11
Neurotransmitters that act
indirectly
promote broader,
longer-lasting effects by acting through intracellular
second-
messenger
molecules, typically via G protein pathways (see Fig-
ure 3.16). In this way their action is similar to that of many
hormones. Te biogenic amines, neuropeptides, and dissolved
gases are indirect neurotransmitters.
Neuromodulator
is a term used to describe a chemical mes-
senger released by a neuron that does not directly cause EPSPs
or IPSPs but instead affects the strength of synaptic transmis-
sion. A neuromodulator may act presynaptically to influence the
synthesis, release, degradation, or reuptake of neurotransmitter.
become hypersensitive and sprout new
receptors in a desperate effort to pick
up dopamine signals. A vicious cycle of
addiction begins: Cocaine is needed to
experience pleasure, but using it suppresses
dopamine release even more.
The dopamine effect alone is not
enough to establish addiction. Another
neurotransmitter, glutamate, which plays
an important role in learning, is required
to maintain addiction. Glutamate signaling
seems to cause more permanent changes
in the brain (synaptic potentiation)
that lead to compulsive drug-seeking
behaviors elicited by external cues. Take,
for example, mice genetically engineered
to lack a particular glutamate receptor
(GluR5). These mice are perfectly willing
to try cocaine but never become addicted.
(Of course, no GluR5 means they’re none
too bright, either.)
Current thinking, then, is that the
rush of pleasure on taking cocaine is due
to dopamine. Glutamate, on the other
hand, is thought to be responsible for the
learning that makes true the perception
“once an addict, always an addict.”
So strong is the combined dopamine
and glutamate system that, even years
later, certain settings can trigger intense
cravings for the drug.
These out-of-control, desperate
cravings are notoriously difficult to
manage. Drug abusers call it “jonesing.”
Traditional antiaddiction drugs take
so long to reduce the cravings that
users commonly drop out of treatment
programs.
How can we break this cycle of
addiction? One way is to prevent cocaine
from ever reaching the brain. Promising
results have been obtained from a vaccine
that prompts the immune system to bind
cocaine molecules, preventing them from
entering the brain. In a clinical trial, this
vaccine dampened addicts’ pleasurable
responses to cocaine and reduced their
use of the drug.
Another approach to breaking the
addiction cycle is to even out the highs
and lows experienced by the drug user
by leveling out brain dopamine levels and
keep the user from “crashing” so badly.
Possibilities include using a much longer-
acting inhibitor of dopamine reuptake or
taking a drug that binds but only partially
activates dopamine receptors.
A final approach to breaking the
addiction cycle is to interrupt the
learned reinforcement that brings on
cravings. An effective ancient African
folk remedy called ibogaine may do
exactly this. However, ibogaine itself
is too toxic for clinical use, as some
unfortunate “underground” users have
discovered. A close synthetic cousin,
18-methoxycoronaridine (18-MC) is much
less toxic and promises to be effective
against not only cocaine but also a
number of other abused drugs. Future
studies will show if it truly works.
The craving for drugs has made
some addicts very creative home
pharmacologists, willing to experiment
with practically anything, no matter how
toxic or dangerous, to get the “buzz”
they need. A cheap mixture of cold
medications, match heads, and iodine in
acetone yields crystal meth—the highly
addictive and once-again popular drug
that wrecks people’s lives and often
explodes their home laboratories. Another
creative mixture, with the street name
of “ill face” or “illy,” involves dipping
marijuana in formaldehyde, drying and
then smoking it. Other remarkable
combinations are the “H-bomb” (ecstasy
mixed with heroin), “A-bomb” (marijuana
with heroin or opium), “sextasy” [ecstasy
mixed with sildenafil (Viagra)], “octane”
(PCP laced with gasoline), and “ozone”
(marijuana, PCP, and crack in a cigarette).
Formaldehyde is known to cause cancer
and gasoline damages the liver, but
the real damage comes from the drugs
themselves.
Take, for example, ecstasy, a drug
that many of its users believe to be
innocuous. In reality, ecstasy (MDMA)
targets serotonin-releasing neurons.
The “rush” of pleasure and energy that
users feel is due to release of serotonin
and other neurotransmitters. However, it
damages and may destroy these neurons,
causing the loss of verbal and spatial
memory. Depression, sleeplessness, and
memory problems may be permanent
consequences—a steep price for a few
moments of pleasure!
People who want pure, effective, and
“safe” drugs of abuse don’t get them on
the street. They get them from doctors or
“pill ladies” [female senior citizens who
sell oxycodone (OxyContin), a powerful
prescription opioid with effects similar to
heroin]. Even people who would never
dream of taking illicit drugs can be caught
in the addictive cycle of prescription drugs.
Prescribed legitimately to relieve severe
pain, oxycodone is meant to be swallowed
whole. Abusers crush the tablets and snort
the powder or dissolve it in water and
inject the solution. Abuse of oxycodone
and its chemical cousin hydrocodone is
spreading rapidly, doubling over the past
four years. Medical examiners across
North America report soaring rates of
oxycodone-related emergency room visits
and deaths. Indeed, emergency room visits
caused by abuse of prescription or over-
the-counter drugs now equal those for
illicit drugs.
The brain, with its complex
biochemistry, always circumvents attempts
to keep it in a euphoric haze. Perhaps this
means that pleasure must be transient
by nature, experienced only against a
background of its absence.
A CLOSER LOOK
(continued)
419
Alternatively, a neuromodulator may act postsynaptically
by altering the sensitivity of the postsynaptic membrane to
neurotransmitter.
Receptors for neuromodulators are not necessarily found
at a synapse. Instead, a neuromodulator may be released from
one cell to act at many cells in its vicinity, similar to paracrines
(chemical messengers that act locally and are quickly de-
stroyed). Te distinction between neurotransmitters and neu-
romodulators is fuzzy, but chemical messengers such as NO,
adenosine, and a number of neuropeptides are o±en referred to
as neuromodulators.
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