PSYCHOPHARMACOLOGY

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PSYCHOPHARMACOLOGY

• The scientific study of psychoactive drugs and
  their effects.

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General Principles of Psychopharmacology

• 1. Drug use in of itself is neither good nor
  badit just is.
• Lets 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.

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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 non-specific
  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.

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Non-specific Factors

• Set
• The physiological and psychological state of the
  user.
• Setting
• The environment and social context in which the
  drug is taken

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Cigarettes to get going or to chill out
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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.
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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

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General Principles of Psychopharmacology

• Drug Effects are influenced by Pharmacokinetics

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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.

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General Principles of Psychopharmacology cont

• Psychokinetic studies clearly indicate that drug
  effects are
• 5. Dose-dependent
• Consider the effects of mild coffee vs espresso!

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General Principles of Psychopharmacology

• 6. Drug Effects are Time-Dependent
• Consider early intoxication vs late

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Early
Later
Way Late
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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

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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

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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.

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Classical Neurotransmitters

• Acetylcholine
• In the brain, it appears to be involved in
  learning/memory, attention as well as sleeping
  and dreaming.

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Classical Neurotransmitters cont

• Dopamine
• implicated in movement control
• Parkinsons Disease
• Dopamine excess may be involved in Schizophrenia.
• involved in the reward system of the brain.

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Classical Neurotransmitters cont

• Norepinephrine
• primarily involved in control of
  alertness/vigilance.
• Possible involvement in mood state

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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.

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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

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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

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More on.Pharmacokinetics

• Administration
• Absorption
• Distribution
• Biotransformation
• Excretion

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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

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Inhalation- a fast route
From lungs a direct shot to brain through carotid
artery
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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

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Distribution

• Refers to factors influencing a drugs ability to
  get to its site of action after absorption
• First Pass effect
• Depends on route of administration
• Protein Complexing

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Role of the Liver in the First Pass Effect.
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BRAIN
LUNGS
INHALATION
RIGHT SIDE OF HEART
LEFT SIDE OF HEART
INTRAVENOUS INJECTION
ORAL
LIVER
INTESTINE
INTRAMUSCULAR INJECTION
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Protein complexing
Proteins in the bloodstream may bind to the drug
and slow or prevent its distribution
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Distribution-Depot binding
Bone, Fat, Muscle, non-specific binding of drug
..affects distribution
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Distribution-Blood-brain barrier limits drug
access to brain
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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..

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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
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Drug Elimination

• Drugs are excreted in a variety of ways
• Urine
• Breath
• Feces
• Sweat
• Can be excreted changed or unchanged (alcohol vs.
  psylocibin)

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Trace Amounts may be detectable for long periods
of time
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Hence Drug testing
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Methods used by Psychopharmacologist

• Dose-Response Curve
• Plots the relation between the dose of the drug
  and the size of the effect

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EFFECT
DOSE (DRUG AMOUNT PER UNIT OF BODY WEIGHT)
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REACTION TIME
Seconds
DOSE ALCOHOL (g/kg)
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DRC Characteristics

• Slope
• gradual versus steep

of Maximal Effect
Drug Dose
-Slope reflects sensitivity of effect to drug
dose
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POTENCY THE DOSE OF A DRUG REQUIRED TO
PRODUCE A GIVEN EFFECT (LOWER VALUE MORE
POTENT) Maximum efficacy upper dose
where response levels out
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Drug A is more Potent than Drug B
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REMEMBER THAT ALL DRUGS HAVE MULTIPLE EFFECTS

• SO DRCs can be developed for each effect..

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NUMBER OF WORDS REMEMBERED
DOSE ALCOHOL (g/kg)
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Aggressive Behavior
DOSE ALCOHOL (g/kg)
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LOSS OF CONSCIOUSNESS
COMA
DEATH
REACTION TIME
OF INDIVIDUALS SHOWING EFFECT
DOSE ALCOHOL (g/kg)
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• 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

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• LD50
• THE DOSE OF A DRUG THAT WILL PRODUCE
  LETHALITY IN 50 OF THE INDIVIDUALS TESTED

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LD50
NUMBER OF DEATHS
10.0
30.0
100.0
DOSE MORPHINE (mg/kg)
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• THERAPEUTIC INDEX
• THE RATIO OF THE LD50 OF A DRUG AND THE
  ED50 OF A PARTICULAR EFFECT
• LD50/ED50

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Calculating the Therapeutic Index. MORPHINE
ANALGESIA
LETHALITY
ED50
LD50
DOSE (mg/kg)
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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 drugs safety
• Higher ratio ? more safe/less toxic
• 20 or more relatively safe, 100 preferred

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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. Johns Wort and Birth Control Pills
  (Pharmacokinetic)
• Potentiation The two drugs together produced
  and enhanced effect
• Alcohol and nicotine

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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

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OTHER FACTORS THAT INFLUENCE DRUG EFFECTU

• Repeated use-
• Tolerance, Sensitization ,Dependence and
  Withdrawal

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Tolerance-Decreased response to drug /Shifting
DRC to the right

• Metabolic
• Liver enzymes
• Cellular
• Receptor down-regulation
• Learned/behavioral
• Context/cues

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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.

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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

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Repeated Self-Administration

• 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

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Animal Research Methods

• Self-administration

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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

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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

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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 gt get food
  Right lever if given saline gt get food
• Give new drug - is it like morphine?
• Left lever - Yes
• Right lever - No

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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

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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

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Drug Self Administration
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Drug Development

• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
  potential , at least 2 species
• Laboratory studies in humans
• Clinical trials

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Institutional Review Board

• Must include physician and lawyer
• Must review all protocols involving human
  participants
• Evaluate Risks/Benefits
• Voluntary, informed consent

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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.
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Drug Interactions

• Antagonism
• Additive Effects/Synergy

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Drug Development

• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
  potential , at least 2 species

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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)

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Drug Development

• Discovery of compound-in vitro tests
• Animal studies--toxicity, efficacy, abuse
  potential , at least 2 species