Chapter 4
2)
Overview of Psychopharmacology (LO 4.1)
 Psychopharmacology- is the study of
the effects of drugs on the nervous
system and behavior.
 Drug- refers to a medication; refers to
a chemical; effective in low doses
 Exogenous- produced from outside of
the body, ruling out chemical
messengers produced by the body,
such as neurotransmitters,
neuromodulators and hormones.
 Drug effects- changes we can observe
in an individual’s physiological
processes and behavior.
 Sites of action- the points at which
molecules of drugs interact with
molecules located on or in cells of the
body, thus affecting some biochemical
processes of these cells.
 Site of action of the opiates-
specialized receptors situated in the
membrane of some neurons.
Pharmacokinetics (LO 4.
 Pharmacokinetics- steps by which
drugs are (1) absorbed (2) distributed
within the body (3) metabolized and
(4) excreted.
ROUTES OF ADMINISTRATION OF
DRUGS
 Intravenous Injection (IV) – vein;
drug is absorbed and distributed
immediately; reach the brain within a
few seconds.
Disadvantage- care and skills are
really necessary in performing this:
entire dose will go to the bloodstream
at once.
 Intraperitoneal Injection (IP)-
abdomen; commonly used to
administer to laboratory animals
Disadvantage- rapid but not as
rapid as an IV injection.
 Intramuscular Injection (IM)- Large
muscle such as those found in the
upper arm, thigh, or buttocks.
 Subcutaneous Injection (SC)- space
beneath the skin.
 Oral Administration- mouth; most
common form of administering
therapeutic drugs to human.
 Sublingual Administration-
administering beneath the tongue.
 Inhalation- many general anesthetics
are gases and administered this way.
 Insufflation- Sniffed, so that they can
come in contact with nasal mucosa.
 Topical administration- absorbed
directly through skin.
  Intracerebral administration- drug Drug Effectiveness( LO 4.3)
directed into the brain- injecting into a
cerebral ventricle.  Dose response curve- measure the
effectiveness of a drug.
 Intracerebroventricular
administration (ICV)-deliver  Therapeutic Index- measure of a
antibiotics directly to the brain; used drug’s margin of safety; 2 numbers are
rarely in human. being obtained.
 50%- dose that
produces the
desired effect.
 Some chemicals cannot be
administered orally because they are
 50%- dose that
destroyed by the stomach acid or
produces toxic
digestive enzymes or because they are
effect.
not absorbed from digestive into the
bloodstream.
 Higher doses of a drug cause
increasingly larger effects until the
 Sniffing or “snorting” is different from
point of maximum effect is reached.
inhalation, they enter circulation
through the mucous membrane of the
 Drug margin of safety is reflected by
nasal passages, not the lungs.
the difference between the dose
response curve for its therapeutic
 Mucous membrane of the nasal
effects and that for its adverse side
passages also provides routes for
effects.
topical administration.
 Drug varies on their effectiveness
Distribution: Entry of drugs into the brain because of these 2 reasons.

 Lipid Solubility- determines the rate  Different drugs-

at which a drug reaches site of action even those that
within the brain; ability of fat-based produce the same
molecules to pass through cell behavioral
membrane. effects- may
have different
 Some deactivating enzymes are also sites of action.
found in blood.
 Drug vary in
 Brain also contains enzymes that their
destroy some drugs. effectiveness has
to do with the
 Enzymes transform molecules of a affinity of the
drug into other forms. drug with its site
of action.
 Sometimes, the transformed molecule
is even more active than the drug  Affinity- the readiness with which the
administered. two molecules join together- for the
sites to which they attach.
  The most desirable drug has a high
affinity for sites of action that produce
therapeutic effects and a low affinity
for sites of action that produce toxic
sides effect.
forms of learning such as classical
conditioning.
Sites of Drug Action
 Most drugs that affects behavior do so
by affecting synaptic transmission.

Effects of repeated administration( LO 4.4)  Drugs that affect synaptic

transmission are classified into two
 Tolerance- When drug administered general categories.
repeatedly and its effect diminish.
1.) Antagonist- Block or
 Sensitization- When a drug inhibit the postsynaptic effects.
administered became more and more
effective. 2.) Agonist- facilitate the
antagonist.
 Withdrawal Symptoms- primarily
the opposite of the effects of drugs  Acetylcholine- neurotransmitter that
itself. is responsible for signaling muscle
contraction in the PNS.
 When the effects of a drug alter these
systems for a prolonged time, Effects of production of neurotransmitter
compensatory mechanism begins to (LO 4.6)
produce the opposite reaction, at least
 Precursors- where most
partially compensating for the
neurotransmitters are produced;
disturbance from the optimal value.
molecule.

 Physical dependence- when a person

 L- DOPA- precursor for dopamine
has repeatedly used a drug enough to
 Neurotransmitter synthesis is
produce withdrawal symptoms when
controlled by enzymes.
they stop using it.

 2 compensatory mechanism Effects on Storage and Release of

 Involves a decrease in the
effectiveness of such
binding.
 Involves the process that
couples the receptors to
ion channels in the
membrane or to the
production of second
membrane.
Placebo Effects( LO 4.5)
 Placebo- an inactive substance
 Placebo responses can be the result of
changes in motivation, expectation or
Neurotransmitter (LO 4.7)
 Vesicle transporter- pump molecules
of the neurotransmitter across the
vesicle membrane, filling the vesicles.
 Vesicle transporters are different from
the transporters found on the terminal
membrane
 Some drugs can block vesicle
transporters by binding.
 Some drugs act as antagonists by
preventing the release of
neurotransmitters from the terminal
button.

Effects on Receptors (LO 4.8)
 Effects depend on where the receptor
is located. What’s its normal effects
are, Whether the drug activates the
receptor or block its actions.
 Receptors are the most important and
complex site of action of drugs in the
nervous system- both in pre and post
synaptic.
 Direct agonist- drug that mimics the
effect of neurotransmitter.
 Drugs that bind with postsynaptic
receptors can also serve as antagonist.
 Receptor blockers/ Direct
antagonist- Molecules of drugs bind
with the receptor but block them from
being activated. They prevent the
neurotransmitter from activating
receptors.
 Noncompetitive binding- molecules
does not compete with molecules of
the neurotransmitter for the same
binding site.
 Indirect antagonist- drug attaches to
one alternative site and prevent ion
channel from opening.
 Ultimate effect of an indirect
antagonist is similar to direct agonist
the only difference is its site of action
is different.
Neurotransmitter and Neuromodulators
 Most synaptic communication in the
brain is accomplished by 2 amino acid
neurotransmitters
1.) Glutamate (excitatory effect)
2.) GABA (inhibitory effect)
 Glycine- secondary inhibitory amino
acid neurotransmitter; found in the
spinal cord and lower brain stem.
 Most activity of local circuits of
neurons involves balances between the
excitatory and inhibitory effects of
these chemicals, which are responsible
for most of the information
transmitted from place to place within
the brain.
 All sensory organs transmit
information to the brain through axons
whose terminals release glutamate.
Neurotransmitter system
 Particular drugs can selectively affect
neurons that secrete particular
neurotransmitters, they can have
specific effects on behavior.
 Not all types of neurons are affected
by all types of drugs.
Amino Acids (LO 4.10)
 Amino acids are used for protein
synthesis.
 It is a challenge to prove that a
particular amino acid is a
neurotransmitter.
 At least 8 amino acids may serve as
neurotransmitters in the mammalian
CNS.
 Two specific amino acids that are
important because they are the most
common neurotransmitter in the CNS.
– Glutamate and GABA.
  Glutamate by itself cannot open the
calcium channel.

Glutamate

 Neurotransmitter, Production,
Reuptake and Destruction
Storage and Release
 Glutamate is removed from the
 Synthesized from a precursor synapse by excitatory amino acid
(glutamine) by enzyme transporters and broken down into its
(glutaminase) building block precursor by the
enzyme glutamine synthase.
 Vesicle glutamate
transporter- package  Failure to remove glutamate from the
glutamate into vesicles. synapse can have negative
consequences.
 Receptors
 Too much glutamate stimulation in the
4 major types of glutamate receptors synapse can produce glutamate
excitotoxicity.
3 receptors are Ionotropic/ direct
agonist
GABA
 NMDA
 Neurotransmitter, Production,
 AMPA
Storage and Release
 Kainate
1 metabotropic  Is an inhibitory
neurotransmitter, and it
 Metabotropic glumate appears to have widespread
receptor. distribution throughout the
brain and spinal cord.
 AMPA receptor- is the most common
glutamate receptor. When glutamate  GABA is produced from a
attaches to binding site, it produces precursor (glutamic acid) by
EPSP the action of an enzyme
(glutamic acid
 NMDA receptor- has special and decarboxylase, or GAD).
very important characteristics.
Contains at least 6 different binding  Reduction in GABA
sites: 4 are located on the exterior of contributes to the like hood
the receptor and 2 located deep within of seizures.
the Ion channel.
 GABA is packaged into
 Calcium serves as a second vesicles by the vesicle
messenger, binding with and GABA transporter, where it
activating various enzymes within the is stored until being released
cell. following an action potential.
  Inhibitory influence is
supplied by GABA secreting
neurons, which are present in
large numbers in the brain.
 Receptors
 Several GABA receptors have
been identified. More
specifically, many drugs
interact with the GABA A
 GABA system here. GABA A
receptors are ionotropic and
control chloride channels.
 GABA A receptors are
complex -they contain at least
five different binding sites.
 muscimol- serves
as direct agonist.
 Bicuculline-
blocks GABA
binding site.
Direct antagonist.
 Benzodiazepines-
second site of
GABA A receptor
bind with this
drug. Diazepam
and Alprazolam
drug are included.
 Alcohol binds with an as yet-
unknown site on GABA A receptor.
 Benzodiazepines are very effective
anxiolytics, or “anxiety-dissolving”
drugs.
 zolpidem (Ambien) and eszopiclone
(Lunesta), are effective sleep
medications.
 Various steroid hormones are
normally produced in the body, and
some hormones related to
progesterone, act on the steroid-
binding site of the GABA A.
 Brain does not produce valium.
 Reuptake and Destruction
 GABA is removed from synapse
by GABA transporters.
 Tiagabine (Gabitril) is a GABA
transporter antagonist used to
increase availability of GABA and
reduce the likelihood of seizures.
 Vigabatrin (Sabril) blocks the
activity of GABA
aminotransferase to increase the
amount of GABA available in the
synapse. Also used as a
therapeutic treatment for seizures
and epilepsy.
Acetylcholine (LO 4.11)
 Pathways
 Neurotransmitter and are
located throughout the brain.
 Most acetylcholine-releasing
neurons are found in specific
locations and pathways in the
CNS.
 Three pathways that received
the most attention, those
originating in the
1. Dorsolateral Pons- plays a role in REM
sleep (dreaming occurs)
2.Basal forebrain - activating cerebral cortex;
facilitating learning especially perceptual
learning.
3.Medial Septum- control the electrical
rhythms of the hippocampus and modulate its
functions: include the formation of particular
kind of memories.
 Neurotransmitter, Production,
Storage and Release
 Acetylcholine is composed of two
precursors: choline and acetyl
coenzyme A.
 choline acetyltransferase (ChAT),
is required to produce ACh from
the precursors.
 ACh is loaded into vesicles by the
vesicle Ach transporter.
 Botulinum toxin (Botox)- is
produced by Clostridium
botulinum, is an extremely potent
poison because the paralysis it can
cause leads to suffocation.
 Botox treatments involve
injections of very dilute solution
of botulinum toxin into facial
muscles to stop muscular
contractions that are causing
wrinkles in the skin.
 Receptors
 There are two types of Ach receptors:
Ionotropic and Metabotropic
1. Ionotropic ACh is stimulated
by nicotine.
2. Metabotropic Ach is stimulated
by muscarine.
 Two ACh receptors are referred to as
nicotinic receptors and muscarinic
receptors.
 Muscarinic receptors- metabotropic
in nature; control ion channels thru the
production of second messenger; their
actions are slower and more prolonged
than those of nicotinic receptors;
Predominate.
 Nicotinic receptors- found at
axoaxonic synapses in the brain,
where they produce presynaptic
facilitation.
 Ach receptors can be block by these 2
drugs:
1. Atropine- blocks muscarinic
receptors; one of its effect is reducing
saliva production.
2.Curare-blocks nicotinic
receptors; one that founds in muscle;
like botulinum toxin, this can cause
paralysis and effects are faster.

Reuptake and Destruction
 Drugs that deactivate AChE are used
for several purposes.
 If the person is given an AChE
inhibitor such as neostigmine, the
person will regain some strength
because the ACh that is released has a
more prolonged effect on the
remaining receptors.

The monoamines (LO 4.12)
 The monoamine neurotransmitters
are produced by several neuron in
the brain.
 Monoaminergic neurons thus serve
to modulate the function of
widespread regions of the brain,
increasing or decreasing the
activities of particular brain
functions.
 Monoamines are considered
“classical” neurotransmitters.
 Dopamine, norepinephrine,
epinephrine, serotonin and
histamine are five chemicals that
belongs to the family of
monoamines.
 Catecholamines- subclass of
monoamines where dopamine,
norepinephrine, and epinephrine
are belong.
Dopamine
Pathways
 Three most important dopamine
pathways originate in midbrain
structures- substantia nigra and
ventral tegmental area.
 Neo striatum- important part of
basal ganglia which involved in the
control of movement.
 Mesolimbic system- located in the
ventral tegmental area and project
their axons to several of the limbic
system.
 Mesocortical system- located in the
ventral tegmental area. Their axons
project to the prefrontal cortex.
 Substantia nigra- this region is
called “black substance” because
this region is normally stained
black with melanin.
Neurotransmitter Production, Storage,
and Release
 Catecholamine synthesis- is
somewhat complicated, but each
step is a simple one. The precursor
molecule is modified slightly, step
by step, until it achieves its final
shape.
 The major precursor for two
catecholamine neurotransmitters.
1. Tyrosine-essential amino
acid that we must obtain for our
diet: modified by the enzyme
tyrosine hydroxylase.
 Reserpine- prevents the storage of
monoamines in synaptic vesicles
by blocking the vesicle
monoamines transporter.
Receptors
 Five metabotropic types of
dopamine receptors. (D1, D2, D3,
D4, D5)
 D1 and D2- most common
receptor.
 D1 and D5- stimulation of
these receptors increases the
production of the second
messenger cyclic AMP.

 D2, D3, and D4- stimulation
of these receptors decreases
production of cyclic AMP.
 Chlorpromazine- blocks D2
receptors and alleviate some
symptoms of hallucination.
Reuptake and Destructions
 Dopamine transporters- are
responsible for removing dopamine
from the synapse.
 Cocaine and methylphenidate
simply block dopamine reuptake.
Because cocaine also blocks
voltage-dependent sodium
channels, it is sometimes used as a
topical anesthetic, especially in the
form of eye drops for eye surgery.
 Methylphenidate- used to enhance
attention and impulse control in
attention-deficit/ hyperactivity
disorder (ADHD).
Norepinephrine
Pathways
 Norepinephrine is found in both the
CNS and PNS.
 Locus coeruleus- cell bodies most
important noradrenergic system
begins here: a nucleus located in
the dorsal pons.
Neurotransmitter Production, Storage,
and Release
 Norepinephrine is synthesized from
dopamine by the enzyme dopamine
β-hydroxylase.
 Fusaric acid- inhibits the activity of
dopamine β-hydroxylase and
blocks the production of
norepinephrine without affecting
the production of dopamine.
 Axonal varicosities- beadlike
swellings of the axonal branches.
Receptors
 All adrenergic receptors are
metabotropic.
 Yohimbine- blocks the adrenergic
auto receptors, resulting in
symptoms of anxiety and increased
heart rate and blood pressure.
 Clonidine(catapres)- agonist at
the norepinephrine auto receptor,
decreasing the activity of this
system and reducing heart rate and
blood pressure.
Reuptake and Destructions
 Moclobemide- specifically blocks
MAO- A and hence serves as a
noradrenergic agonist.
Serotonin
Pathways
 Serotonin plays a role in the
regulation of mood; in the control
of eating, sleep, and arousal; and in
the regulation of pain.
 The two most important clusters of
serotonergic cell bodies are found
 in the dorsal and medial raphe
nuclei, and we will restrict our
discussion to these clusters. The
word raphe means “seam” or
“crease” and refers to the fact that
most of the raphe nuclei are found
at or near the midline “seam” of the
brain stem.
Histamine
Pathways
 The cell bodies of histaminergic
neurons are found in only one
place of the brain called
tuberomammillary nucleus.

Neurotransmitter Production, Storage,  Plays an important role in

and Release wakefulness.
 Precursor for serotonin is the
amino acid tryptophan.
 The enzyme tryptophan Neurotransmitter Production, Storage,
hydroxylase acts on tryptophan, and Release.
producing 5-HTP (5-  Histamine is produced from the
hydroxytryptophan). The enzyme amino acid precursor histidine by
5-HTP decarboxylase converts 5- the action of the enzyme histidine
HTP to 5-HT (serotonin). decarboxylase.
Receptors
 All 5-HT receptors are Receptors
metabotropic except for the 5-HT3
receptor, which is ionotropic.  Diphenhydramine- sleep aids that
contain this goal, is to cross the
blood brain barrier to produce
Reuptake and Destructions drowsiness.

 The serotonin transporter is

responsible for removing 5- HT Peptides( LO 4.13)
from the synapse.
 Peptides consist of two or more
 Fenfluramine- cause the release of amino acids linked together by
serotonin as well as inhibits its peptide bonds.
reuptake. Neurotransmitter Production, Storage,
and Release.
 MDMA(methylenedioxymethamph
etamine or ecstasy) binds with  Peptides are produced from
norepinephrine and 5-HT precursor molecules.
transporters and causes them to run
backward, releasing these  There is no mechanism for
neurotransmitters and inhibiting reuptake and recycling of peptides.
their reuptake, resulting in
excitatory and hallucinogenic
effects.
  One of the best-known families of
peptides are the endogenous
opioids.
 Opium, morphine, heroin and
oxycodone reduce pain because
they have direct effects on the
brain.
 THC produces analgesia and
sedation, stimulates appetite,
reduces nausea caused by drugs
used to treat cancer relieves asthma
attacks, decreases pressure within
the eyes in patients with glaucoma,
and reduces the symptoms of
certain motor disorders.

 Anandamide- first natural ligand

Receptors for the THC receptor.

 Enkephalines-natural ligands for

these receptors.

 3 different types of opiate

receptors- μ (mu), δ (delta), and Κ
(kappa).

 Many synthetic opiates, including

heroin, methadone, and oxycodone,
have been developed, and some are
used clinically as analgesics.

Lipids (LO 4.14)

 Endocannabinoids- natural
ligands for the receptors that are
responsible for the physiological

effects of the active ingredient in

marijuana.