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Chapter 4
Psychopharmacology
Psychopharmacology
 The study of the effects of dugs on the nervous system and on
behavior
 Q: What is a drug?
 A: “An exogenous chemical not necessary for normal cellular
functioning that significantly alters the functions of certain cells of
the body when taken in relatively low doses”
 Drug effect – the changes a drug produces in an animal’s
physiological processes and behavior
 Sites of action – the locations at which molecules of drug interact
with molecules located on or in cells of the body, thus affecting
some biochemical processes of these cells
Principles of Psychopharmacology
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Pharmacokinetics – the process by which drugs are absorbed, distributed
within the body, metabolized, and excreted
Routes of administration
 Intravenous (IV) injection – directly into a vein; fastest route
 Intraperitoneal (IP) injection – into the peritoneal cavity – the space that
surrounds the stomach, intestines, liver, and other abdominal organs
 Intramuscluar (IM) injection – into a muscle
 Subcutaneous (SC) injection – into the space beneath the skin
 Oral administration – admin into the mouth, so that it is swallowed; most
common with humans
 Sublingual admin – placing substance beneath tongue
 Intrarectal admin – into the rectum
 Inhalation – admin of a vaporous substance into lungs
 Topical admin – directly onto skin or mucous membrane
 Intracerebroventricular (ICV) admin – into one of the cerebral ventricles; to
allow for widespread distribution in the brain
Principles of Psychopharmacology
 Distribution of drugs within the body
 Several factors determine the rate at which a drug in the bloodstream
reaches sites of action within the brain:
 Lipid solubility: BBB blocks only water-soluble molecules; thus, lipidsoluble molecules can pass into brain and distribute themselves
 Depot binding – binding of a drug with various tissues of the body or with
proteins in the blood; causes drugs to not reach their site of action
 e.g. Albumin – a protein found in the blood that transports free fatty acids and
can bind with some lipid-soluble drugs
 Can delay or prolong the effects of a drug
 Inactivation and Excretion
 Drugs do not remain in body indefinitely
 Most deactivated by enzymes
 Excreted by kidneys
Drug effectiveness
 The best way to measure the
effectiveness of a drug is to
plot a dose-response curve
 Do this by giving subjects
various doses of a drug and
plotting effects
 Increasingly stronger doses of
a drug causes increasingly
larger effects, until a
maximum effect is reached
Drug effectiveness
 One measure of a drug’s margin of safety is its therapeutic index
 The ratio b/t the dose that produces the desired effect in 50% of
the animals (ED 50) and the dose that produces toxic effects in
50% of the animals (LD 50)
 The lower the therapeutic dose is, the more care must be taken
when prescribing the drug
 Why do drugs vary in effectiveness?
 Different drugs may have different sites of action
 Affinity – the readiness with which 2 molecules join together; drugs in
CNS produce effects by binding to receptors, transport molecules or
enzymes
 The higher the affinity, the lower the concentration needed to produce
effects
Effects of repeated administration
 In some cases, when a drug is administered repeatedly its effects
will diminish, i.e. develop tolerance
 e.g. heroin, once taken regularly enough, individual will suffer
withdrawal symptoms (opposite to those produced by a drug) when
they stop taking it; caused by same mech as tolerance
 Tolerance is the body’s attempt to compensate for the effects of a
drug
 In other cases, a drug will become more and more effective,
sensitization
 Less common than tolerance
 Some drug effects show tolerance while others may show
sensitization
 e.g. cocaine; repeated admin may causes more movement disorders,
while euphoric effects may show tolerance
Placebo effects
 An innocuous substance that has no specific physiological effect
 Often used for control groups in clinical drug studies
Sites of drug action
 Most drugs affecting behavior
do so by affecting synaptic
transmission:
 Antagonist – a drug that
opposes or inhibits the
effects of a particular NT on
the postsynaptic cell
 Agonist – a drug that
facilitates the effects of a
particular NT on the
postsynaptic cell
Sites of drug action
 Effects on production of NT
 precursors can increase rate of NT synthesis and release; agonist
(Step 1)
 NT synthesis is controlled by enzymes; some drugs can inactive
these enzymes, thus preventing NT production; antagonist (Step 2 in
diagram)
 Effects of storage and release of NT
 transporter molecules that fill synaptic vesicles with molecules of NT
can be blocked by a drug; thus, preventing NT to fill vesicles;
antagonist (Step 3)
 Some drugs prevent release of NT from terminal button by
deactivating proteins that help fuse vesicles to membrane; antagonist
(Step 5)
 some drugs can trigger release of NT; agonist (Step 4)
Sites of drug action
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Effects on receptors
 Some drugs can bind to postsynaptic receptors like NT
 Direct agonist – a drug that mimics the effects of a NT by binding with and
acting on a receptor (Step 6)
 Receptor blocker – a drug that binds with a receptor but does not activate it;
prevents the natural ligand from binding with the receptor (Step 7)
 Some receptors have multiple binding sites; NT can bind to main sites, while
other ligands can bind to alternative sites
 these alternative sites can be blocked by a drug, termed noncompetitive binding
 drug attached to alt site could prevent ion channels from opening; indirect antagonist
 drug attaches to alt site and facilitates opening of ion channel; indirect agonist
 some presynaptic membranes have autoreceptors that regulate amount of NT
released; stimulation of autoreceptors causes less NT to be released
 drugs that activate autoreceptors act as antagonists  less NT released (Step 8)
 drugs that block autoreceptors act as agonists  more NT released (Step 9)
Sites of drug action
 Effects on reuptake or destruction of NT
 drugs can attach to transporter molecules responsible for reuptake
and block it; thus NT in synapse for longer duration; agonist (Step 10)
 drugs can bind with enzyme that destroys NT, preventing enzyme
from working; agonist (Step 11)
Neurotransmitters and Neuromodulators
 In the brain, most synaptic communication is accomplished by 2
NT:
 One with excitatory effects: glutamate
 One with inhibitory effects: GABA
 Most of the activity of local circuits of neurons involves balances
b/t the excitatory and inhibitory effects of these chemicals
 Most other NT have modulating effects, i.e. they tend to activate or
inhibit entire circuits of neurons that are involved in particular brain
functions
Acetylcholine
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Primary NT secreted by efferent axons of the CNS
All muscular movement is accomplished by the release of ACh, also found in
ganglia of ANS and at target organs of the parasymp branch of the ANS
Involved mostly in 3 systems in brain:
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Composed of choline and acetate
Synthesis:
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Acetyl-CoA and choline are combined by choline acetyltransferase (ChAT)
2 drugs affect the release of ACh:
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Dorsolateral pons, basal forebrain, & medial septum
Botulinum toxin – ACh antagonist; prevents release by terminal buttons; found in
improperly canned food
Black widow spider venom – stimulates release of ACh
Deactivated by acetylcholinesterase (AChE), which is present in the presynaptic
membrane, and produces choline and acetate
Two types of ACh receptors:
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Nicotinic – ionotropic ACh receptor that is stimulated by nicotine and blocked by curare
Muscarinic – metabotropic ACh receptor that is stimulated by muscarine and blocked by
atropine; slower action, longer lasting
Monoamines
 Catecholamines:
 Dopamine
 Norepinephrine
 Epinephrine
 Indolamines
 Serotonin
Dopamine (DA)
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Produces both excitatory
and inhibitory postsynaptic
potentials, depending on
postsynaptic receptor
Implicated in movement,
attention, learning, and
reinforcing effects of drugs
Synthesis of
catecholamines:
1.
2.
3.
Tyrosine (obtained via
diet) converted to LDOPA by tyrosine
hydroxylase
L-DOPA converted to DA
by DOPA decarboxylase
DA converted to
Norepinephrine (NE) by
DA β-hydroxylase
Dopaminergic systems
 Nigrostriatal system – originates in the substantia nigra and
terminates in the neostriatum (caudate and putamen); control of
movement
 Mesolimbic system – originates in ventral tegmental area (VTA)
and terminates in the nucleus accumbens, amygdala, &
hippocampus; reward pathway
 Mesocortical system – originates in VTA and terminates in
prefrontal cortex; formation of STM, planning, strategies
Dopamine
 Parkinson’s disease – a neurological disease caused by
degeneration of DA neurons in nigrostriatal system; movement
disorder with symptoms of tremors, rigid limbs, poor balance,
difficulty initiating movements; individuals with Parkinson’s are
given L-DOPA as Tx
 Several types of DA subreceptors: D1 and D2 most common
 Other drugs effecting DA
 AMPT
 Reserpine
 Apomorphine
 Monoamine oxidase (MAO) – enzyme that destroys
catecholamines
Norepinephrine (NE) & Epinephrine
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Aka Noradrenaline & adrenaline
NE found in neurons in ANS
Epinephrine produced by adrenal glands
NE synthesis is finished in the vesicles of the terminal button
 DA fills the vesicles, and is then converted to NE via DA β-hydroxylase
 Fusaric acid blocks activity of this enzyme and prevents production of NE
without affecting DA
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Excess NE is destroyed by MAO, type A
Cell bodies of most important NE system are in locus coeruleus
Most noradrenergic cells release NE via axonal varicosities (beadlike
swellings of the axonal branches) instead of terminal button
Several types of subreceptors:
 β1 & β2 receptors, and α1 & α2 receptors: sensitive to both NE and epinephrine,
all metabotropic with GPCRs
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In general, behavioral effects are excitatory
Serotonin (5-HT)
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Complex behavioral effects: regulation of mood, control of eating, sleep, and
arousal, regulation of pain
Precursor is tryptophan, which is obtained through diet; converted to 5-HTP by the
enzyme tryptophan hydroxylase; which is converted to 5-HT by the enzyme 5-HTP
decarboxylase
Most 5-HT neurons found in raphe nuclei of the pons, medulla and midbrain and
project to cerebral cortex; also innervate basal ganglia, dentate gyrus and
hippocampal formation
5-HT release from varicosities rather than terminal buttons; 2 types
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D system – originates in dorsal raphe nucleus; thin axonal fibers that do not form
synapses with other neurons (i.e. 5-HT serves as modulator here)
M system – originates in median raphe nucleus; thick axonal fibers, form conventional
synapses
2 systems have different behavioral effects
At least 9 different subreceptors
Drugs that inhibit reuptake of 5-HT (SSRIs) most widely used clinically for mental
disorders (e.g. fluoxetine, or Prozac)
LSD and MDMA affects 5-HT systems
Amino Acids
 At least 8 amino acids have been suggested to serve additionally
as NT
 Glutamate
 GABA
 Glycine
 Peptides
Glutamate
 Principle excitatory NT in the CNS
 Produced in abundance, no way to disrupt synthesis without
disrupting other cellular activities
 4 types of receptors:
 NMDA – ionotropic, controls calcium channel that is normally blocked,
and allows influx of calcium so it can serve as a 2nd messenger;
involved in forming new memories
 AMPA – ionotropic, controls sodium channel, stimulated by AMPA
 Kainate – ionotropic, controls sodium channel, stimulated by kainic
acid
 Metabotropic glutamate receptor – sensitive to glutamate
 PCP – a drug that binds with the PCP binding site of the NMDA
receptor and serves as an indirect antagonist; hallucinogenic drug
GABA
 Primary inhibitory NT in CNS
 Produced from glutamic acid by the enzyme glutamic acid
decarboxylase (GAD)
 2 subreceptors:
 GABAA – have at least 5 different binding sites:
 primary for GABA, of which muscimol acts a agonist and bicuculline acts
as antagonist
 2nd binding site binds with drugs in benzodiazepines (e.g. Valium;
anxiolytic – anxiety-reducing)
 3rd binding site binds with barbituates
 GABAB
Glycine
 Inhibitory NT in SC and lower portions of brain
 Receptor is ionotropic, controls chloride channel, and thus
produces inhibitory postsynaptic potentials
 Strychnine – glycine antagonist
Peptides
 Neurons in the CNS release a large variety of peptides from all
parts of the terminal button, not just active zone, allowing
molecules to travel to other cells
 Best known family of peptides is the endogenous opioid family
(opioid refers to natural ligands, opiate to drugs)
 e.g. enkephalin
 3 types of opiate receptors:
 μ (mu)
 δ (delta)
 κ (kappa)
 Several neural systems activated: analgesic, fleeing and hiding
behaviors, reinforcement
 Naloxone – opiate receptor antagonist
Lipids
 various substances derived from lipids can serve as NT
 Cannabinoids – endogenous ligand for receptors that bind with
THC, the active ingredient in marijuana
 2 types of cannabinoid receptors: CB1 and CB2, both metabotropic
 THC produces analgesia, sedation, stimulates appetite, reduces
nausea (used with cancer treatments), aids in glaucoma; reduces
concentration and memory, alters visual and auditory perceptions,
etc.
 Anandamide – natural ligand that binds to cannabinoid receptor
Nucleosides
 compound that consists of a sugar molecule bound with a purine
or pyrimidine base
 Adenosine – serves as neuromodulator in brain, released when
cells are short of fuel or oxygen
 Agonists have general inhibitory effects on behavior
 Caffeine is antagonist, thus producing excitatory effects
Soluble gases
 Neurons use at least 2 simple, soluble gases, nitric oxide (NO)
and carbon monoxide (CO), to communicate with each other
 NO used as a messenger in many parts of the body, e.g. control
muscle walls of intestines, dilates blood vessels in brain, etc.