As briefly described in the preceding chapter, neurotransmitters are chemical signals released from presynaptic nerve terminals into the synaptic cleft. The subsequent binding of neurotransmitters to specific receptors on postsynaptic neurons (or other classes of target cells) transiently changes the electrical properties of the target cells, leading to an enormous variety of postsynaptic effects (see Chapters 7 and 8).

The notion that electrical information can be transferred from one neuron to the next by means of chemical signaling was the subject of intense debate through the first half of the twentieth century. A key experiment that supported this idea was performed in 1926 by German physiologist Otto Loewi. Acting on an idea that allegedly came to him in the middle of the night, Loewi proved that electrical stimulation of the vagus nerve slows the heartbeat by releasing a chemical signal. He isolated and perfused the hearts of two frogs, monitoring the rates at which they were beating (Figure 6.1). The gist of his experiment was to collect the perfusate flowing through the stimulated heart and transfer it to the second heart. Even though the second heart had not been stimulated, its beat also slowed, showing that the vagus nerve regulates the heart rate by releasing a chemical that accumulates in the perfusate. Originally referred to as “vagus substance,” the agent was later shown to be acetylcholine (ACh), which over the years has become the most thoroughly studied neurotransmitter. ACh acts not only in the heart but at a variety of postsynaptic targets in the central and peripheral nervous systems, preeminently at the neuromuscular junction of striated muscles and in the visceral motor system (see Chapters 5 and 21).

Figure 6.1

Loewi's experiment demonstrating chemical neurotransmission. (A) Diagram of experimental setup. (B) Where the vagus nerve of an isolated frog's heart was stimulated, the heart rate decreased (upper panel). If the perfusion fluid from the stimulated heart (more...)

Over the years, a number of formal criteria have emerged that definitively identify a substance as a neurotransmitter (Box A). Nonetheless, identifying the neurotransmitters active at any particular synapse remains a difficult undertaking, and for many synapses (particularly in the brain), the nature of the neurotransmitter is not well established. Substances that have not met all the criteria outlined in Box A are referred to as “putative” neurotransmitters.

Box A

Criteria That Define a Neurotransmitter.

The distinctive characteristics of neurotransmitters, compared to other signaling molecules, are made clearer by comparison with the actions of the hormones secreted by the endocrine system. Hormones typically influence target cells far removed from the hormone-secreting cell (see Chapter 8). This “action at a distance” is achieved by the release of hormones into the bloodstream. In contrast, the distance over which neurotransmitters act is miniscule. At many synapses, transmitters bind only to receptors on the postsynaptic cell that directly underlies the presynaptic terminal (Figure 6.2A); in such cases, the transmitter acts over distances less than a micrometer. Even when neurotransmitters diffuse locally to alter the electrical properties of multiple postsynaptic (and sometimes presynaptic) cells in the vicinity (Figure 6.2B), they act only over distances of tens to hundreds of micrometers. While the elongated axonal processes of neurons allow neurotransmitters to be released as much as a meter away from the neuronal cell body, these transmitters still act only near the presynaptic site of release (Figure 6.2C).

Figure 6.2

Localization of neurotransmitter action. Neurotransmitters in general act either locally (A), by altering the electrical excitability of a small region of a single postsynaptic cell, or more diffusely (B), by altering the electrical excitability of a (more...)

While the distinction between neurotransmitters and hormones is generally clear-cut, a substance can act as a neurotransmitter in one region of the brain while serving as a hormone elsewhere. For example, vasopressin and oxytocin, two peptide hormones that are released into the circulation from the posterior pituitary, also function as neurotransmitters at a number of central synapses. A number of other peptides also serve as both hormones and neurotransmitters.