1. A chemical substance that is secreted from the pre*synaptic nerve terminal into the synaptic cleft and acts as a *stimulus on the post-synaptic terminal.

2. A chemical substance that is released by a neuron and acts as a stimulus on a cellular target.

'Neurotransmitter' is a term nowadays in use not only by neuroscientists but also by the lay person citing from the popular science columns. Yet both the concept and the term were nonexistent only a century ago. At that time it was thought that nerve-nerve and nerve-muscle communication is always electrical ("synapse). The first to propose explicitly that a chemical substance, adrenaline, is liberated from the sympathetic nerve terminal to act upon its muscle target, was Elliott (1904). But the story actually starts earlier. The mere idea that a nerve may release a chemical substance for communicating with other cells was proposed by ou Bois-Reymond in 1877 (cited in Dale 1938). The first hints of evidence were provided by an English physician, George Oliver, who spent his leisure time inventing clinical instruments and testing them on his own family members (Dale 1948). One of these instruments was designed to measure the thickness of an artery under the skin. Oliver (how horrible) injected extracts of various animal glands into his young son. Using his new instrument, he observed that an extract of the adrenal gland altered the diameter of the artery. He rushed to tell the story to Professor Schafer in London, who was experimenting on blood pressure in dogs. Together they replicated the experiment, this time without Oliver's son, whose name somehow did not enter the scientific literature (Oliver and Schafer 1894). This has led to the identification of some physiological effects of the extract, which was later to become known as 'adrenaline'. Lewandowsky, Langley, and others subsequently described additional physiological properties of adrenaline (e.g. Langley 1905). This was the background for Elliot's suggestion that adrenaline relays information from the nerve to the muscle.

Adrenaline was indeed the first substance to be proposed as a transmitter, but the first transmitter substance to be isolated as such from living tissue was "acetylcholine (Loewi 1936; Dale 1954). Synthesized by chemists and extracted from the rye fungus (ergot), acetylcholine was found to be a potent cardiac blocker. The trail of experiments that had culminated in its identification in the nervous system started with an instance of "state-dependent memory. The person beyond the critical experiment, Otto Loewi, was a restless sleeper. One night he awoke suddenly with the idea that if the vagus nerve inhibits the heart by liberating a chemical substance, this substance might diffuse out into a solution left in contact with the heart, and then transferred to inhibit another heart. He scrabbled the plan of the experiment on a scrap of paper and went to sleep again. Alas, the next morning he could not decipher his scribbles. He spent the whole day trying to understand what he wrote, but in vain. The next night he awoke again, with vivid recall of the experimental plan. There are two versions on what actually happened later (Cannon 1934; Finger 2000). In the more romantic version, which clearly fits a movie script, Loewi dashed off to his lab in the middle of the night to perform the experiment. In the second, more mundane version, he wrote a detailed account of what he had in mind and went to sleep again. In any case, by the subsequent day the experiment was done. Loewi took two frogs, removed their heart, and placed each in a salt solution. He left the terminal of the vagus nerve on one heart but removed it from the other. He then stimulated the vagus nerve on the first heart, collected aliquots of the bath solution, and transferred it to the chamber containing the second heart. The denervated heart slowed down. This meant that the stimulation of the vagus secreted into the solution a compound that was capable of controlling the heart in the absence of the nerve. After much additional work, the compound, first dubbed Vagusstoff ('vagus substance'), was identified as acetylcholine. It is told that since that discovery, Loewi became ardently interested in dreams (Finger 2000). But this is another story.

The "classic view of a neurotransmitter is provided in definition 1 above: a substance released from the presynaptic on to the postsynaptic terminal, triggering there a cascade of events that result in excitation (excitatory neurotransmitter) or inhibition (inhibitory neurotransmitter). This is a point-to-point, or one-to-one, unidirectional communication. With time, the concept of 'neurotransmission' was expanded. First, it was found that neurotransmitter molecules could act on the same neuron that releases them, usually to modulate transmitter release (reviewed in Powis and Bunn 1995). This is still a one-to-one communication, but the cellular target is also the source of the signal, i.e. the presynaptic rather than the postsynaptic terminal. Second, it was found that neurotransmitters could act by diffusion on distant targets in the absence of direct synaptic contacts. This one-to-many communication is termed 'volume transmission' (Zoli et al. 1999). It is especially relevant to the concept of'neuromodulation' (see below). Third, it was discovered that some compounds that transmit information between neurons, such as the gas nitric oxide (NO, Zhang and Snyder 1995), are not released via specific synaptic sites to bind to membrane receptors, but instead diffuse out of the membrane to adjacent cells to interact with intracellu-lar receptors. This is either one-to-one or one-to-few communication. Further, these compounds convey information from the postsynaptic into the presynaptic terminal, contrary to the conventional wisdom of neurotransmission; they are therefore termed 'retrograde messengers' (e.g. Figure 42b, p. 150). Finally, neuro-transmitters act on and released by glia cells as well, although only little is so far known on this topic (Araque et al. 1999).1 All these modes of transmission are accommodated by the more comprehensive definition 2 above.

We are currently familiar with scores of transmitter substances, and even the simplest nervous system contains a surprising number of them (Brownlee and Fairweather 1999). The classical transmitters are small molecules, such as acetylcholine or "glutamate. About 10 are identified, most of which are amino acids (the building blocks of proteins) or their derivatives (acetylcholine is an exception). To these we should add the neuroactive peptides, which are much more numerous (Cooper et al. 1996) Endogenous opioids are only one example. And to these we should add the 'nonconven-tional' transmitters such as gases and small lipid molecules (Medina and Izquierdo 1995; Zhang and Snyder 1995). At this point in our discussion, two additional points deserve attention. First, how do we decide whether a compound is a neurotransmitter? Several attempts have been made to identify the relevant "criteria (e.g. Werman 1966). These criteria must fit not only the classical view of chemical transmission (definition 1) but also the more modern views (definition 2). The only universal criteria are probably the release from a neuron and the action as a stimulus on a target cell. Of course, the transmitter must be synthesized, and later degraded or removed from its site of action, but these functions must not necessarily be carried out by the source and the target cell, respectively.

Another point is the distinction between a 'neurotransmitter' and a 'neuromodulator' (Kaczmarek and Levitan 1987; Harris-Warrick and Marder 1991; Lopez and Brown 1992; Katz and Frost 1996). Conventionally, when this distinction is used, the term 'neurotrans-mitter' is reserved to those stimuli that transmit fast information between one neuron and another in a one-to-one mode (definition 1 above). They exert their effect by directly gating "ion channels ('ionotropic "receptors') in the target neuron. In contrast, 'neuro-modulators' modify the ability of neurons to respond to neurotransmitters and by other stimuli, commonly by indirectly modulating ionic channel complexes, for example, via 'metabotropic "receptors', their downstream "intracellular signal transduction cascades and "protein kinases. Neuromodulators alter the intrinsic properties of neurons, affect their excitability and ability to extract signal from noise, and hence gate, rescale, and bias incoming information. This enriches the computational and representational "capacity of the circuit and, furthermore, encodes at the cellular "level parameters such as "attention, "context, and internal states (e.g. Hasselmo 1995; Shulz et al. 2000). However, in the literature, and apparently also in real life, the distinction between neurotransmitters and neuromodulators is not rigorous. For example, is glycine acting on the regulatory site of the "glutamater-gic N-methyl-o-aspartate receptor, a modulator or transmitter? Or, most authors would consider NO as a transmitter, but it is not limited to a one-to-one communication mode, and does not directly gate channels. It is therefore useful to consider types of transmitter substances as components of a whole spectrum, ranging from fast-acting, bona fide transmitters, to slow-acting, diffusing, bona-fide modulators.

In the context of memory research, we should note that neurotransmitters and neuromodulators are molecular stimuli that in their concerted activity convey to the target neurons and circuit information about "percepts, activated "internal representations, and endogenous brain states (e.g. Hasselmo 1995; McGaugh and Cahill 1997; Arnsten 1998; Fellous 1999). Therefore they are particularly relevant to the "acquisition and "retrieval phases in the operation of those circuits that encode the relevant representations. The specific combination of neurotransmitters and neuromodulators arriving at the synapse at any given point in time is critical in determining whether the synapse will change as a consequence of the experience, and if so, for how long (e.g. "coincidence detection, "long-term potentiation). But the role of the transmitters themselves is transient. Even in those cases in which the retention of learned information in a circuit is believed to be based on the modulation of transmitter release (e.g. "Aplysia), the transmitter molecules do not store information over a prolonged time; the persistent alteration in their availability is a consequence of a lasting changes in other cellular components, such as channels, receptors, or cytoskeletal elements and transmitter-release mechanisms.

Selected associations: Acetylcholine, Acquisition, Glutamate, Receptor, Synapse

1Glia (Greek for 'glue'), or neuroglia, is a generic term that refers to multiple types of non-neuronal cells in the nervous system, which fulfil multiple roles in providing a proper microenvironment, and metabolic and functional support for neuronal function. The possibility that glia cells have a computational role in the brain should not be excluded. See also *synapse.

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