Download Nervous System

PSYCHOPHARMACOLOGY
• The scientific study of psychoactive drugs
and their effects.
General Principles of
Psychopharmacology
• 1. Drug use in of itself is neither good nor
bad…it just is.
– Let’s study the phenomena objectively, without preconceived moral judgment.
• 2. All drugs have multiple effects
– Therapeutic and side-effects may be context dependent..i.e. SSRIs may
be used as a sleep aid, or drowsiness may be seen as a side effect.
General Principles of
Psychopharmacology
3. Drugs do not produce effects that are
outside the organisms behavioral repertoire.
– Instead they may magnify or diminish “normal behaviors, or alter
the probability or context of responses, etc..
4. Drug effects are influenced by “nonspecific” factors
– In many cases the environmental context may alter a drugs’ effects. The
physiological state and Psychological “set” of the individual may also
have major influences.
Non-specific Factors
• “Set”
The physiological and psychological state
of the user.
Setting
The environment and social context in
which the drug is taken
Cigarettes to “get going” or to
“chill out”
Non-specific drug effects cont’
The “Placebo Effect”
Effects NOT based on specific biological actions of
the drug, but instead are produced in some way by the
Expectations of the user.
Placebo Effect• Placebo- Latin for "I shall please.”
• A placebo is an inert substance,..sugar pill..sham
medication
• Typically about 35% + of subjects are responsive.
• Has been effective in treating Pain, anxiety,
depression, etc.
• Some people may even experience placebo side
effects/withdrawal
General Principles of
Psychopharmacology
Drug Effects are influenced by
“Pharmacokinetics
Pharmacokinetics
– the influences of route of drug administration,
drug absorption, drug distribution, drug
transformation, and drug elimination.
– These factors influence how fast and how
much of a drug gets to its’ sites of action, as
well as the duration of a drugs’ effects.
General Principles of
Psychopharmacology cont’
• Psychokinetic studies clearly indicate that
drug effects are:
• 5. Dose-dependent
– Consider the effects of mild coffee vs espresso!
General Principles of
Psychopharmacology
• 6. Drug Effects are Time-Dependent
– Consider early intoxication vs late
Early
Later
Way Late
Drug Effects are influenced by
“Pharmacodynamics”
• Drug effects on the target tissue
• psychoactive drugs produce effects in the central
nervous system (CNS)
– Many psychoactive drugs bind to
“Neurotransmitter receptors”
• And alter the activity of brain cells ( neurons) and their functional
relationships with other neurons
• More on this later
General Principles of
Psychopharmacology cont’
• Pharmacodynamic studies clearly indicate
that drug effects are:
• 7. dependent on the type of drug and its’
site of action
DRUG SITES OF ACTION
(more when we cover the nervous system)
• Different Psychoactive Drugs affect
different Neurotransmitter Systems in the
Brain that in turn have different
consequences for behavior, thought and
mood.
Classical Neurotransmitters
• Acetylcholine
– In the brain, it appears to be involved in
learning/memory, attention as well as sleeping
and dreaming.
Classical Neurotransmitters
cont’
Dopamine
•implicated in movement control
– Parkinson’s Disease
•Dopamine excess may be involved in
Schizophrenia.
•involved in the “reward system of the brain.”
Classical Neurotransmitters
cont’
• Norepinephrine
– primarily involved in control of
alertness/vigilance.
– Possible involvement in mood state
Classical Neurotransmitters
cont’
• Serotonin
–plays a role in the regulation of mood
–It also has a role in the control of eating, sleep
and arousal.
Classical Neurotransmitters
cont’
• Endorphin/ Enkephalin
– Modulates the experience of pain
– Controls breathing and heart rate, cough reflex,
nausea and vomiting
– Modulates feelings of euphoria and reward
Classical Neurotransmitters
cont’
GABA
– Most prevalent inhibitory neurotransmitter in
the brain
– GABA secreted by “local” interneurons all over
the brain.
– Implicated in relaxation/anti-anxiety
More on….
Pharmacokinetics
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•
Administration
Absorption
Distribution
Biotransformation
Excretion
DRUG
ADMINISTERED
DRUG
ABSORBED
DRUG
DISTRIBUTED
DRUG
METABOLIZED
DRUG
ELIMINATED
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•
•
Routes of Administration
Oral
Intramuscular (IM)
Intraperitoneal (IP)
Intravenous (IV)
Inhalation
Intracranial (IC)
Intracerebroventricular
Topical
Inhalation- a fast route
From lungs a direct shot to brain through
carotid artery
Absorption
• Moving from the site of administration to the
bloodstream
– Drugs first travel in the bloodstream to get to sites of
action
– How fast do drugs leave the site of administration?
• Route
• Acidity/Alkalinity
• Absorption relates to bioavailability
– The amount of the drug that reaches the bloodstream
and/or site of action
Distribution
• Refers to factors influencing a drug’s ability to get
to its site of action after absorption
– First Pass effect
• Depends on route of administration
– Protein Complexing
Role of the Liver in the “First
Pass Effect.”
BRAIN
LUNGS
INTRAVENOUS
INJECTION
RIGHT
SIDE
OF
HEART
INHALATION
LEFT
SIDE
OF
HEART
ORAL
LIVER
INTESTINE
INTRAMUSCULAR
INJECTION
Protein complexing
Proteins in the bloodstream may bind to the drug and slow
or prevent its distribution
Distribution-Depot binding
Bone, Fat, Muscle, nonspecific binding of drug
..affects distribution
Distribution-Blood-brain barrier
limits drug access to brain
Biotransformation/Metabolism
Drug Metabolization – Enzymes break down the drug
molecules to prepare them for ELIMINATION
 Biotranformation occurs mainly in LIVER, but can occur in
the nervous system, or in the blood stream as well
 Enzymes break down drugs into metabolites
 Metabolites can be active or inactive
 Some drugs are not transformed at all..
Metabolism usually occurs at a
characteristic rate for a given drug
Drug Half-Lifes
The amount of time
necessary for one half of the active
compound to be metabolized
** Note most drugs obey the
law of first order Kinetics
Drug Elimination
• Drugs are excreted in a variety of ways
–
–
–
–
Urine
Breath
Feces
Sweat
• Can be excreted changed or unchanged
(alcohol vs. psylocibin)
Trace Amounts may be detectable
for long periods of time
Hence: Drug testing
Methods used by
Psychopharmacologist
Dose-Response Curve
• Plots the relation between the dose of the
drug and the size of the effect
100
75
EFFECT
50
25
0
DOSE
(DRUG AMOUNT PER UNIT OF BODY WEIGHT)
REACTION TIME
100
Seconds
75
50
25
0
DOSE ALCOHOL (g/kg)
DRC Characteristics
• Slope
– gradual versus
steep
100
80
60
% of
Maximal
Effect
40
20
0
0
200
400
600
800
Drug Dose
-Slope reflects
sensitivity of effect
to drug dose
POTENCY
THE DOSE OF A DRUG REQUIRED
TO PRODUCE A GIVEN EFFECT
(LOWER VALUE = MORE POTENT)
Maximum efficacy
upper dose where response levels out
Drug A is more Potent than Drug B
REMEMBER THAT ALL DRUGS
HAVE MULTIPLE EFFECTS……
• SO DRCs can be developed for each effect..
NUMBER OF WORDS
REMEMBERED
20
15
10
5
0
DOSE ALCOHOL (g/kg)
Aggressive Behavior
20
15
10
5
0
DOSE ALCOHOL (g/kg)
LOSS OF
CONSCIOUSNESS
% OF INDIVIDUALS
SHOWING EFFECT
100
REACTION TIME
75
50
25
0
DOSE ALCOHOL (g/kg)
COMA
DEATH
ED50
•NOT-THE
DOSE OF A DRUG
REQUIRED TO PRODUCE A 1/2
MAXIMAL EFFECT
•ED50 IS- THE
DOSE OF A DRUG
REQUIRED TO PRODUCE A GIVEN
EFFECT IN 50% OF THE
INDIVIDUALS TESTED
LD50
• THE DOSE OF A DRUG THAT WILL
PRODUCE LETHALITY IN 50% OF
THE INDIVIDUALS TESTED
LD50
20
15
NUMBER OF
DEATHS
10
5
0
10.0
30.0
DOSE MORPHINE (mg/kg)
100.0
THERAPEUTIC INDEX
• THE RATIO OF THE LD50 OF A
DRUG AND THE ED50 OF A
PARTICULAR EFFECT
LD50/ED50
Calculating the “Therapeutic
Index.”
MORPHINE
ANALGESIA
LETHALITY
20
15
10
5
ED50
0
DOSE (mg/kg)
LD50
Effective vs. Lethal Dose
• Effective Dose (ED)
– Dose level for chosen
effect in % of population
– ED50, dose in which
drug is effective for 50%
of population
• Lethal Dose (LD)
– Dose level for death in %
of population
– LD50 = lethal dose for
50% of the population
• Therapeutic Index
– LD50/ED50 - Serves as margin
of drug’s safety
– Higher ratio  more
safe/less toxic
– 20 or more = relatively
safe, 100 preferred
Drug Interactions
• Using multiple drugs increases the complexity of
the experience
– Antagonism – One drug inhibits the effect of another
drug
• Cocaine and alcohol (Pharmacodynamic)
• St. John’s Wort and Birth Control Pills (Pharmacokinetic)
– Potentiation – The two drugs together produced and
enhanced effect
• Alcohol and nicotine
Street “dynamics”
• Reality is that with illicit drugs,
pharmacodynamics is ignored
• Most drugs are diluted
– Changes ED
• Most are “cut” with dangerous compounds
– Changes LD
• Sometimes dose is too high, leading to
acute toxicity
– Potentiation and Antagonism work here
OTHER FACTORS THAT
INFLUENCE DRUG EFFECTU
Repeated useTolerance, Sensitization ,Dependence
and Withdrawal
Tolerance-Decreased response to
drug /Shifting DRC to the right
– Metabolic
• Liver enzymes
– Cellular
• Receptor down-regulation
– Learned/behavioral
• Context/cues
Tolerance cont’
• Acute vs. Protracted
– Acute is within a single administration
• Cross-tolerance
– Tolerance to one drug leads to tolerance of other drugs
in the same class.
Sensitization- Increased
response to a drug with repeated
use/Shifting DRC to the left
• Cocaine is a good example of a
drug that induces tolerance
(euphoria) and sensitization
(movement)
Cocaine-induced sensitization can
lead to, exaggerated
stereotypical behaviors and
seizures
Repeated Self-Administration
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•
•
Mesolimbic dopamine
system
Abused drugs all tend to
activate this system
3 stages
– Pleasure
– Associative learning
through classical
conditioning
– Incentive salience
•
•
Craving (wanting)
Get DA release by
cues/context alone
Animal Research Methods
• Self-administration
Behavioral Pharmacology
• Study of the relationship between the physiological actions
of drugs and their effects on behavior and psychological
function
• Uses the principles of operant and classical conditioning to
examine the effects of drugs as well as the differences and
similarities between drugs
–
–
–
–
Self-administration studies
Discrimination studies
Conditioned place preference studies
Conflict paradigm studies
Self-administration
• Train animal to press
lever for drug
administration
– All drugs shown to be
SA by animals are SA by
humans
• Alcohol
• Cocaine
• THC
Drug Discrimination
Drugs can serve as discriminative
stimuli
– Animals learn to respond in certain
ways in the presence of a drug
– Discrimination is related to
interoceptive cue
– Using these techniques, it appears
that animals classify drugs just like
humans
– Amphetamine and
cocaine alike, but
different from morphine,
while morphine is like
heroin and other opiates
Method to ask animals about the
interoceptive cues associated
with different drugs
Press left lever if on morphine >
get food
Right lever if given saline > get
food
Give new drug - is it like
morphine?
– Left lever - Yes
– Right lever - No
Conditioned Place Preference
• Pair drug administration
with a place in the
environment
• Give animal a choice of
where to hang out.
• Measure where animal
spends time
Conflict Paradigm
• Train animal to
associate both
reinforcement and
punishment with a
certain behavior
– Food and shock
w/lever press
• Administer a drug to
test effects
– Xanax
Tail-flick
test
Light
source
Hot plate
test
Drug Self Administration
Drug Development
• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
potential , at least 2 species
• Laboratory studies in humans
• Clinical trials
Institutional Review Board
• Must include physician and lawyer
• Must review all protocols involving human
participants
• Evaluate Risks/Benefits
• Voluntary, informed consent
Double-Blind- to control for
placebo effects and
experimenter bias
Neither the subject nor the
experimenter knows which
condition (drug or placebo) the
subject is in.
Drug Interactions
• Antagonism
• Additive Effects/Synergy
Drug Development
• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
potential , at least 2 species
Institutional Animal Care & Use
Committee
• Includes Veterinarian and Ethics expert
• Evaluates all proposals
• Weigh medical/scientific benefits
against risk to animals
• May refuse protocol or require changes
• Unannounced site inspections (2/yr)
Drug Development
• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
potential , at least 2 species