on the terminals of sensory axons (Figure 21–5B). Although there are a great variety of synaptic connections in these hierarchical systems, the fact that a limited number of transmitters are used by these neurons indicates that any major pharmacologic manipulation of this system will have a profound effect on the overall excitability of the CNS. For instance, selectively blocking GABAA receptors with a drug such as picrotoxin results in generalized convulsions. Thus, although the mechanism of action of picrotoxin is specific in blocking the effects of GABA, the overall functional effect appears to be quite nonspecific, because GABA-mediated synaptic inhibition is so widely utilized in the brain.
Neuronal systems containing many of the other neurotransmitters, including the monoamines and acetylcholine, differ in fundamental ways from the hierarchical systems. These neurotransmitters are produced by only a limited number of neurons whose cell bodies are located in small discrete nuclei, often in the brain stem. For example, noradrenergic cell bodies are found primarily in a compact cell group called the locus coeruleus located in the caudal pontine central gray matter and number only approximately 12,000 neurons on each side of the human brain. However, from these limited nuclei, these neurons project widely and diffusely throughout the brain and spinal cord (Figure 21–6). Because the axons from these diffusely projecting neurons are fine and unmyelinated, they conduct very slowly, at about 0.5 m/s. The axons branch repeatedly and are extraordinarily divergent. Branches from the same neuron can innervate several functionally different parts of the CNS, synapsing onto and modulating neurons within the hierarchical systems. In the neocortex, these fibers have a tangential organization and therefore can influence large areas of cortex. In addition, most neurotransmitters utilized by diffuse neuronal systems, including norepinephrine, act predominantly on metabotropic receptors and therefore initiate long-lasting synaptic effects. Based on these observations, it is clear that the monoamine systems cannot be conveying topographically specific types of information; rather, vast areas of the CNS must be affected simultaneously and in a rather uniform way. It is not surprising, then, that these systems have been implicated in such global functions as sleeping and waking, attention, appetite, and emotional states.
VTA Locus coeruleus A1, A2, A5, A7 SN
FIGURE 21–6 Diffuse neurotransmitter pathways in the CNS. For each of the neurotransmitter pathways shown, the cell bodies are located in discrete brain stem or basal forebrain nuclei and project widely throughout the CNS. These diffuse systems largely modulate the function of the hierarchical pathways. Serotonin neurons, for example, are found in the midline raphe nuclei in the forebrain and send extraordinarily divergent projections to nearly all regions of the CNS. Other diffusely projecting neurotransmitter pathways include the histamine and orexin systems (not shown). A1–A7, adrenergic brain stem nuclei; Ch5-Ch8, cholinergic brain stem nuclei; DB, diagonal band of Broca; MSN, medial septal nucleus; SN, substantia nigra; VTA, ventral tegmental area.
Because drug selectivity is based on the fact that different pathways use different transmitters, a primary goal of neuroscience has been to identify the neurotransmitters in CNS pathways. Establishing that a chemical substance is a transmitter has been far more difficult for central synapses than for peripheral synapses. The following criteria were established for transmitter identification.
1.
Localization: A suspected transmitter must reside in the presynaptic terminal of the pathway of interest.
2.
Release: A suspected transmitter must be released from a neuron in response to neuronal activity and in a calcium-dependent manner.
3.
Synaptic Mimicry: Application of the candidate substance should produce a response that mimics the action of the transmitter released by nerve stimulation, and application of a selective antagonist should block the response.