With the use of in vitro preparations and sophisticated electrophysiological recording techniques, we are beginning to understand in great detail how a wide variety of putative neurotransmitters alter neuronal excitability. Many of these recent results have changed our previous conceptualization of excitatory and inhibitory synaptic transmission. For example, as we reviewed, it is now clear that in many regions of brain, EPSPs, although mediated by a single neurotransmitter, glutamate, are composed of two components that subserve distinct functions. Similarly, the elucidation of the different properties of GABA(A) and GABA(B) receptors has demonstrated that inhibition in the brain is also not a single process but most likely has at least two components. It is also now well established that many neurotransmitter receptors are coupled to second messengers, the activation of which in turn alters ion channel activity. Many of these second messenger systems modulated voltage-dependent channels, resulting not in a simple membrane depolarization or hyperpolarization but rather an effect that depends on the membrane potential of the cell, a property that is constantly changing in both the spatial and temporal domains. This type of modulation can result in drastic changes in the cells' input-output properties. By being coupled to the same second messenger system or G protein, distinct neurotransmitter receptors may induce the same electrophysiological response. Figure 1 shows this convergence of action of various neurotransmitter receptors onto two types of ion channels, an inwardly rectifying K+ channel (I(K)) and a Ca2+-activated K+ channel (I(AHP). In many cases this convergence can be seen in a single type of neuron. Thus GABA(B), 5-HT(1a), A1, and probably SS receptors are coupled to the same K+ channel in CA1 hippocampal pyramidal cells. In locus coeruleus neurons, μ-opioid, α2-noradrenergic, SS, and probably GABA(B) receptors all activate the same K+ conductance. In lateral parabrachial neurons, μ-opioid, M2, and GABA(B) receptors increase the same K+ conductance. Finally, in substantia nigra neurons, GABA(B) and D2 receptors, activate the same K+ conductance. For I(AHP), all of the neurotransmitters listed act on CA1 hippocampal pyramidal cells and converge onto the same K+ conductance. The receptor subtype of the 5-HT effect and the coupling mechanism for the 5-HT and ACh effects have not been clearly established. In addition to convergence, the use of G proteins and second messenger systems to mediate the actions of neurotransmitters may offer additional advantages. For example, parts of a cell spatially segregated from a given receptor could be affected by activation of that receptor via its coupling to diffusible second messengers. Actions mediated by second messengers might be long lasting and more subject to subtle, long-term modulations. It is also likely that neurotransmitters that activate receptors coupled to G proteins and second messengers have functionally important biochemical effects in addition to directly modulating ion channels. Although different neurotransmitters often appear to have similar electrophysiological actions, they can also be shown to have quite distinct actions, primarily because they activate a variety of subtypes of receptors that are coupled to distinct G proteins and second messengers. Thus the same neurotransmitter can have distinct actions on different cells or different parts of the same cell because of the differential distribution of receptor subtypes. A corollary of this is that if a given neurotransmitter is known to have different actions in different brain regions, it most likely is because the receptors it is activating are distinct. Figures 2-4 show this striking divergence of action for five different neurotransmitters. Glutamate probably activates five types of receptor. Three of these, the AMPA, the kainate, and the NMDA receptors, cause a rapid increase in cation conductance without an intervening coupling molecule. A subtype of quisqualate receptor, which differs pharmacologically from the quisqualate receptor linked to ion channels (now generally referred to as the AMPA receptor), is coupled to PI turnover. The physiological consequence of activating this receptor has yet to be observed in CNS neurons. Activation of the AP4 receptor causes a presynaptic inhibition in a number of pathways within the CNS, perhaps by decreasing Ca2+ entry into the nerve terminal. There is only limited data that glutamate can act on this presynaptic receptor. γ-Aminobutyric acid activates two types of receptors. The GABA(A) recepors rapidly open Cl- channels without an intervening coupling molecule.