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Drugs and the Nervous System

The activity of the nervous system is mediated by many kinds of interneurons releasing one or
another neurotransmitter such as

noradrenaline

gamma aminobutyric acid (GABA)

dopamine

glutamate (Glu)

acetylcholine (ACh)

serotonin

Link to discussion of synapses and their neurotransmitters.


Presynaptic neurons

synthesize and package their neurotransmitter in vesicles for release (by exocytosis) at
the synapse

often have "reuptake" transporters that reclaim the transmitter back into the cell when
it has done its job.

Postsynaptic neurons display receptors to which the neurotransmitter binds.


All of this machinery provides many targets for alteration by exogenous chemicals; that is,
psychoactive chemicals introduced into the body. These drugs fall into several distinct families.

Stimulants
The most widely used stimulants are

caffeine (in coffee, tea, and cola beverages)

nicotine (in cigarettes)

amphetamines

cocaine

All of these drugs mimic the stimulation provided by the sympathetic nervous system.
Link to discussion of the sympathetic nervous system.
Nicotine binds to a subset of acetylcholine (ACh) receptors. ACh is a neurotransmitter at
synapses early in the pathways of sympathetic stimulation. Although a weak drug in one sense,
nicotine is strongly addictive. The use of chewing gum and skin patches containing nicotine is
designed to satisfy the craving for nicotine while avoiding the serious health effects of other
ingredients in cigarette smoke.
Amphetamines and cocaine bind to thus blocking transporters used for the reuptake of
dopamine (and noradrenaline) into presynaptic neurons. This causes the level of dopamine to
rise in the synapses. High levels of dopamine in an area of the brain called the nucleus
accumbens appear to mediate the pleasurable effects associated with these (as well as other)
psychoactive drugs.
Some amphetamines:
Generic name

Trade name

dextroamphetamine sulfate

Dexedrine

methylphenidate

Ritalin

pemoline

Cylert

mixture of 4 amphetamines

Adderall

The chief medical uses for amphetamines and amphetamine-like drugs are

to help people lose weight (because they suppress appetite);

to help children with attention deficit/hyperactivity disorder (ADHD) to perform better in


school.

At first glance, this second use seems counterproductive. This controversial procedure seems to
work by increasing the alertness of the child so that it can focus its energies more effectively on
the tasks in front of it.

Fen-Phen
Fen-Phen refers to a mixture of two amphetamine-like drugs

fenfluramine

phentermine

that were prescribed for losing weight. Because of reports of occasional very serious side effects,
the mixture is no longer available and fenfluramine has been removed from the U.S. market.

Cocaine
Cocaine has been used for thousands of years by certain tribes in the Andes of South America.
Cocaine and some of its relatives have legitimate medical uses as local anesthetics (e.g.,
lidocaine). However, the widespread recreational use of cocaine has created serious social
problems.
Immunity to cocaine addiction? In order to achieve its effects, cocaine must cross the so-called
blood-brain barrier. If antibodies are bound to the cocaine molecule, it cannot cross. This has
raised the possibility of immunizing people against cocaine. It works in mice.

Sedatives
Sedatives induce sleep.
They include

ethanol (beverage alcohol)

barbiturates, such as
o phenobarbital
o secobarbital (Seconal)

meprobamate (Miltown, Equanil)

Ethanol
Ethyl alcohol (ethanol) is, by a wide margin, the most widely used drug in most of the world. Its
popularity comes not from its sedative effect but from the sense of well-being that it induces at
low doses. Perhaps low doses sedate those parts of the brain involved with, for example, tension
and anxiety and in this way produce a sense of euphoria. However, higher doses depress brain
centers involved in such important functions as pain sensation, coordination, and balance. At
sufficiently high doses, the reticular formation can be depressed enough to cause loss of
consciousness.
Ethanol binds to NMDA receptors in the brain (inhibiting them) and perhaps to GABAA
receptors as well.

Barbiturates

Barbiturates are often prescribed as sleeping pills and also to prevent seizures.
Barbiturates mimic some of the action of ethanol, particularly in their ability to depress the
reticular formation (thus promoting sleep) and, in high doses, the medulla oblongata (thus
stopping breathing).
Barbiturates bind to a subset of GABA receptors designated GABAA receptors. These are ligandgated channels that enhance the flow of chloride ions (Cl) into the postsynaptic neuron, thus
increasing its resting potential and making it less likely to fire. By binding to the GABAA
receptor, barbiturates (and perhaps ethanol) increase the natural inhibitory effect of GABA
synapses. Barbiturates and alcohol act additively the combination producing a depression
greater than either one alone. The combination is a frequent cause of suicide, both accidental and
planned.

Meprobamate
Meprobamate is prescribed as a tranquilizer, but its action is quite different from the tranquilizers
discussed below. Its molecular activity is like that of other sedatives and in combination with
them can produce a lethal overdose. All sedatives produce two related physiological effects:

tolerance the necessity for a steadily-increasing dose to achieve the same


physiological and psychological effects

physical dependence withdrawal of the drug precipitates unpleasant physical and


psychological symptoms.

These traits are also shared with nicotine, opiates, and other psychoactive drugs.

Local Anesthetics
These chemical relatives of cocaine act by blocking the voltage-gated Na+ channels of sensory
neurons preventing them from generating action potentials. [Discussion] They are injected or
applied topically and block transmission not only in pain-conducting neurons but in others as
well (causing general numbness).
Examples:

lidocaine (Xylocaine)

procaine (Novocaine)

Inhaled Anesthetics
Most of these are volatile hydrocarbons or ethers. Diethyl ether and chloroform are seldom used
today, having been replaced by safer alternatives such as isofluorane, an fluorinated ether.

They bind to GABA receptors in the spinal cord and brain decreasing the sensitivity of the
postsynaptic neurons.

Other Hydrocarbons
1,4-Butanediol is a common solvent. When ingested, it is converted into -hydroxybutyrate, an
increasingly-popular (and illegal) "club drug". -Hydroxybutyrate acts on GABAB receptors.
Conversion of 1,4-butanediol to -hydroxybutyrate requires the enzyme alcohol dehydrogenase,
the same enzyme used to metabolize ethanol. Ingesting both ethanol and 1,4-butanediol delays
the effects of the latter.

Opiates
These are substances isolated from the opium poppy or synthetic relatives. (They are also called
opioids.)
Examples:

morphine

codeine

heroin

fentanyl (a synthetic that is <30 times more potent than heroin and ~80 times more
potent than morphine)

methadone

oxycodone

Opiates depress nerve transmission in sensory pathways of the spinal cord and brain that signal
pain. This explains why opiates are such effective pain killers.
Opiates also inhibit brain centers controlling coughing, breathing, and intestinal motility. Both
morphine and codeine are used as pain killers, and codeine is also used in cough medicine.
Opiates are exceedingly addictive, quickly producing tolerance and dependence. Although heroin
is even more effective as a painkiller than morphine and codeine, it is so highly addictive that its
use is illegal. Methadone is a synthetic opiate that is used to break addiction to heroin (and
replace it with addiction to methadone).
Opiates bind to so-called mu () receptors . These G-protein-coupled receptors are located on
the subsynaptic membrane of neurons involved in the transmission of pain signals. Their natural
ligands are two pentapeptides (containing five amino acids):

Met-enkephalin (Tyr-Gly-Gly-Phe-Met-COO-)

Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu-COO-)

Release of enkephalins suppresses the transmission of pain signals. (Little is to be gained by


having the perception of pain increase indefinitely in proportion to the amount of damage done
to the body. Beyond a certain point, it makes sense to have a system that decreases its own
sensitivity in the face of massive, intractable pain.)
By binding to enkephalin receptors, opiates like morphine enhance the pain-killing effects of
enkephalin neurons. Opiate tolerance can be explained, at least in part, as a homeostatic response
that reduces the sensitivity of the system to compensate for continued exposure to high levels of
morphine or heroin. When the drug is stopped, the system is no longer as sensitive to the
soothing effects of the enkephalin neurons and the pain of withdrawal is produced.
Mu () receptors are also found on the cells in the medulla oblongata that regulate breathing.
This accounts for the suppressive effect opiates have on breathing.

Opiate antagonists
Opiate antagonists such as

naloxone (Narcan)

naltrexone (ReVia)

bind to receptors but instead of activating them, they prevent the binding of the opiates
themselves. In fact, if the receptors are already occupied by, for example, heroin molecules,
naloxone will push the heroin molecules off and quickly rescue the patient from a drug
overdose. Naltrexone is used to help recovering heroin addicts stay drug-free.

Antipsychotics
Antipsychotics (also called "neuroleptics") are used to treat schizophrenia, a common and
devastating mental disease. They act by binding to one class of receptors for the neurotransmitter
dopamine. There are two groups currently in use:

"Typical" antipsychotics (sometimes referred to as "major tranquilizers"). Examples:


o chlorpromazine
o haloperidol (Haldol)

"Atypical" antipsychotics (also referred to as "second generation" antipsychotics).


Examples:

o resperidone (Resperdal)
o olanzapine (Zyprexa)
o quetiapine (Seroquel)

Tranquilizers
Tranquilizers act like sedatives in reducing anxiety and tensions but do not have their sleepinducing effect.
Most belong to a group called benzodiazepines and include such commonly-prescribed drugs as
Librium, Valium, Halcion, and Xanax.
The benzodiazepines act on interneurons that use the inhibitory neurotransmitter GABA. By
binding to GABAA receptors on the postsynaptic membrane, they enhance the action of GABA at
the synapse. [Further discussion]
This is the same receptor to which barbiturates (and perhaps ethanol) bind. Thus although
Librium and Valium seem safe enough when used alone, combining them with ethanol or
barbiturates can be (and often has been) lethal.

Antidepressants
Antidepressants fall into four chemical categories (of which we shall examine three). Most share
a common property: they increase the amount of serotonin at synapses that use it as a
neurotransmitter.

Monoamine oxidase (MAO) inhibitors


These drugs act on a mitochondrial enzyme that breaks down monoamines such as
noradrenaline and serotonin. By inhibiting the enzyme in presynaptic serotonin-releasing
neurons, more serotonin is deposited in the synapse. Some examples: Parnate, Nardil,
Marplan. For several reasons, MAO inhibitors are not used much anymore.

Tricyclics
These drugs block the reuptake of noradrenaline, dopamine, and serotonin causing an
increase in the level of these neurotransmitters in the synapse.
Examples:
Generic name

Trade name

imipramine

Tofranil

clomiprimine

Anafranil

amitriptyline

Elavil

imipramine

Tofranil

Although tricyclics are still prescribed for pain relief, their role as antidepressants has largely
been taken over by the selective serotonin reuptake inhibitors (SSRIs).

Selective Serotonin Reuptake Inhibitors (SSRIs)


As the name suggests, these drugs inhibit the reuptake of serotonin but not of noradrenaline.
Examples:
Generic name

Trade name

fluoxetine

Prozac

paroxetine

Paxil

sertraline

Zoloft

fluvoxamine

Luvox

Although all these drugs quickly increase the amount of serotonin in the brain, there is more to
the story than that. Unlike most psychoactive drugs, antidepressants do not relieve the symptoms
of depression until a week or more after dosing begins. During this period, the number of
serotonin receptors on the postsynaptic membranes decreases. How this translates into relief of
symptoms is not yet understood.

Bupropion
Bupropion (e.g., Wellbutrin) is a novel drug that blocks the reuptake of noradrenaline and
dopamine. Although it does not interfere with the uptake of serotonin, it also appears to be an
effective antidepressant.

Atomoxetine
This drug (Strattera) selectively interferes with the reuptake of noradrenaline. It is used in
children with attention deficit/hyperactivity disorder (ADHD).

Psychedelics
Psychedelic drugs distort sensory perceptions, especially sight and sound.

Some such as

mescaline

psilocybin and

dimethyltryptamine (DMT)

are natural plant products.


The photograph (courtesy of Dr. Richard
Evans Schultes) shows the peyote cactus in
flower. The cactus head contains several psychedelic chemicals, of which mescaline is the most
important. Dried cactus heads ("mescal buttons") have been used since pre-Columbian times in
the religious ceremonies of native peoples in Mexico. About a century ago, this religious use
spread to some tribes in the United States and Canada who, in 1922, became incorporated into
the Native American Church.
Other psychedelic drugs are synthetic. These include

lysergic acid diethylamide (LSD)

dimethoxymethylamphetamine (DOM or "STP")

methylenedioxymethamphetamine (MDMA or "ecstasy")

As their name suggests, DOM and MDMA also share the stimulant qualities of amphetamines.
All the psychedelics have a molecular structure that resembles serotonin and probably bind to
serotonin receptors on the postsynaptic membrane.

Phencyclidine (PCP)
PCP is used as an anesthetic in veterinary medicine.
Used (illicitly) by humans (called "crystal" or "angel dust"), it can produce a wide variety of
powerful reactions resembling those of stimulants as well as psychedelics.
Unlike the other psychedelics, it binds to (and inhibits) NMDA receptors (in the hippocampus
and other parts of the forebrain).

Marijuana
The active ingredient in marijuana is delta-9-tetrahydrocannabinol (9-THC). It binds to

CB1 receptors (G-protein-coupled receptors) that are present on presynaptic membranes


in many parts of the brain;

CB2 receptors are also found in the brain as well as being highly-expressed on cells of the
immune system (e.g., B cells and T cells).

THC produces

the drowsiness of sedatives like alcohol

the dulling of pain (like opiates) and

in high doses, the perception-distorting effects of the psychedelics.

Unlike sedatives and opiates, however, tolerance to THC does not occur. In fact, the drug is
excreted so slowly from the body that, with repeated use, a given response is achieved by a lower
dose.
The natural ligands of the CB receptors are

anandamide and

2-arachidonylglycerol (2-AG).

Both of these compounds are produced from phospholipids.


What are these natural ligands doing? They probably will turn out to have multiple effects, but
the clearest ones so far are their effects on

appetite
Mice
o given anandamide eat more than normal while
o those whose genes for the CB1 receptor have been "knocked out" eat less than
normal.
These findings will be no surprise to the ill humans (e.g., with cancer or AIDS) who find
that marijuana improves their appetite.
Rimonabant (Acomplia), a drug that blocks the ability of the body's natural CB1 ligands
to bind the CB1 receptor is sold in Europe as an appetite suppressant. (Because of its
side effects, it has not been approved for use in the U.S.)

development of correct synaptic connections in the embryonic brain. Mice whose genes
for the CB1 receptor have been knocked out develop defects in the wiring pattern of
interneurons in their brain (which may account for the cognitive defects that have been
reported in the children of women who used marijuana during pregnancy).

neuronal activity in the adult brain. Mice whose genes for the CB1 receptor have been
knocked out are more susceptible to epileptic seizures. Marijuana has been used for
centuries to control epileptic seizures in humans.

suppressing contact dermatitis. Knockout mice lacking CB1 and CB2 receptors mount a
more vigorous allergic inflammatory response to agents (like nickel) that elicit contact
sensitivity.

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