Until relatively recently, it was believed that a given neuron produced only a single type of neurotransmitter. There is now convincing evidence, however, that many types of neurons contain and release two or more different neurotransmitters. There are now numerous examples of different peptides being present in the same terminal, as well as cases in which two small-molecule neurotransmitters are found within the same presynaptic ending, or in which a peptide neurotransmitter is found along with a small-molecule neurotransmitter. When more than one transmitter is present within a nerve terminal, the molecules are called co-transmitters. Because each class of transmitter tends to be packaged in a separate population of synaptic vesicles, co-transmitters typically are segregated within a presynaptic terminal (there are, however, instances in which two or more co-transmitters are present in the same synaptic vesicle).

Having more than one transmitter lends considerable versatility to synaptic transmission. In particular, since co-transmitters are often packaged in different types of vesicles, the transmitters need not be released simultaneously. For example, low-frequency stimulation often releases only small neurotransmitters, whereas high-frequency stimulation is required to release neuropeptides from the same presynaptic terminals (Figure 6.5). As a result, the chemical signaling properties of a synapse often change according to the level of presynaptic activity.

Figure 6.5

Differential release of neuropeptide and small-molecule co-transmitters. Low-frequency stimulation preferentially raises the Ca²⁺ concentration close to the membrane, favoring the release of transmitter from small clear-core vesicles docked at presynaptic (more...)

This differential release of co-transmitters is probably based on the distribution of Ca²⁺ and vesicles in presynaptic terminals. Whereas the vesicles containing small-molecule transmitters are typically docked at the plasma membrane in advance of Ca²⁺ entry, vesicles containing peptide transmitters are farther away from the plasma membrane (see Figures 6.5 and 6.7). At low firing frequencies, the concentration of Ca²⁺ may increase only in the vicinity of presynaptic Ca²⁺ channels, limiting release to small-molecule transmitters because only the vesicles containing these agents are immediately adjacent to the channels. High-frequency stimulation increases the Ca²⁺ concentration more evenly throughout the presynaptic terminal, thereby inducing the release of neuropeptides as well.