198 Chapter 7
marijuana impairs attention, learning, and memory; some
studies suggest that, in chronic marijuana users, this impair-
ment may persist even after the drug is no longer in the body.
These deleterious effects, particularly on “working memory”
(the ability to hold and process bouts of information), limit the
therapeutic uses of THC, which include treatments for pain,
nausea, and other conditions. More concerning, evidence sug-
gests that the frequent use of marijuana decreases IQ points
significantly, and even more so if the person starts using mari-
juana during the teenage years.
Gases as Neurotransmitters
Because gases that function as neurotransmitters can easily pass
through the phospholipid bilayer of the plasma membrane, they
diffuse out of the neuron as they are produced. Nitric oxide
(NO) was the first gas to be identified as a neurotransmitter. Pro-
duced by nitric oxide synthetase from the amino acid l-arginine
in the cells of many organs, nitric oxide’s actions are very dif-
ferent from those of the more familiar nitrous oxide (N 2 O), or
laughing gas, sometimes used as a mild anesthetic in dentistry.
Nitric oxide has a number of different roles in the body.
Within blood vessels, it acts as a local tissue regulator that causes
the smooth muscles of those vessels to relax, so that the blood ves-
sels dilate. This role will be described in conjunction with the cir-
culatory system in chapter 14, section 14.3. Within macrophages
and other cells, nitric oxide helps to kill bacteria. This activity is
described in conjunction with the immune system in chapter 15,
section 15.1. In addition, nitric oxide is a neurotransmitter of cer-
tain neurons in both the PNS and the CNS. It diffuses out of the
presynaptic axon and into neighboring cells by simply passing
through the plasma membranes. In some cases, nitric oxide is
also produced by the postsynaptic neuron and can diffuse back
to the presynaptic neuron to act as a retrograde neurotransmitter
(chapter 8; see fig. 8.16). Once in the target cells, NO exerts its
effects by stimulating the production of cyclic guanosine mono-
phosphate (cGMP), which acts as a second messenger.
In the PNS, nitric oxide is released by some neurons that
innervate the gastrointestinal tract, penis, respiratory passages,
and cerebral blood vessels. These are autonomic neurons that
cause smooth muscle relaxation in their target organs. This can
produce, for example, the engorgement of the spongy tissue of
the penis with blood. In fact, scientists now believe that erec-
tion of the penis results from the action of nitric oxide, and
indeed the drug Viagra works by increasing this action of nitric
oxide (as described in chapter 20; see fig. 20.22).
In addition to nitric oxide, another gas— carbon monoxide
(CO) —may function as a neurotransmitter. Certain neurons,
including those of the cerebellum and olfactory epithelium,
have been shown to produce carbon monoxide (derived from
the conversion of one pigment molecule, heme, to another, bili-
verdin; see fig. 18.22). Also, carbon monoxide, like nitric oxide,
has been shown to stimulate the production of cGMP within the
neurons. Experiments suggest that carbon monoxide may pro-
mote odor adaptation in olfactory neurons, contributing to the
regulation of olfactory sensitivity. Other physiological functions
of neuronal carbon monoxide have also been suggested, includ-
ing neuroendocrine regulation in the hypothalamus.
A third gas, hydrogen sulfide (H 2 S) —known by most
people for its putrid odor—is generated in the nervous, cardio-
vascular, and other systems. Although it is toxic at greater than
physiological amounts, the production of H 2 S by the nervous
and other systems has been proposed to support a number of
physiological functions.ATP and Adenosine as Neurotransmitters
Adenosine triphosphate (ATP) and adenosine are classified chem-
ically as purines (chapter 2) and have multiple cellular functions.
The plasma membrane is impermeable to organic molecules with
phosphate groups, trapping ATP inside cells to serve as the uni-
versal energy carrier of cell metabolism. However, neurons and
astrocytes can release ATP by exocytosis of synaptic vesicles, and
this extracellular ATP, as well as adenosine produced from it by
an extracellular enzyme on the outer surface of tissue cells, can
function as neurotransmitters. Nonneural cells also can release
ATP into the extracellular environment by different means to
serve various functions. The purine neurotransmitters are released
as cotransmitters; that is, they are released together with other
neurotransmitters, such as with glutamate or GABA in the CNS.
Purinergic receptors, designated P1 (for ATP) and P2 (for ade-
nosine), are found in neurons and glial cells and have been impli-
cated in a variety of physiological and pathological processes. For
example, the dilation of cerebral blood vessels in response to ATP
released by astrocytes was discussed in section 7.1.
Through the activation of different subtypes of purinergic
receptors, ATP and adenosine serve as neurotransmitters when
released as cotransmitters by neurons. Examples in the PNS
include ATP released with norepinephrine in the stimulation
of blood vessel constriction and with ACh in the stimulation of
intestinal contractions. When ATP and adenosine are released
by nonneural cells, they serve as paracrine regulators (chap-
ter 6, section 6.5). Examples of ATP and adenosine acting as
paracrine regulators include their roles in blood clotting (when
released by blood platelets), in stimulating neurons for taste
(when released by taste bud cells), and in stimulating neurons
for pain (when released by damaged tissues).| CHECKPOINT
14a. Explain the significance of glutamate in the brain and
of NMDA receptors.
14b. Describe the mechanism of action of glycine and
GABA as neurotransmitters, and discuss their
significance.
15a. Give examples of endogenous opioid polypeptides,
and discuss their significance.
15b. Explain how nitric acid is produced in the body, and
describe its functions.