NEUROTRANSMITTERS AND THEIR RECEPTORS 203the sensorimotor system. The autonomic nervous system is further divided into two
parts:sympatheticandparasympathetic. The sympathetic portion deals with the “fight
or flight” response, speeding up the heart and increasing breathing rate during times of
stress; the parasympathetic portion allows us to slow down during times of relaxation.
There is considerable structural difference between the neurons of the autonomic and
sensorimotor systems. In the sensorimotor system, a motoneuron may originate from a
ventral horn of the spinal cord and continue without interruption, through a myelinated
A-fiber, to the muscle. The neuron usually branches in the muscle and forms neuro-
muscular endplates on each muscle fiber, creating a single motor unit. By contrast, the
autonomic nervous system interposes a peripheral ganglionic synapsebetween the CNS
and an organ, acting as a kind of switching station. The neurons in the sympathetic ner-
vous system originate in the upper and middle part of the spinal cord and form myeli-
nated B-fibers. Each such fiber makes synaptic connection with the ganglion cell,
which continues in a postganglionic, nonmyelinated C-fiber that then synapses on a
smooth-muscle cell, a gland, or another neuron. In the sympathetic system, the ganglia
are usually in the paravertebral chain, or within some other specialized ganglia. In the
parasympathetic nervous system, the ganglia are buried in the effector organs and there-
fore have only short postganglionic fibers.
As will be shown in this chapter, designing drugs to treat specific diseases of the CNS
is challenging and fraught with frequent failure. The diagnostic approach to neurologi-
cal disease involves localization of the lesion followed by determination of the nature of
the lesion. The disease is localized by examining the individual to ascertain which verti-
cal pathways (e.g., descending tracts such as the corticospinal tract carrying information
from the brain to the body, or ascending tracts such as the spinothalamic tract carrying
sensory information to the brain) and horizontal pathways (e.g., spinal nerves carrying
information to a particular level of the spinal cord, or visual pathways taking informa-
tion from the eyes to the occipital cortex) are involved; by determining where the verti-
cal and horizontal tracts meet, it is possible to localize the lesion. Next, it is necessary
to determine the nature of the pathology that is causing problems at this location: devel-
opmental (cerebral palsy), degenerative (Alzheimer’s, Parkinson’s diseases), infectious
(meningitis, encephalitis), inflammatory (multiple sclerosis), neoplastic (brain tumor),
nutritional (thiamine deficiency causing Wernicke’s encephalopathy), trauma (concus-
sion), toxic (alcoholism, environmental poison, drug side effect), or vascular (stroke).
Designing drugs to treat such problems is not a trivial task. Although the disease may
be localized, site-specific delivery of the drug is usually not possible. A focal cortical
injury may be causing seizures, but the anticonvulsant drug will reach all areas of the
brain, not just the focal area. In fact, it may not even be possible to get the drug into the
brain. The blood–brain barrier (chapter 3) will preclude many molecules with desirable
therapeutic properties. Also, various areas of the brain are highly interconnected; block-
ing a neurotransmitter receptor may have far-reaching consequences that extend beyond
the area of interest. Despite these difficulties, medicinal chemistry of neuroactive sub-
stances is a rapidly expanding area. Furthermore, drugs targeting neurotransmitters are
not exclusively used for the treatment of CNS disorders. Since the brain controls
numerous functions throughout the body, modification of neurotransmitters enables the
treatment of many non-neurologic problems such as high blood pressure, cardiac
arrhythmias, pulmonary bronchospasm, and irritable bowel syndrome (section 4.10).