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CHAPTER 21 Introduction to the Pharmacology of CNS Drugs 373

and release of endocannabinoids, which then bind to receptors on
the presynaptic terminal. Although the gas nitric oxide (NO) has A
long been proposed as a retrograde messenger, its physiologic role Feed-forward and
in the CNS is still not well understood. recurrent interaction
The selectivity of CNS drug action is based on two primary
factors. First, with a few exceptions, different neurotransmitters
are released by different groups of neurons. These transmitters
are often segregated into neuronal systems that subserve broadly E B
different CNS functions. That this segregation occurs has pro- Axoaxonic interaction
vided neuroscientists with a powerful pharmacologic approach
for analyzing CNS function and treating pathologic conditions. E Feed-forward
Second, there is a multiplicity of receptors for each neurotransmit- I Local circuit
ter. For example, there are at least 14 different serotonin receptors I neurons
encoded by different genes. These receptors often have differential E
cellular distributions throughout the CNS, allowing for the devel- Recurrent
opment of drugs that selectively target particular receptors and
CNS functions. Relay E E Local
neurons I circuit
neuron
CELLULAR ORGANIZATION
OF THE BRAIN

Most of the neuronal systems in the CNS can be divided into two E Relay
broad categories: hierarchical systems and nonspecific or diffuse neurons
neuronal systems.

Hierarchical Systems
Hierarchical systems include all the pathways directly involved
in sensory perception and motor control. These pathways are
generally clearly delineated, being composed of large myelinated FIGURE 21–5 Hierarchical pathways in the CNS. A shows parts
of three excitatory relay neurons (blue) and two types of local inhibi-
fibers that can often conduct action potentials at a rate of more tory interneuron pathways, recurrent and feed-forward. The inhibi-
than 50 m/s. The information is typically phasic and occurs in tory neurons are shown in gray. B shows the pathway responsible for
bursts of action potentials. In sensory systems, the information axoaxonic presynaptic inhibition in which the axon of an inhibitory
is processed sequentially by successive integrations at each relay neuron (gray) synapses onto the presynaptic axon terminal of an
nucleus on its way to the cortex. A lesion at any link incapacitates excitatory fiber (blue) to inhibit its neurotransmitter release.
the system.
Within each nucleus and in the cortex, there are two types
of cells: relay or projection neurons and local circuit neurons on the terminals of sensory axons (Figure 21–5B). Although there
(Figure 21–5A). The projection neurons form the interconnect- are a great variety of synaptic connections in these hierarchical
ing pathways that transmit signals over long distances. Their systems, the fact that a limited number of transmitters are used by
cell bodies are relatively large, and their axons can project long these neurons indicates that any major pharmacologic manipu-
distances but also emit small collaterals that synapse onto local lation of this system will have a profound effect on the overall
interneurons. These neurons are excitatory, and their synaptic excitability of the CNS. For instance, selectively blocking GABA
influences, which involve ionotropic receptors, are very short- receptors with a drug such as picrotoxin results in generalized con- A
lived. The excitatory transmitter released from these cells is, in vulsions. Thus, although the mechanism of action of picrotoxin
most instances, glutamate. is specific in blocking the effects of GABA, the overall functional
Local circuit neurons are typically smaller than projection effect appears to be quite nonspecific, because GABA-mediated
neurons, and their axons arborize in the immediate vicinity of the synaptic inhibition is so widely utilized in the brain.
cell body. Most of these neurons are inhibitory, and they release
either GABA or glycine. They synapse primarily on the cell body Nonspecific or Diffuse Neuronal Systems
of the projection neurons but can also synapse on the dendrites of
projection neurons as well as with each other. Two common types Neuronal systems containing many of the other neurotransmit-
of pathways for these neurons (Figure 21–5A) include recurrent ters, including the monoamines and acetylcholine, differ in
feedback pathways and feed-forward pathways. A special class of fundamental ways from the hierarchical systems. These neu-
local circuit neurons in the spinal cord forms axoaxonic synapses rotransmitters are produced by only a limited number of neurons