194 Chapter 7
7.6 Other Neurotransmitters
A surprisingly large number of diverse molecules appear to
function as neurotransmitters. These include some amino
acids and their derivatives, many polypeptides, and even
the gas nitric oxide.Norepinephrine as a Neurotransmitter
Norepinephrine, like ACh, is used as a neurotransmitter in
both the PNS and the CNS. Sympathetic neurons of the PNS
use norepinephrine as a neurotransmitter at their synapse with
smooth muscles, cardiac muscle, and glands. Some neurons in
the CNS also use norepinephrine as a neurotransmitter; these
neurons seem to be involved in general behavioral arousal. This
would help to explain the mental arousal elicited by amphet-
amines, which stimulate pathways in which norepinephrine is
used as a neurotransmitter. Drugs that increase norepinephrine
stimulation of synaptic transmission in the CNS (including the
tricyclic antidepressants and others) have been used to treat
clinical depression. However, such drugs also stimulate the
PNS pathways that use norepinephrine, and so can promote
sympathetic nerve effects that raise blood pressure.
CLINICAL APPLICATION
Cocaine is abused because it elevates energy and mood, an
effect produced through the activation of the mesolimbic reward
pathway of the brain (and reduced by drug tolerance and
addiction.) Cocaine exerts these effects because it crosses the
blood-brain barrier and blocks the reuptake of dopamine. How-
ever, it also blocks the reuptake transporters for norepineph-
rine and serotonin—it is a triple reuptake inhibitor. In addition to
this broad action, cocaine is dangerous because it also blocks
membrane Na^1 channels (section 7.2). Through all of these
actions, cocaine constricts coronary arteries, raises cardiac
rate and blood pressure, and promotes heart disease, stroke,
seizures, ulcers of the digestive tract, and kidney damage.Clinical Investigation CLUES
Denise frequently used cocaine.- What is the mechanism of cocaine action on the
nervous system? - How might her use of cocaine have led to her
seizure at the restaurant?
| CHECKPOINT
12a. List the monoamines and indicate their chemical
relationships.
12b. Explain how monoamines are inactivated at the synapse
and how this process can be clinically manipulated.
13a. Describe the relationship between dopaminergic
neurons, Parkinson’s disease, and schizophrenia.
13b. Explain how cocaine and amphetamines produce
their effects in the brain. What are the dangers of
these drugs?LEARNING OUTCOMESAfter studying this section, you should be able to:- Explain the action and significance of GABA and
glycine as inhibitory neurotransmitters. - Describe some of the other categories of
neurotransmitters in the CNS.
Amino Acids as Neurotransmitters
Excitatory Neurotransmitters
The amino acids glutamic acid and, to a lesser degree, aspar-
tic acid, function as excitatory neurotransmitters in the CNS.
Glutamic acid (or glutamate ), indeed, is the major excitatory
neurotransmitter in the brain, producing excitatory postsynap-
tic potentials (EPSPs) in at least 80% of the synapses in the
cerebral cortex. The energy consumed by active transport car-
riers needed to maintain the ionic gradients for these EPSPs
constitutes the major energy requirement of the brain (action
potentials produced by axons are more energy efficient than
EPSPs). Astrocytes take glutamate from the synaptic cleft,
as previously described, and couple this to increased glucose
uptake and increased blood flow via vasodilation to the more
active brain regions.
Research has revealed that each of the glutamate recep-
tors encloses an ion channel, similar to the arrangement seen
in the nicotinic ACh receptors (see fig. 7.26 ). Among these
EPSP-producing glutamate receptors, three subtypes can be
distinguished. These are named according to the molecules
(other than glutamate) that they bind: (1) NMDA receptors
(named for N-methyl-D-aspartate); (2) AMPA receptors; and
(3) kainate receptors. NMDA and AMPA receptors are illus-
trated in chapter 8, figure 8.16.
The NMDA receptors for glutamate are involved in mem-
ory storage, as will be discussed in section 7.7 and chapter 8,
section 8.2. These receptors have a channel pore that is blocked
by Mg^2 and the simple binding of glutamate to these recep-
tors cannot open the channels. Instead, two other conditions
must be met at the same time: (1) the NMDA receptor must
also bind to glycine (or D-serine, which is produced by astro-
cytes); and (2) the membrane must be partially depolarized at
this time by a different neurotransmitter molecule that binds to
a different receptor (for example, by glutamate binding to the
AMPA receptors, as shown in fig. 8.16). Depolarization causes
Mg^2 1 to be released from the NMDA channel pore, unblock-
ing the channel and allowing the entry of Ca^2 1 and Na^1 (and