Ganong's Review of Medical Physiology, 23rd Edition

140 SECTION IIPhysiology of Nerve & Muscle Cells

motor control, and the mesocortical system, which arises
primarily in the ventral tegmental area (Figure 7–2). The
mesocortical system projects to the nucleus accumbens and
limbic subcortical areas, and it is involved in reward behav-
ior and addiction. Studies by PET scanning in normal
humans show that a steady loss of dopamine receptors occurs
in the basal ganglia with age. The loss is greater in men than
in women.

Dopamine Receptors

Five different dopamine receptors have been cloned, and
several of these exist in multiple forms. This provides for va-
riety in the type of responses produced by dopamine. Most,
but perhaps not all, of the responses to these receptors are
mediated by heterotrimeric G proteins. One of the two forms
of D 2 receptors can form a heterodimer with the somatosta-
tin SST5 receptor, further increasing the dopamine response
menu. Overstimulation of D 2 receptors is thought to be re-
lated to schizophrenia (see Clinical Box 7–4). D 3 receptors
are highly localized, especially to the nucleus accumbens
(Figure 7–2). D 4 receptors have a greater affinity than the
other dopamine receptors for the “atypical” antipsychotic
drug clozapine, which is effective in schizophrenia but pro-
duces fewer extrapyramidal side effects than the other major
tranquilizers do.

EXCITATORY & INHIBITORY

AMINO ACIDS

Glutamate

The amino acid glutamate is the main excitatory transmitter
in the brain and spinal cord, and it has been calculated that it
is the transmitter responsible for 75% of the excitatory trans-
mission in the brain. Glutamate is formed by reductive amina-
tion of the Krebs cycle intermediate α-ketoglutarate in the
cytoplasm. The reaction is reversible, but in glutaminergic
neurons, glutamate is concentrated in synaptic vesicles by the
vesicle-bound transporter BPN1. The cytoplasmic store of
glutamine is enriched by three transporters that import
glutamate from the interstitial fluid, and two additional trans-
porters carry glutamate into astrocytes, where it is converted
to glutamine and passed on to glutaminergic neurons. The in-
teraction of astrocytes and glutaminergic neurons is shown in
Figure 7–8. Released glutamate is taken up by astrocytes and
converted to glutamine, which passes back to the neurons and
is converted back to glutamate, which is released as the synap-
tic transmitter. Uptake into neurons and astrocytes is the main
mechanism for removal of glutamate from synapses.

Glutamate Receptors

Glutamate receptors are of two types: metabotropic receptors
and ionotropic receptors. The metabotropic receptors are G
protein-coupled receptors that increase intracellular IP 3 and

CLINICAL BOX 7-4

Schizophrenia

Schizophrenia is an illness that involves deficits of multiple

brain systems that alter an individual’s inner thoughts as well

as their interactions with others. Individuals with schizophre-

nia suffer from hallucinations, delusions, and racing

thoughts (positive symptoms); and they experience apathy,

difficulty dealing with novel situations, and little spontaneity

or motivation (negative symptoms). Worldwide, about 1–2%

of the population lives with schizophrenia. A combination of

genetic, biological, cultural, and psychological factors con-

tributes to the illness. A large amount of evidence indicates

that a defect in the mesocortical system is responsible for

the development of at least some of the symptoms of

schizophrenia. Attention was initially focused on overstimu-

lation of limbic D 2 dopamine receptors. Amphetamine,

which causes release of dopamine as well as norepinephrine

in the brain, causes a schizophrenialike psychosis; brain le-

vels of D 2 receptors are said to be elevated in schizophrenics;

and there is a clear positive correlation between the antis-

chizophrenic activity of many drugs and their ability to block

D 2 receptors. However, several recently developed drugs are

effective antipsychotic agents but bind D 2 receptors to a lim-

ited degree. Instead, they bind to D 4 receptors, and there is

active ongoing research into the possibility that these recep-

tors are abnormal in individuals with schizophrenia.

FIGURE 7–8 The glutamate–glutamine cycle through

glutaminergic neurons and astrocytes. Glutamate released into the

synaptic cleft is taken up by a Na+-dependent glutamate transporter,

and in the astrocyte it is converted to glutamine. The glutamine enters

the neuron and is converted to glutamate. Glucose is transported out

of capillaries and enters astrocytes and neurons. In astrocytes, it is me-

tabolized to lactate, producing two ATPs. One of these powers the

conversion of glutamate to glutamine, and the other is used by Na+–

K+ ATPase to transport three Na+ out of the cell in exchange for two K+.

In neurons, the glucose is metabolized further through the citric acid

cycle, producing 34 ATPs.

Glucose

Capillary

Lactate

Lactate

ATP

ATP

34 ATP Gln

Glu

3Na+

3Na+

2K+

Glutaminergic

synapse

Astrocyte

Gln

Glu

Glu