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CHAPTER 4: PSYCHOPHARMACOLOGY
Neurotransmitters, Neuromodulators, and Neurohormones
Identifying Neurotransmitters
Types of Neurotransmitters
Drug Actions at the Synapse
Agonists and Antagonists
Neurotransmitter Production
Neurotransmitter Storage
Neurotransmitter Release
Receptor Effects
Reuptake Effects and Enzymatic Degradation
Basic Principles of Drug Effects
Administration of Drugs
Individual Differences in Reponse
Placebo Effects
Tolerance and Withrawal
Addiction
Effects of Psychoactive Drugs
Stimulants
Opiates
Marijuana
Other Hallucinogens
Alcohol
St. John’s Wort
NEUROTRANSMITTERS, NEUROMODULATORS, AND
NEUROHORMONES
● Chemical messengers fall into three general categories:
○ Neurotransmitters
○ Neuromodulators
○ neurohormones.
● Neurotransmitters act on neurons in their own immediate vicinity, generally at a
synapse.
● Neuromodulators are chemical messengers that act on neurons somewhat farther away
by diffusing away from their site of release.
● Neurohormones are capable of producing effects at target cells quite distant from their
site of release.
○ Neurohormones often travel in the blood supply to reach their final
targets.
● Regardless of the distance traveled, these chemical messengers will interact only
with other cells that have specialized receptor sites to receive them.
neurotransmitter A chemical messenger that communicates across a
synapse
neuromodulator A chemical messenger that communicates with target cells
more distant than the synapse by diffusing away from the
point of release
neurohormone A chemical messenger that communicates with target cells
at great distance, often by traveling through the
circulation
Identifying Neurotransmitters
Neurotransmitters are substances released by one cell at a synapse that produce a
reaction in a target cell.
Beyond this basic definition, neuroscientists generally agree with the following
additional criteria:
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1. A neurotransmitter must be synthesized within the neuron. small-molecule transmitters One of a group of chemical messengers that includes
2. In response to the arrival of an action potential, the substance is released in amino acids and amines.
sufficient quantities to produce an effect on the postsynaptic cell.
3. We should be able to duplicate the action of a suspected neurotransmitter neuropeptides A peptide that acts as a neurotransmitter, a
experimentally on a postsynaptic cell. neuromodulator, or a neurohormone.
4. Some mechanism exists that ends the interaction between the
neurotransmitter and the postsynaptic cell. amino acids An essential component of proteins.

● small-molecule transmitters ⇒ respond rapidly as neurotransmitters

○ neuropeptides ⇒ for the slower process of neuromodulation.

● Small-molecule transmitters ⇒ synthesized in the axon terminal

○ neuropeptides ⇒ synthesized in the cell body and must be
transported the length of the axon.

● Vesicles containing neuropeptides are used only once

● Compared to the release of small-molecule transmitters, the release of
neuropeptide vesicles requires higher levels of calcium, which in turn requires a
higher rate of action potentials reaching the axon terminal.
● Neuropeptides diffuse away from the synapse
○ the small molecule transmitters are deactivated by reuptake or
enzymes.

● Early pharmacological pioneer Henry Dale proposed that a single neuron could
contain one and only one type of neurotransmitter.
○ was only partially correct.
● Most neurons using neuropeptides also contain a small-molecule transmitter
Types of Neurotransmitter ○ In these cases, the peptide modulates the effects of the
small-molecule transmitter at the synapse
● Major neurotransmitters fall into two classes:
○ small-molecule transmitters
○ neuropeptides.
● The small-molecule transmitters can be further divided into:
○ amino acids
○ amines which are derived from amino acids.
● Neuropeptides are chains of amino acids.
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ACh.

acetylcholinesterase (AChE) An enzyme that breaks down the neurotransmitter

acetylcholine.

● ACh is the primary neurotransmitter at the neuromuscular junction, the synapse

between a neuron and a muscle fiber
○ essential to the operation of the autonomic nervous system.
● All preganglionic synapses in the autonomic nervous system use ACh as their
neurotransmitter.
The Small-Molecule Transmitters ● Postganglionic synapses in the parasympathetic division of the autonomic
nervous system also use ACh.
● A number of small-molecule substances meet all or most of the preceding criteria
specified for neurotransmitters and appear to play a vital role in ● cholinergic neurons are widely distributed in the brain.
neurotransmission: ● Major groups of cholinergic neurons located in:
○ Acetylcholine ○ basal forebrain
○ five monoamines ○ septum
○ several amino acids ○ brainstem project to the neocortex
○ energy molecule adenosine triphosphate (ATP) and its byproducts. ○ hippocampus
○ amygdala.
● Neurons that use acetylcholine (ACh) as their major neurotransmitter are
referred to as cholinergic neurons.
○ The cholingeric neuron obtains the building block choline from
dietary fats.

● A second building block, acetyl coenzyme A (acetyl CoA), results from the
metabolic activities of mitochondria, so it is abundantly present in most cells.
● The enzyme choline acetyltransferase (ChAT) acts on these two building blocks,
or precursors, to produce the neurotransmitter acetylcholine.
○ The presence of the enzyme ChAT provides a useful marker for
identifying cholinergic neurons ⇒ ChAT is found only in neurons
that produce ACh.

acetylcholine (ACh) A major small-molecule neurotransmitter used at the

neuromuscular junction, in the autonomic nervous
system, and in the central nervous system

● Cholinergic neurons also manufacture the enzyme acetylcholinesterase (AChE).

○ AChE is released into the synaptic gap, where it breaks down any
ACh in that location.
○ The choline resulting from the breakdown of ACh can then be
recaptured by the presynaptic neuron and resynthesized into more
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● Receptors are either single-step ionotropic or multiple-step metabotropic in

structure.
● Nicotinic receptors:
○ fast ionotropic receptors.
○ found at the neuromuscular junction, which is logical given the need
for speed in muscular responses.
● Muscarinic receptors:
○ slower metabotropic receptors.
● The central nervous system contains both nicotinic and muscarinic receptors, but
the muscarinic are more common
● Both types of receptors are also found in the autonomic nervous system

● The five monoamines are further divided into two subgroups:

○ catecholamines (dopamine, norepinephrine, and epinephrine)
○ indoleamines (serotonin and melatonin).
● All of the monoamines are subject to reuptake from the synaptic gap following
release.
● Within the axon terminal, monoamines that are not encased in vesicles are
broken down by the action of the enzyme monoamine oxidase (MAO).

monoamines One of a major group of biogenic amine

neurotransmitters, including dopamine, norepinephrine,
epinephrine, and serotonin

● Many subtypes of cholinergic receptors are found in the nervous system catecholamines A member of a group of related biogenic amines that
● Two major subtypes are known as: includes dopamine, epinephrine, and norepinephrine.
○ nicotinic receptors
○ muscarinic receptors. indoleamines One of a subgroup of monoamines, including serotonin
● These receptors take their names from substances other than ACh to which they and melatonin.
also react.
○ a nicotinic receptor responds to both ACh and to nicotine, found in monoamine oxidase (MAO) An enzyme that breaks down monoamines.
all tobacco products
○ muscarinic receptor responds to both ACh and muscarine ⇒ a ● Catecholamine synthesis begins with the amino acid tyrosine.
substance derived from the hallucinogenic (and highly poisonous) mushroom ○ All neurons containing a catecholamine also contain the enzyme
Amanita muscaria tyrosine hydroxylase (TH).
○ When TH acts on tyrosine ⇒ the end product is L-dopa (L-
nicotinic receptors A postsynaptic receptor that responds to nicotine and dihydroxyphenylalanine).
ACh ● The production of dopamine requires one step following the synthesis of L-dopa.
○ The enzyme dopa decarboxylase acts on L-dopa to produce
muscarinic receptors A postsynaptic receptor that responds to both ACh and dopamine.
muscarine ○ Dopamine is converted to norepinephrine by the action of the

enzyme dopamine β-hydroxylase (DBH).
○ This last step takes place within the synaptic vesicles.
○ Finally, the catecholamine epinephrine is produced by the reaction
between norepinephrine and the enzyme phenylethanolamine
N-methyltransferase (PNMT).
● The synthesis of epinephrine is complicated.
○ PNMT exists in the intracellular fluid of the axon terminal of neurons
that use epinephrine.
○ Once norepinephrine is synthesized within synaptic vesicles, it must
be released back into the intracellular fluid, where it is converted by
PNMT into epinephrine.
○ The epinephrine is then transported back into vesicles.
L-dopa (L- A substance produced during the synthesis of
dihydroxyphenylalanine) catecholamines that is also administered as a treatment
for Parkinson’s disease.
dopamine A major monoamine and catecholamine neurotransmitter
implicated in motor control, reward, and psychosis.
norepinephrine A major monoamine and catecholamine
neurotransmitter.
epinephrine One of the monoamine/ catecholamine neurotransmitters;
also known as adrenaline.
Catecholamines Share a Common
Synthesis Pathway
The catecholamines, including dopamine,
norepinephrine, and epinephrine, are synthesized from
the substrate tyrosine. Tyrosine is converted into
L-dopa by the action of tyrosine hydroxylase. L-dopa is
converted into dopamine by dopa decarboxylase. The
action of dopamine β-hydroxylase on dopamine
produces norepinephrine. When norepinephrine reacts
with phenylethanolamine N- methyltransferase,
epinephrine is produced.
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● Dopamine is widely distributed throughout the brain
○ involved with systems mediating movement, reinforcement, and
planning.
● Three major dopamine pathways originate in the midbrain:
● Projections from the substantia nigra of the midbrain to the basal ganglia of the
cerebral hemispheres provide an important modulation of motor activity.
○ This pathway appears to be particularly damaged in cases of
Parkinson’s disease, in which patients have great difficulties
initiating movement
● Another dopaminergic pathway, the mesolimbic system, arises in the ventral
tegmentum of the midbrain and projects to various parts of the limbic system,
including the:
■ Hippocampus
■ Amygdala
■ Nucleus accumbens.
○ The mesolimbic system participates in feelings of reward, and it
plays an important role in addiction.
● Another group of dopaminergic neurons in the ventral tegmentum projects to
parts of the frontal lobe of the cerebral cortex.
○ These neurons participate in higher-level cognitive functions,
including the planning of behavior.
● multiple receptor subtypes also exist for dopamine, labeled D1 through D5 in
order of their discovery.
○ All of these receptors are of the slow metabotropic variety.
○ D2 receptors ⇒ serve as both postsynaptic receptors and presynaptic
autoreceptors.
● autoreceptors help the presynaptic neuron monitor its synthesis and release of
neurotransmitter substance.
● The D2 receptor class has been implicated in both reward and psychotic behavior
● Epinephrine ⇒ adrenalin
● Norepinephrine ⇒ noradrenalin
● Neurons releasing epinephrine ⇒ adrenergic
● Neurons releasing norepinephrine ⇒ noradrenergic.
● Epinephrine plays a limited role as a central nervous system neurotransmitter.
● The “adrenalin rush” we associate with stress actually results from the release of
epinephrine from the adrenal glands located above the kidneys in the lower back
into the blood supply.
● Neurons that secrete norepinephrine are found in:
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○ Pons
○ Medulla
○ Hypothalamus.
● Probably the most significant source of norepinephrine is the locus coeruleus of
the pons
○ Projections from the locus coeruleus go to the spinal cord and nearly
every major part of the brain.
○ The primary result of activity in these circuits is to increase arousal
and vigilance.
● In the peripheral nervous system, norepinephrine is found at the postganglionic
synapses of the sympathetic nervous system, which is also involved in arousal.

● There are at least four receptor types that respond to either norepinephrine or
epinephrine.
○ found in both the central nervous system and target organs that
respond to sympathetic nervous system activity and neurohormones.
● All of these receptors are metabotropic

● The synthesis of serotonin, begins with the amino acid tryptophan.

○ Tryptophan is obtained from dietary sources, including grains, meat,
and dairy products.
● Two chemical reactions are required to convert tryptophan into serotonin.
1. the action of the enzyme tryptophan hydroxylase, which converts
tryptophan to 5- hydroxytryptophan (5-HTP).
2. the 5-HTP is converted to serotonin by the action of the enzyme 5-HTP
decarboxylase.
serotonin A major monoamine and indoleamine neurotransmitter
believed to participate in the regulation of mood, sleep,
and appetite.
● Serotonergic neurons are few in number.
○ Estimates suggest there might be as few as 200,000 serotonergic
neurons in the human brain
○ Most of these neurons are located in the raphe nuclei of the
brainstem.
○ Their projections travel to the spinal cord, the cerebellum, the limbic
system, and the neocortex.
● Serotonergic activity has been implicated in a variety of behaviors, including
sleep, mood, and appetite.
● At least 15 subtypes of serotonergic receptors have been identified
○ most function as metabotropic receptors

Amino Acid Neurotransmitters.

○ Glutamate
○ Gamma-aminobutyric acid (GABA).
● Glutamate (also known as glutamic acid) is among the 20 basic amino acids that
are used to build other proteins.

gamma-aminobutyric acid A major inhibitory amino acid neurotransmitter

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(GABA) postsynaptic cell.

○ When the membrane becomes sufficiently depolarized, the
● Glutamate is the most frequently used excitatory neurotransmitter in the magnesium ions will be ejected from the NMDA receptor, allowing it
central nervous system to open.
○ synthesized from α-ketoglutarate.
■ Once released, glutamate is taken up by both neurons and
astrocytes.
● The synaptic area must be cleared of excess glutamate because extended action of
glutamate on neurons can be toxic.

● Some people appear to be oversensitive to the common food additive

monosodium glutamate (MSG), which consists of a combination of glutamate
and sodium.
● Adverse reactions include:
○ chest pain
○ headache
○ nausea
○ rapid heartbeat.
● However, the Food and Drug Administration (FDA) views MSG as a safe food
additive for most adults
● ACh receptors were named nicotinic or muscarinic.
● The three glutamate receptors are:
○ N-methyl-D-aspartate (NMDA) receptor
○ the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid
(AMPA) receptor
○ kainate receptor.
● Both the AMPA receptor, and the kainate receptor operate by controlling a
sodium channel.
● When these receptors bind a molecule of glutamate ⇒ a sodium channel opens
⇒ an EPSP is produced.
● NMDA receptors are apparently unique in that they are both voltage-dependent
and ligand-dependent.
○ they will not open unless glutamate is present and the postsynaptic
membrane is depolarized at the same time.
○ At the typical negative resting potentials of the postsynaptic neuron,
the ion channels of NMDA receptors are blocked by magnesium ions.
○ However, because NMDA and AMPA receptors are usually found
near one another on the same postsynaptic membrane, sodium
moving through the nearby AMPA receptors will depolarize the
● NMDA receptors are also unusual in their ability to allow both positively charged
sodium and calcium ions to enter the cell, which further depolarizes the cell.
● calcium activates enzyme sequences that result in structural and biochemical
changes.
○ Because of calcium’s ability to trigger lasting changes in neurons, the
NMDA receptor is thought to participate in functions such as
long-term memory.
● The action of calcium upon entering the cell is also responsible for the toxicity of
excess glutamate levels
○ As more glutamate stimulates NMDA receptors, more calcium enters
neurons.
○ The resulting excess enzyme activity can literally digest and kill the
affected neuron.
○ This process might be responsible for much damage following
strokes and in a number of brain diseases
● GABA serves as the major inhibitory neurotransmitter of the central nervous system.
○ synthesized from glutamate through the action of the enzyme
glutamic acid decarboxylase (GAD).
● There are two types of GABA receptors, referred to as GABAA and GABAB.
○ GABAA receptors, are ionotropic chloride channels, which allow
negatively charged chloride ions to enter the cell.
○ GABAB receptors are metabotropic potassium channels, which
allow positively charged potassium ions to leave the cell.
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● Hyperpolarization occurs whenever negative ions enter the cell or when positive
ions leave the cell.

● Adenosine triphosphate (ATP) and its byproducts, particularly adenosine, also

act as neurotransmitters in the central nervous system and in connections
between autonomic neurons and the vas deferens, bladder, heart, and gut.
● ATP frequently coexists in high concentrations in vesicles containing other
neurotransmitters, particularly the catecholamines.
● Adenosine inhibits the release of a wide range of classical neurotransmitters
○ ATP is involved with the perception of pain

adenosine A byproduct of adenosine triphosphate (ATP) that

functions as a neurotransmitter.

Neuropeptides

● There are at least 40 different peptides that act as neurotransmitters,

neuromodulators, and neurohormones.
● Neuropeptides often coexist in the same neuron with a small-molecule
neurotransmitter and modify its effect.
● A single neuron can contain and release several different neuropeptides.

● Among the neuropeptides are substance P, which is involved in the perception of

pain, and the endogenous morphines (endorphins), substances manufactured in the
body that act on the same receptors as opiate drugs.
● Peptides involved with digestion, including insulin and cholecystokinin (CCK),
have neurotransmitter functions in addition to their better-known impact on the
processing of nutrients
● Other peptides released from the pituitary gland, such as oxytocin and
vasopressin, act as both neurotransmitters and hormones

Drug Actions at the Synapse
Many drugs produce their psychoactive effects through actions at the synapse.
Drugs can affect synthesis of neurotransmitters, storage of neurotransmitters within
the axon terminal, neurotransmitter release, reuptake or enzyme activity following
release, and interactions with either pre- or postsynaptic receptor sites
Agonists and Antagonists
● Drugs that enhance the activity of a neurotransmitter are known as agonists.
● Drugs that reduce the activity of a neurotransmitter are known as antagonists.
● The outcome of the action of an agonist or antagonist depends on the normal
effects of the neurotransmitter.
○ If a neurotransmitter generally has an inhibitory effect on the
postsynaptic neuron
⇒ the action of an agonist would increase the amount of inhibitory
input
⇒ resulting in reduced postsynaptic activity.
● The action of an antagonist at this same synapse, interfering with the inhibitory
neurotransmitter, would result in greater than normal postsynaptic activity.
● Consider the case of caffeine. Caffeine produces behavioral stimulation.
● caffeine is an antagonist for adenosine ⇒ reduces adenosine’s effects.
○ Because adenosine typically acts as an inhibitor at the synapse,
inhibiting an inhibitor leads to behavioral excitation.
agonists Substance that promotes the activity of a neurotransmitter
antagonists Substance that reduces the action of a neurotransmitter.
Neurotransmitter Production
● Manipulating the synthesis of a neurotransmitter will affect the amount available
for release.
● Substances that promote increased production will act as agonists
● whereas substances that interfere with production will act as antagonists.
● The simplest way to boost the rate of neurotransmitter synthesis is to provide
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larger quantities of the basic building blocks, or precursors, for the
neurotransmitter.
● Serotonin levels can be raised by eating high carbohydrate meals, which result in
more tryptophan crossing the blood–brain barrier to be synthesized into
serotonin
● Drugs can exert antagonistic effects by interfering with the synthesis pathways of
neurotransmitters.
● the drug α-methyl-p-tyrosine (AMPT), which interferes with the activity of tyrosine
hydroxylase (TH).
Neurotransmitter Storage
● Certain drugs have an antagonistic effect by interfering with the storage of
neurotransmitters in vesicles within the neuron.
○ For example, the drug reserpine, used to reduce blood pressure,
interferes with the uptake of monoamines into synaptic vesicles.
○ As a result, abnormally small quantities of monoamine
neurotransmitters are available for release in response to the arrival
of action potentials.
○ Reserpine’s interference with the monoamine serotonin often results
in profound depression.
reserpine A substance derived from a plant that depletes supplies of
monoamines by interfering with the uptake of
monoamines into synaptic vesicles; used to treat high
blood pressure but often produces depression
Receptor Effects
● Drugs often modify the release of neurotransmitters in response to the arrival of
an action potential.
● Some drugs affect release by interacting with presynaptic autoreceptors.
● Other drugs interact directly with the proteins responsible for exocytosis, which
is the process responsible for the release of neurotransmitter molecules into the
synapse
● Exocytosis is promoted by agonists but blocked by antagonists.
● black widow spider venom is a cholinergic agonist, promoting greater than
normal release of ACh at the neuromuscular junction.
○ Greater release of ACh overstimulates muscle fibers, leading to
convulsions.
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○ In severe cases, the pace of release outstrips the neuron’s ability to

produce and package ACh, and the neuron essentially runs out of
neurotransmitter.
○ As a result, convulsions are followed by muscle paralysis.

● Other drugs act as antagonists by preventing neurotransmitter release.

● Powerful toxins produced by Clostridium botulinum bacteria, found in spoiled
food, prevent the release of ACh at the neuromuscular junction and at synapses of
the autonomic nervous system.
○ The resulting disease, botulism, leads rapidly to paralysis and death.

Botox® is the trade name for one of the seven botulinum toxins.
● Botox is used to paralyze muscles to prevent the formation of wrinkles and to
treat a variety of medical conditions involving excess muscle tension.
○ Concerns have been raised about the ability of Botox to move from
the injection site back to the brain, using retrograde transport in
neurons

botulism A fatal condition produced by bacteria in spoiled food, in

which a toxin produced by the bacteria prevents the
release of ACh

Drug Interactions at the Cholinergic Synapse

Drugs can interact with many ongoing processes at the synapse. Agonists at the cholinergic synapse, which
appear in green, include black widow spider venom, nicotine, and dietary choline. Spider venom enhances
ACh release, and nicotine activates ACh receptors. Increased intake of dietary choline can increase
production of ACh. Antagonists, which appear in red, include botulin toxin, curare, and organophosphates.
Botulin toxin blocks the release of ACh, and curare blocks ACh receptors. Organophosphates break down
the enzyme AChE, so they technically serve as ACh agonists. Although a reduction in AChE activity might
initially boost ACh activity, it eventually has a toxic effect on ACh receptors

Receptor Effects

● By far, the greatest number of drug interactions occur at the receptor.

● In some cases, drugs are similar enough in chemical composition to mimic the
action of neurotransmitters at the receptor site.
● In other cases, drugs can block synaptic activity by occupying a binding site on a
receptor without activating the receptor.
● Many receptors have multiple types of binding sites.
○ Drugs that occupy one or more of these sites can indirectly influence
the activity of the receptor.

● Using the lock-and-key analogy of receptor site activity, both neurotransmitters
and agonists at the receptor site act like keys that can open locks.
○ Antagonists act like a poorly made key that fits in the lock but fails to
open it.
● The nicotinic and muscarinic receptors received their names due to their ability
to respond to both ACh and nicotine or to both ACh and muscarine, respectively.
● Both nicotine and muscarine are classified as cholinergic agonists.
● Other drugs, such as curare, act by blocking these receptors.
○ Curare is derived from plant species found in the Amazon
● A number of important drugs exert their influence on the GABAA receptor.
● The purpose for these multiple binding sites is not currently understood.
● Although only one binding site is activated by GABA itself, there are at least five
other binding sites on the GABAA receptor.
○ These additional sites can be activated by the benzodiazepines, a
class of tranquilizers that includes diazepam (Valium), alcohol, and
barbiturates, which are used in anesthesia and in the control of
seizures.
○ Barbiturates can single-handedly activate the GABAA receptor
without any GABA present at all
○ Benzodiazepines and alcohol increase the receptor’s response to
GABA but only when they occupy binding sites at the same time
GABA is present.
● Because GABA has a hyperpolarizing, or inhibitory, effect on postsynaptic
neurons, GABA agonists enhance inhibition.
○ The combined action of alcohol, benzodiazepines, or barbiturates at
the same GABAA receptor can produce a life-threatening level of
neural inhibition.
curare A substance derived from Amazonian plants that causes
paralysis by blocking the nicotinic ACh receptor.
benzodiazepines A major tranquilizer that acts as a GABA agonist.
barbiturates A drug that produces strong sedation by acting as a
GABA agonist
Reuptake Effects and Enzymatic Degradation
Drugs that affect the deactivation of neurotransmitters.
● Some of these drugs influence the reuptake of neurotransmitters, whereas others
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act on enzymes that break down released neurotransmitters.
● Drugs that interfere with either reuptake or enzymatic degradation of
neurotransmitters are usually powerful agonists.
● They promote the activity of the neurotransmitter by allowing more of the
released substance to stay active in the synapse for a longer period of time
● drugs that inhibit the reuptake of dopamine include--
○ Cocaine
○ Amphetamine
○ methylphenidate (Ritalin).
● Consequently, each of these drugs is a powerful dopamine agonist.
● Another important class of reuptake inhibitors includes those that act on
serotonin.
● This group includes the antidepressant medication fluoxetine (Prozac).
○ People who suffer from major depressive disorder generally have
lower than normal levels of serotonin activity.
○ With slower reuptake, existing serotonin can remain more active in
the synapse for a longer period of time, providing some relief from
symptoms of depression.
● At the cholinergic synapse, the enzyme acetylcholinesterase (AChE) deactivates
ACh.
● Organophosphates, pesticides originally developed as chemical warfare agents,
interfere with the action of AChE.
○ Although the initial effect of drugs that interfere with AChE is to
boost
● ACh activity, too much ACh at the neuromuscular junction eventually has a toxic
effect on ACh receptors.
○ The receptors stop responding to ACh, leading to paralysis and, in
some cases, death

Drug Interactions at the Dopaminergic Synapse
L-dopa serves as a dopaminergic agonist by promoting increased dopamine synthesis, and amphetamine
increases the release of dopamine. Cocaine, amphetamine, and methylphenidate are dopamine reuptake
inhibitors. Apomorphine activates dopaminergic receptors. Reserpine exerts an antagonistic effect by
interfering with the uptake of monoamines into synaptic vesicles. Some medications used to treat
schizophrenia block dopaminergic receptors.
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Drug Interactions at the Serotonergic Synapse
Agonists at the serotonergic synapse include tryptophans, MDMA (ecstasy), many headache remedies,
MAO inhibitors, and selective serotonin reuptake inhibitors (SSRIs), including Prozac. Antagonists for
serotonin include reserpine and some medications used to treat negative symptoms of schizophrenia.
“Negative” symptoms of schizophrenia include social withdrawal and lack of initiative
BASIC PRINCIPLES OF
Administration of Drugs
● Once in the blood supply, a drug’s effects are dependent on its concentration.
● Your body has several protective mechanisms designed to deactivate toxins.
○ The liver uses enzymes to deactivate substances in the blood.
● The blood–brain barrier prevents many toxins from entering the tissues of the
nervous system.
● The area postrema, located in the lower brainstem, reacts to the presence of
circulating toxins by initiating a vomiting reflex.
○ In some cases involving ingested toxins, vomiting clears the stomach
and prevents further damage.

area postrema A brainstem area, in which the blood–brain barrier is
more permeable, that triggers vomiting in response to the
detection of circulating toxins.
Individual Differences In Response
● Drug effects experienced by individuals are influenced by a number of factors,
including body weight, gender, and genetics.
● Larger bodies have more blood than smaller bodies and therefore require larger
quantities of a drug to reach an equivalent concentration.
● Gender effects can be seen in alcohol, which is diluted by the water in muscle
tissue.
○ Because a man typically has more muscle than a woman with the
same weight, the concentration of alcohol in his blood will be lower
than in hers after consuming the same number of drinks.
● Genetic differences affect a liver enzyme, aldehyde dehydrogenase (ALDH),
which participates in the metabolism of alcohol.
○ With low levels of ALDH, alcohol byproducts build up and produce
flushing, rapid heartbeat, muscle weakness, and dizziness.
○ Many Asians lack genes for one type of ALDH and therefore
experience more unpleasant symptoms associated with drinking
Placebo Effects
● Drug effects are often influenced by a user’s expectations.
○ These indirect outcomes are known as placebo effects. (A placebo,
from the Latin “I will please,” is an inactive substance.)
● Because placebo effects often show considerable variation among individuals,
researchers have not reached a consensus about their importance.
● Convincing demonstrations of placebos occur in response to pain.
○ When a participant expects a placebo to reduce pain, brain imaging
demonstrates activation of the endorphin system.
● The standard method for controlling placebo effects is the double-blind
experiment.
● The first blind refers to the participant.
● The second blind refers to the researcher.
● To prevent biased observations, the researcher will not know which participants
are receiving placebo and which are receiving the drugs until after the experiment
is concluded.
● For example, efforts to determine the relative benefits of using smoked marijuana
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for medical purposes (as opposed to traditional pharmaceuticals containing
cannabinoids) are handicapped by the obvious difficulty of finding a believable
placebo.
placebo effect Perceived benefit from inactive substances or procedures
double-blind experiment A research design in which neither the participant nor the
experimenter knows whether the participant is receiving a
drug or a placebo until after the research is concluded
Tolerance And Withdrawal
● When a drug’s effects are lessened as a result of repeated administration,
tolerance has developed.
○ To obtain the desired effects, the person needs to administer greater
and greater quantities of the drug.
● Tolerance effects can occur due to—
○ changes in enzymes
○ changes at the level of the synapse such as changes in receptor
density
○ learning.
● Not all effects of the same drug show equal levels of tolerance.
○ For instance, barbiturates produce both general feelings of sedation
and depressed breathing.
○ The sedative effect of barbiturates rapidly shows tolerance, but the
depression of breathing does not.
○ As the abuser of barbiturates takes more and more of the drug to
achieve the sedative effect, he or she runs an increasing risk of death
due to breathing problems
tolerance The process in which more of a drug is needed to produce
the same effect.
● Classical conditioning associated with drug use can also produce tolerance.
● The body’s efforts to compensate for drug administration become conditioned, or
associated, with the stimuli involved with drug administration.
○ This learned component of tolerance might contribute to some cases
of drug overdose.
○ Addicts shooting up in unfamiliar locations may be more prone to
overdoses than addicts in a familiar environment
● Withdrawal occurs when use of some substances is reduced or discontinued.

● In general, withdrawal effects are the opposite of the effects caused by the
discontinued drug.
● A person in withdrawal from a sedative will become agitated, whereas a person in
withdrawal from a stimulant will become lethargic.
● It is likely that most characteristics of a withdrawal syndrome reflect the same
compensation mechanisms that are responsible for tolerance.
● drug effects and compensatory mechanisms generally cancel each other out,
leading to fairly stable behavior.
○ When the drug is no longer present, the compensation alone becomes
apparent.
● Heroin, nicotine, and even caffeine are associated with significant withdrawal
symptoms, but cocaine is not
● Symptoms of withdrawal might motivate the addict to administer the drug again,
but avoiding withdrawal symptoms is not the sole source of compulsive drug
seeking and use.
ADDICTION
● The traditional distinction made between physical and psychological dependence
has probably outlived its usefulness.
● Drugs such as cocaine are quite addictive in spite of lacking powerful signs of
physical dependence, such as an accompanying withdrawal syndrome.
● The defining feature of an addiction is the compulsive need to use the drug
repeatedly
addiction A compulsive craving for drug effects or other experience
Causes of Addiction
● A likely basis for addiction is the ability of a drug to stimulate our natural neural
systems of reward, which we experience as feelings of pleasure.
● These systems reward us for engaging in behaviors that are important either for
our personal survival or for the survival of the species.
● When we eat due to hunger, drink due to thirst, or engage in sexual behavior, the
same reward circuits of the brain are activated. Even the possibility of winning
money activates the brain’s reward circuits
● These behaviors produce activity in dopamine circuits in the brainstem and, quite
notably, in the mesolimbic system and in the nucleus accumbens
● Addictive drugs produce a variety of behavioral effects, but many share the ability
to stimulate more intense and longer-lasting dopamine release than we typically
14
see in response to environmental events
● Drugs that do not influence either dopamine or the nucleus accumbens are often
used habitually, but they do not seem to elicit the cravings and compulsive use
associated with addiction.
● LSD seems to have little if any effect on dopamine circuits at recreational doses.
● People do not seem to be addicted to LSD, although they might choose to use it
regularly.
nucleus accumbens A dopaminergic structure believed to participate in
reward and addiction.
● Considerable research evidence shows that an interruption to the mesolimbic
reward system, including the nucleus accumbens, reduces an animal’s
administration of addictive drugs.
● Animals can be addicted to drugs through regular injections.
● Once addicted, the animals will self-administer the drug by pressing a bar to
activate an intravenous dose of the drug.
● Lesions of the nucleus accumbens reduce self- administration
● In addition, selective damage to dopaminergic neurons will also reduce
self-administration.
● Because damage to dopaminergic neurons and to the nucleus accumbens reduces
drug dependency, you might be wondering why these techniques are not used to
assist human addicts as well.
● We do not treat addiction in this manner because damaging these general reward
circuits could deprive addicts of all pleasure. It’s unlikely that addicts would
choose such a course of action.
● Dopamine is not only associated with the reward aspects of addiction but also
plays a role in attention to stimuli and motivation.
● Based on imaging studies with addicts, Nora Volkow and her colleagues (2004)
speculate that continued drug abuse reduces addicts’ responses to normal
environmental rewards.
● At the same time, addicts show a hyperactive response to stimuli associated with
drug use such as the sight of drug paraphernalia.
● In addition, disrupted dopamine activity due to repeated drug abuse results in
lower levels of frontal lobe activity, which in turn can account for the poor
decision making and lack of inhibition seen in addicts.
● Although our interests center on the physical actions of drugs, we should not lose
sight of environmental factors that cause and maintain addiction.
● As the Vietnam War began to wind down, the American health system braced for

an anticipated epidemic of heroin addiction among the returning servicemen.
● Due to the obvious stress of war and the ready availability of heroin in Southeast
Asia, many soldiers had used heroin habitually.
● However, their behavior on returning to the United States took health providers
completely by surprise. Fewer than 10 percent of addicted veterans relapsed, in
contrast to the 70 percent relapse rate among young civilian addicts
Treatment of Addiction
Once an addiction has been established, it is remarkably difficult to end it..
● A variety of medications have been used to assist addicts, and many more are
under development. Methadone is frequently used to wean heroin addicts away
from their addiction. Methadone prevents withdrawal symptoms, yet it does not
produce the major psychological effects of heroin.
● Alcoholics are frequently treated with disulfiram, or Antabuse, which interferes
with the activity of the enzyme ALDH in metabolizing alcohol.
● This medication produces a number of unpleasant symptoms when alcohol is
consumed.
● other medications prevent the behavioral effects of a drug altogether, reducing
any incentive to administer the drug. Vaccinations against addiction to cocaine,
nicotine, methamphetamine, phencyclidine (PCP) and other drugs of abuse are
under development
● These vaccinations work by stimulating the immune system, which binds
molecules of the problem drug, preventing or delaying its movement from the
blood into the brain.
● Kosten and his colleagues (2002) reported that three injections of a cocaine
vaccine produced few side effects and long-term production of antibodies to
cocaine in prior users.
● If this turns out to be a feasible strategy, people at risk for addiction might
choose to be immunized.
● However, vaccinations raise troubling ethical and practical issues.
● What if a vaccinated addict simply chooses to abuse another substance? What if
vaccinations prevent responses to medical treatments such as drugs for pain
relief?
Effects of Psychoactive Drugs
Psychoactive drugs are usually administered to obtain a particular psychological
effect.
15
By definition, these drugs circumvent the protective systems of the blood–brain
barrier to gain access to the central nervous system.
Stimulants
Stimulant drugs share the capacity to increase alertness and mobility.
As a result, these drugs have been widely embraced among cultures, such as our own,
in which productivity and hard work are valued.
Caffeine
For most people, caffeine increases blood pressure and heart rate, improves
concentration, and wards off sleepiness.
The substance is found in tea, coffee, cola drinks, and a number of over-the-counter
pain relievers.
● Caffeine produces its behavioral effects by acting as an antagonist for adenosine.
● Caffeine produces excitation by blocking adenosine receptors, reducing the
normal inhibitory activity of adenosine.
● Caffeine’s interference with adenosine’s inhibition in the hippocampus and
neocortex probably accounts for the alertness associated with its use.
● Interference with normal adenosine activity in the basal ganglia produces
improvements in reaction time.
● Caffeine is addictive in the sense that it produces a withdrawal syndrome.
Because caffeine reduces blood circulation to the brain, withdrawal can produce
severe headaches due to suddenly increased blood flow.
● Not too surprisingly, caffeine withdrawal also produces feelings of fatigue. Some
people experience cardiac arrhythmias in response to caffeine.
● Because caffeine crosses the placenta easily, and the fetus and newborn are
relatively unable to metabolize caffeine, it is prudent for pregnant and nursing
women to abstain from all sources of caffeine and related compounds
● Caffeine use is correlated with lower rates of Parkinson’s diseaseIt is possible that
personality or lifestyle factors associated with caffeine use are responsible for this
correlation, but evidence for caffeine’s ability to protect neurons from
Parkinson’s-like damage has been reported in animals
● A Parkinson’s-like syndrome can be artificially produced by injecting mice with a
toxin known as MPTP, which reduces dopamine levels in the basal ganglia. If the
MPTP injections are preceded by caffeine, little or no drop in dopamine occurs

● Although such research is far too premature to justify advocating coffee drinking
to prevent Parkinson’s disease, it is certainly intriguing.
Nicotine
● After caffeine, the most commonly used stimulant in the United States is
nicotine, usually delivered in the form of smoking or chewing tobacco. Nicotine
increases heart rate and blood pressure, promotes the release of adrenaline into
the circulation, reduces fatigue, and heightens cognitive performance. In the
peripheral nervous system, nicotine produces muscular relaxation.
● In spite of the known negative consequences of smoking, nicotine continues to be
a widely used substance, particularly among American youth.
● One of the most remarkable statistics regarding nicotine is that nearly half of the
cigarettes in the United States are consumed by people with diagnosable mental
disorders
● Several explanations might account for these data.
● People with mental illnesses could be seeking to relieve their symptoms through
the use of nicotine More troubling are suggestions that nicotine use actually
contributes to the development of mental illnesses, especially depression
● Nicotine has its primary effect as an agonist at the nicotinic cholinergic receptor.
● These receptors exist not only at the neuromuscular junction but also at several
locations in the brain.
● Nicotine’s action on the cholinergic system arising in the basal forebrain,
described earlier, is probably responsible for increased alertness and cognitive
performance.
● In addition to its effects on cholinergic systems, nicotine also stimulates
dopaminergic neurons in the nucleus accumbens
● This action on the nucleus accumbens is the likely source of the addictive
properties of nicotine.
● Symptoms of withdrawal include inability to concentrate and restlessness.
nicotine A stimulant drug that is the major active component
found in tobacco.
Cocaine and Amphetamine
● The behavioral effects of cocaine and amphetamine are quite similar to one
another because both drugs are powerful dopamine agonists. These drugs are
among the most addictive drugs known.
● A single recreational dose of cocaine is sufficient to produce addiction in mice
16
● In spite of the similarity in behavioral outcomes, the modes of action for these
drugs are somewhat different.
● Cocaine acts as a dopamine reuptake inhibitor, whereas amphetamine has a dual
action at synapses that use dopamine and norepinephrine.
● Amphetamine, and its widely abused form known as methamphetamine,
stimulate dopamine and norepinephrine release and inhibit their reuptake.
● The result of the use of these drugs is higher activity at dopaminergic synapses.
● At lower doses, these drugs produce alertness, elevated mood, confidence, and a
sense of well-being. At higher doses, these drugs can produce symptoms that are
similar to schizophrenia
● Users often experience hallucinations, particularly in the form of tactile
sensations such as feeling bugs on the skin.
● They frequently suffer from paranoid delusions, thinking that others wish to
harm them.
● In some cases, they show repetitive motor behaviors, particularly chewing
movements or grinding of the teeth.
● Methamphetamine users are at least 11 times more likely to experience these
psychotic symptoms than nonusers
cocaine A powerful, addictive dopamine agonist derived from the
leaves of the coca plant of South America.
amphetamine A highly addictive drug that acts as a potent dopamine
agonist.
methamphetamine A variation of amphetamine that is cheaply produced and
widely abused in the United States.
● Cocaine was originally used by the indigenous people of Peru as a mild stimulant
and appetite suppressant.
● Sigmund Freud recommended cocaine as an antidepressant in his 1885 book,
Über Coca (On Coca).
● Freud became disenchanted with the drug after he became aware of its potential
for addiction. Historically, many popular products contained some form of
cocaine
● The original formulation of Coca-Cola included extracts of the coca leaf.
○ When cocaine was designated as an illegal substance, Coca-Cola
simply substituted caffeine to compensate for the missing stimulant
while retaining the remaining extracts of the coca leaf in its highly
guarded secret formula.

● Amphetamine was originally developed as a treatment for asthma. Inhalers
containing amphetamine were sold without prescription throughout the 1940s in
spite of the fact that people were opening the inhalers and ingesting the contents.
● During the past 50 years, amphetamine has been widely used by pilots and
military personnel to ward off fatigue.
● In the 1960s, many Americans received prescriptions for amphetamine as a diet
aid because it does suppress appetite.
● More recently, methamphetamine has emerged as a major drug of abuse, due to
its cheap and easy manufacturing process. Long-term use in humans leads to
extensive neural damage, in addition to the more obvious loss of teeth
Clubs Drugs: Ecstasy and GHB
● MDMA (3,4-methylenedioxymethamphetamine, or ecstasy) is a currently popular
relative of amphetamine among youth.
● Structurally, MDMA is similar to both methamphetamine and the hallucinogen
mescaline. MDMA increases heart rate, blood pressure, and body temperature for
a period of about three to six hours.
● In some cases, dehydration, exhaustion, hypothermia, and convulsions occur
● MDMA appears to produce increased sociability by stimulating the release of
serotonin and the neurohormone oxytocin
Ecstasy (MDMA) A close relative of amphetamine that produces its
behavioral effects by stimulating the release of serotonin.
● MDMA is toxic to serotonergic neurons in humans and other animals,
● Using PET scans, researchers have demonstrated that the neurons of people
using MDMA are less able to bind serotonin, even after lengthy periods of
abstinence
● The reduction in sensitivity to serotonin is probably responsible for the
depression frequently experienced as a result of MDMA use In addition to
producing depression, MDMA use leads to significant memory deficits for at
least two years following the last dose
● Although some psychodynamic (Freudian) therapists have claimed that MDMA
has potential benefits in psychotherapy, particularly for post-traumatic stress
disorder (PTSD), research evidence for such benefits is lacking
● Gamma-hydroxybutyrate (GHB) is a liquid sedative rather than a stimulant.
● However, because it is often taken in conjunction with MDMA, it makes sense to
include it in our current discussion.
● GHB is a naturally occurring substance that is similar in structure to GABA.
17
● Use of GHB moved from the bodybuilding community, where it was marketed as
a diet aid and muscle builder, to the club scene due to its ability to produce
alcohol-like intoxication.
● GHB is also known as a “date rape” drug due to its sedative action. GHB is
responsible for a hazardous withdrawal syndrome similar to that found in chronic
alcoholics.
● Because of its ability to mimic the inhibitory effects of GABA, it is particularly
dangerous when combined with alcohol and other GABA agonists
gamma-hydroxybutyrate An illegal liquid sedative that appears to affect the
(GHB) thresholds of response for a number of neurotransmitters.
Opiates
● Among the natural psychoactive substances found in the sap of the opium poppy
(Papaver somniferum) are morphine and codeine.
● Heroin is synthesized from morphine.
● Opiates have legitimate medical purposes, including pain management, cough
suppression, and the treatment of diarrhea.
● Before opiates became illegal in the United States around the time of World War
I, many medicinal remedies, such as the opium-alcohol mix known as laudanum,
were widely used by Americans in all walks of life.
● Illegal opiate use is fairly steady worldwide, with about 8 million users, or 0.14
percent of the population.
● Oxycodone hydrochloride (Oxycontin), a relatively new opiate painkiller, has been
responsible for a wave of opiate abuse in the United States.
● Rates of nonprescription Oxycontin use among 12th graders rose 40 percent
between 2002 and 2005 (NIDA, 2006)
● At low doses, such as those typically used in medicine, opiates produce a sense of
euphoria, pain relief, a lack of anxiety, muscle relaxation, and sleep.
● Higher doses characteristic of abuse produce a tremendous euphoria or rush.
● The physical mechanism for this response is unclear. With yet higher doses,
opiates depress respiration, potentially leading to death.
● Pert, Snowman, and Snyder (1974) identified three receptors in the brain that bind
with opiates.
● neuropeptides produced within the body that activated the opiate receptors in the
vas deferens of mice
● named these neuropeptides endogenous morphines, shortened to endorphins.
● Why would we have naturally occurring substances similar to opiates? These

endorphins probably help us escape emergency situations in spite of extreme
pain.
● Opiates mimic the effects of our bodies’ own endorphins at the opiate receptors
morphine A compound extracted from opium, used to treat pain.
codeine An opium derivative used medicinally for cough
suppression and pain relief.
opiate An active substance derived from the opium poppy
endorphins A naturally occurring neuropeptide that is very closely
related to opioids
Marijuana
● Cannabis, from the Cannabis sativa, or hemp plantis another drug with a long
human history.
● It was included in the pharmacy written by Chinese emperor Shen Neng nearly
5,000 years ago.
● Marco Polo’s writings documented the rituals of the Hashashins, young men in
the Middle East who used cannabis to prepare for war.The name of this group is
the source of our English word, assassins.
● Cannabis first appeared in Europe when Napoleon’s soldiers brought it back to
Paris from Egypt.
● Marijuana, the smoked form of cannabis, came to the United States in the early
1900s.
● Marijuana experienced a huge increase in use during the 1960s and remains the
most commonly used illegal substance in the United States today.
● The behavioral effects of cannabis are often so subtle that many people report no
changes at all in response to its use.
● Most individuals experience some excitation and mild euphoria, but others
experience depression and social withdrawal.
● At higher doses, cannabis produces hallucinations, leading to its classification as
a hallucinogen. Marijuana’s ability to control nausea has led to a controversy
regarding its use as a legal medicine.
● Although the components of marijuana that suppress nausea are available by
prescription in pill form, advocates for medical marijuana argue that the effect of
the pills is not as robust as smoking marijuana
● As we mentioned earlier, it is virtually impossible to devise the double-blind
experiments needed to resolve this issue scientifically.
18
● Cannabis contains over 50 psychoactive compounds, known as cannabinoids.
● Cannabinoids have been implicated in a wide variety of processes, including pain,
appetite, learning, and movement. The most important of these is
tetrahydrocannabinol (THC).
● THC produces some of its behavioral effects by serving as an agonist at receptors
for endogenous cannabinoids, substances produced within the body that are very
similar to THC in chemical composition.
● Two types of cannabinoid receptors have been identified, CB1 and CB2, that
interact primarily with endogenous cannabinoids, anandamide and sn-2
arachidonylglycerol (2-AG), respectively
● CB1 receptors are found in the basal ganglia, cerebellum, and neocortex but are
especially numerous in the hippocampus and prefrontal cortex.
tetrahydrocannabinol (THC) The major ingredient of cannabis
anandamide A naturally occurring brain chemical that interacts with
cannabinoid receptors.
sn-2 arachidonylglycerol A possible candidate for a naturally occurring
(2-AG) cannabinoid in the nervous system.
● The presence of cannabinoid receptors in the hippocampus and prefrontal cortex
might explain why THC appears to have negative effects on memory formation
● In addition to directly activating cannabinoid receptors in the hippocampus,
THC might also adversely influence hippocampal activity by inhibiting glutamate
release
● Because THC has the ability to produce dopamine release at the nucleus
accumbens, it has the potential to produce dependency
● Marijuana uniquely distorts a person’s sense of time, distance, and speed. Within
2 hours of smoking, impairment of driving ability is similar to people with a
blood alcohol level greater than 0.1, or those who would be legally too drunk to
drive
● Marijuana is probably not a good choice for those who have a family history of
schizophrenia
● A 25-year longitudinal study indicated that daily cannabis use nearly doubled the
risk of psychotic symptoms in young people under the age of 25 years
Other Hallucinogens
● Hallucinogens share the ability to produce hallucinations, or false perceptions.
Eastern mystic religions, with their ritualistic use of hallucinogens, were

introduced to Europe as a result of early commerce with India and Asia
Mushrooms
● Among the most ancient hallucinogens is the Amanita muscaria mushroom,
which was used for religious purposes across Scandinavia and Siberia.
● The Amanita mushroom is the source of two psychoactive substances, muscimol
and ibotenic acid.
● Muscimol acts as a GABA agonist, whereas ibotenic acid acts as an agonist for
glutamate
● Muscimol’s ability to promote the inhibitory action of GABA leads to vivid
hallucination. Western-hemisphere mushrooms contain psilocin and psilocybin.
● Psilocybin acts as a serotonin agonist that produces vivid visual hallucinations
and a psychotic state similar to a first episode of schizophrenia
Mescaline
● The green peyote cactus (Lophophora williamsii) is a source for mescaline, which
was popularized by Aldous Huxley in his book The Doors of Perception (1954).
● Like many hallucinogens, mescaline appears to act on serotonergic neurons, but
the exact mechanism of action is not known
mescaline The active hallucinogenic ingredient found in the peyote
cactus.
Phencyclidine (PCP)
● Phencyclidine (PCP) produces a particularly unpleasant set of symptoms. In
addition to experiencing vivid hallucinations, users often become aggressive to
the point of being physically violent, and muscular tone is either rigid or too
flexible.
● High doses can cause coma or convulsions. PCP acts as an antagonist at the
NMDA glutamate receptor. In addition, PCP serves as a dopamine agonist by
promoting release.
● Because this drug often leads to a schizophrenia-like psychosis, it has been
suggested that schizophrenia might involve both dopamine and glutamate activity
Phencyclidine (PCP) A hallucinogen that acts as an antagonist at the NMDA
glutamate receptor
LSD
19
● In 1938, the researcher Albert Hoffman reported some unusual sensations after
absorbing a compound, lysergic acid diethylamide (LSD), through his skin.
● LSD moved out of the laboratory and into the community after Timothy Leary
and other investigators at Harvard University began experimenting with the drug.
● Hollywood embraced the new drug, and actor Cary Grant and others used LSD in
psychotherapy
● The glamour surrounding LSD didn’t last long. It became associated with the
infamous killing rampages of Charles Manson and his followers.
● Timothy Leary was sent to jail, and LSD was classified as a Schedule I drug,
having no known medicinal value.
lysergic acid diethylamide A hallucinogenic drug that resembles serotonin.
(LSD)
● LSD is chemically similar to serotonin and, along with other hallucinogens,
appears to act as a serotonergic agonist in the cerebral cortex (
● However, LSD’s ability to produce hallucination remains poorly understood. LSD
produces tolerance but not withdrawal It does not appear to cause addiction,
although users might administer the drug habitually out of preference for the
effects.
● A major but uncommon negative consequence of LSD use is the experience of
flashbacks, intrusive and unwanted hallucinations, which can continue long after
the person has stopped using the substance
● The occurrence of flashbacks suggests that LSD produces some long-term
changes in brain function, but the nature of these changes is not currently
understood.
Alcohol
● At lower doses, alcohol dilates blood vessels, providing a warm, flushed feeling. It
reduces anxiety, promotes assertiveness, and reduces behavioral inhibitions,
causing people’s behavior to be “silly” or “fun.”
● At higher doses, however, assertiveness becomes aggression, and disinhibition
can lead to overtly risky behaviors. Motor coordination drops, leading to the
alcohol-induced carnage on streets and highways.
● At very high doses, coma and death can result from suppression of respiration or
aspiration of vomit.
● Alcohol can be quite addictive.
○ A family history of alcoholism is associated with a 300 percent
increase in the risk of alcoholism
 20

● Alcohol produces its main effects by acting as an agonist at the GABAA receptor,
which normally produces neural inhibition.
● Alcohol’s antianxiety and sedative effects, which are not unlike those caused by
the benzodiazepines, probably result from action at this site.
● Alcohol also stimulates dopaminergic pathways, which might explain the
euphoric and addictive qualities of the drug.
● Alcohol’s antagonism at the NMDA glutamate receptor might produce the
characteristic memory problems associated with alcohol.
● Alcohol appears to act on opiate receptors as well. Administration of the opiate
antagonist naloxone reduces alcohol consumption (Froelich, Harts, Lumeng, & Li,
1990)
as ephedrine have only recently been banned.
● St. John’s wort has been widely used as an antidepressant at least since the
Middle Ages. Its active ingredient, hypericin, acts as a serotonin reuptake
inhibitor.
● In addition, hypericin inhibits monoamine oxidase, an enzyme that breaks down
all of the monoamines, including serotonin.
● Controlled research has suggested that St. John’s wort is effective in cases of mild
depression but not in cases of more severe depression
● St. John’s wort is notable for its frequent adverse interactions with other
traditional medicines, including chemotherapy

● Alcohol produces rapid tolerance. St.John’s wort An herb that is frequently used to selftreat mild
● One source of tolerance is an increase in the production of liver enzymes that depressio
eliminate alcohol from the system. Another source of tolerance is changes in
receptor number and characteristics, especially at the GABAA receptor and the
NMDA glutamate receptor.
● These changes produce a dramatic and possibly life-threatening withdrawal
syndrome. The person will experience sweating, nausea and vomiting,
sleeplessness, and anxiety. In some cases, hallucinations and dangerous seizures
occur.

● Alcohol has a number of detrimental effects on health.

● Chronic use of alcohol damages several areas of the brain, including the frontal
lobes, which are responsible for many of our higher-order cognitive functions
● Alcoholism can lead indirectly to Korsakoff ’s syndrome, in which the ability to
form new memories is impaired. The lack of dietary thiamine (vitamin B1)
common among alcoholics leads to damage to the hippocampus
● Alcohol can also have devastating effects on the developing fetus, which are
explained more fully in Chapter 5. In addition, as little as a half ounce of alcohol
per day significantly raises the risk of breast cancer for women with a genetic
vulnerability for the disease
● Countering these health concerns are findings that light to moderate alcohol
consumption (about ½ drink per day) is correlated with reduced risk for heart
disease

St. John’s Wort

● Dozens of herbal products are currently available in the United States.

● Few of these substances have undergone the type of testing and evaluation given
to prescription drugs prior to approval. Consequently, dangerous chemicals such