Chapter 6
postural pressure changes, the fl uid ultimately fl ows to the top
of the outer surface of the brain, where most of it enters the
bloodstream through one-way valves in large veins. Thus, the
central nervous system literally fl oats in a cushion of cerebro-
spinal fl uid. Because the brain and spinal cord are soft, delicate
tissues, they are somewhat protected by this shock-absorbing
fl uid from sudden and jarring movements. If the outfl ow is
obstructed, cerebrospinal fl uid accumulates, causing
(“water on the brain”). In severe, untreated cases,
the resulting elevation of pressure in the ventricles causes
compression of the brain’s blood vessels, which may lead to
inadequate blood fl ow to the neurons, neuronal damage, and
mental retardation.
Under normal conditions, glucose is the only substrate
metabolized by the brain to supply its energy requirements,
and most of the energy from the oxidative breakdown of glu-
cose is transferred to ATP. The brain’s glycogen stores are
negligible, so it depends upon a continuous blood supply of
glucose and oxygen. In fact, the most common form of brain
damage is caused by a decreased blood supply to a region of
the brain. When neurons in the region are without a blood
supply and deprived of nutrients and oxygen for even a few
minutes, they cease to function and die. This neuronal death,
when it results from vascular disease, is called a
Although the adult brain makes up only 2 percent of the
body weight, it receives 12 to 15 percent of the total blood
supply, which supports its high oxygen utilization. If the
blood fl ow to a region of the brain is reduced to 10 to 25
percent of its normal level, energy-dependent membrane ion
pumps begin to fail, membrane ion gradients decrease, extra-
cellular potassium concentration increases, and membranes
The exchange of substances between blood and extra-
cellular fl uid in the central nervous system is different from
the more-or-less unrestricted diffusion of nonprotein sub-
stances from blood to extracellular fl uid in the other organs
of the body. A complex group of
blood-brain barrier
nisms closely control both the kinds of substances that enter
the extracellular fl uid of the brain and the rates at which they
enter. These mechanisms minimize the ability of many harm-
ful substances to reach the neurons, but they also reduce the
access of the immune system to the brain.
The blood-brain barrier, which comprises the cells that
line the smallest blood vessels in the brain, has both ana-
tomical structures, such as tight junctions, and physiological
transport systems that handle different classes of substances
in different ways. Substances that dissolve readily in the lipid
components of the plasma membranes enter the brain quickly.
Therefore, the extracellular fl uid of the brain and spinal cord
is a product of, but chemically different from, the blood.
The blood-brain barrier accounts for some drug actions,
too, as we can see from the following scenario. Morphine
differs chemically from heroin only slightly: morphine has
two hydroxyl groups, whereas heroin has two acetyl groups
). This small difference renders heroin more lipid-
soluble and able to cross the blood-brain barrier more readily
than morphine. As soon as heroin enters the brain, however,
enzymes remove the acetyl groups from heroin and change
it to morphine. The morphine, less soluble in lipid, is then
effectively trapped in the brain, where it may have prolonged
effects. Other drugs that have rapid effects in the central ner-
vous system because of their high lipid solubility are barbitu-
rates, nicotine, caffeine, and alcohol.
Many substances that do not dissolve readily in lip-
ids, such as glucose and other important substrates of brain
metabolism, nonetheless enter the brain quite rapidly by com-
bining with membrane transport proteins in the cells that line
the smallest brain blood vessels. Similar transport systems also
move substances out of the brain and into the blood, prevent-
ing the buildup of molecules that could interfere with brain
A barrier is also present between the blood in the capil-
laries of the choroid plexuses and the cerebrospinal fl
uid, and
cerebrospinal fl uid is a selective secretion. For example, potas-
sium and calcium concentrations are slightly lower in cerebro-
spinal fl uid than in plasma, whereas the sodium and chloride
concentrations are slightly higher. The choroid plexuses also
trap toxic heavy metals such as lead, thus affording a degree of
protection to the brain.
The cerebrospinal fl uid and the extracellular fl
uid of
the central nervous system are, over time, in diffusion equi-
librium. Thus, the restrictive, selective barrier mechanisms in
the capillaries and choroid plexuses regulate the extracellular
environment of the neurons of the brain and spinal cord.
Nicotine is the world’s third most widely used drug, behind
caffeine and alcohol.
is a plant alkaloid compound
that constitutes 1 to 2 percent of smoking tobacco. It is
also contained in treatments for smoking cessation such as
nasal sprays, chewing gums, and transdermal patches. Its
hydrophobic structure allows rapid absorption through lung
capillaries, mucous membranes, skin, and the blood-brain
barrier. Nicotine binds tightly, and lends its name to a type of
neurotransmitter receptor distributed widely in the nervous
and muscular systems—nicotinic acetylcholine receptors
(N-AChRs). These receptors mediate (1) end-plate potentials
at neuromuscular junctions; (2) excitatory postsynaptic
potentials within ganglia of the autonomic nervous system;
(3) the release of catecholamines from the adrenal medulla;
and (4) presynaptic facilitation of excitatory neurotransmitter
release at widespread synapses in the brain, including the
release of dopamine in the brain’s principal “reward” pathway.
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