In the mammalian central nervous system (CNS) there are literally billions of neuronal synapses with each employing a particular neurotransmitter. A neurotransmitter can be either excitatory or inhibitory, depending on whether it produces depolarization or hyperpolarization of the neuronal membrane, respectively. Furthermore, the duration of transmitter action either may be in the low millisecond time range or it may show a prolonged latency and duration of action spanning tenths of seconds or seconds. An attractive model for neuronal organization suggests that there is considerable specificity of the various transmitters for these differing roles. While such "classical neurotransmitters" as acetylcholine and the catecholamines, dopamine and norepinephrine, may show either excitatory or inhibitory actions, they also, in most if not all cases, act in the CNS by mechanisms that are of prolonged duration and serve to modulate the intensity of millisecond excitatory or inhibitory impulses. Escalating evidence suggests that the neurotransmitter receptors for these systems are coupled to gated ion channels via guanine nucleotide-binding proteins (G proteins) and second messenger intermediates. This mechanism provides great flexibility for adjusting the intensities and durations of many different stimuli. In contrast, millisecond neurotransmitters act on receptors that are coupled to a gated ion channel located on the same transmembrane protein molecule. This arrangement allows microsecond triggering of channel opening in response to binding of the effector molecule. Like the slow-acting modulatory neurotransmitters, millisecond neurotransmitters may also exhibit inhibitory or excitatory effects. For example, the neurotransmitters y-aminobutyric acid (GABA) and glycine are thought to be millisecond inhibitory neurotransmitters. However, the most prevalent neurotransmitter class in the mammalian CNS would appear to be the millisecond excitatory neurotransmitters. Foremost among the candidates for millisecond excitatory neurotransmitters in the CNS are the acidic amino acids Lglutamic acid (1) and L-aspartic acid (2). Glutamic acid, in particular, has been shown to satisfy many of the criteria required for a substance to be designated as a neurotransmitter. It has been over 30 years since HayashiQ first reported the convulsant effects of L-glutamic acid and over 25 years since Curtis et al.1° showed through intracellular recording that glutamic acid was capable of depolarizing individual neurons in the mammalian CNS. Since that time a wide array of electrophysiological, biochemical, pharmacological, and anatomical studies have been carried out using excitatory amino acids. These studies and in particular the studies that have utilized various agonists and antagonists of excitatory neurotransmission have indicated that at least four receptor systems may mediate the actions of the excitatory amino acids. Three of these receptors, the N-methyl-D-aspartate (NMDA) receptor, the quisqualate receptor, and the kainate receptor were named after the agonists N-methyl-D-aspartic acid (3), quisqualic acid (4), and a-kainic acid (5), respectively. The fourth, the AP4 receptor, was named for a potent antagonist of specific excitatory pathways of the CNS, namely, ~-2-amino-4 phosphonobutanoic acid (6). There is increasing evidence that these prototypic pharmacological agents, particularly quisqualic acid and 6, may mediate multiple functions in the CNS. Therefore, identification of additional subclasses of excitatory amino acid receptors appears likely.