate, which potently blocks spinal synaptic excitation in the absence of depressant action on excitatory amino acid-induced responses.