Pharmacology of Psychomotor Stimulants

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Pharmacology of Psychomotor Stimulants

• Lecture 5

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STIMULANTS

• An agent (as a drug) that produces a temporary
  increase of the functional activity or efficiency
  of an organism or any of its parts.
• An agent, especially a chemical agent such as
  caffeine, that temporarily arouses or accelerates
  physiological or organic activity.

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PSYCHOSTIMULANTS (Drugs that stimulate the CNS)

• Increases in heart rate, pupil dilation, oxygen
  levels rise, elevation of mood, feelings of
  euphoria, reduced fatigue, increased arousal
• Anxiety, insomnia, irritability, and possibly
  schizophrenic-like symptoms (amphetamine-induced
  psychosis)
• Amphetamines (meth), Cocaine, Caffeine, Nicotine

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STIMULANTS TYPES

• Powerful
• Dependence formation
• Criminalized use
• Socially unacceptable

• Mild
• Dependence manageable
• Legal
• Socially acceptable

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COCAINE HISTORY

• Inca empire 5000 B.C.
• Natives of the Andes (Peru, Bolivia, and
  Colombia).
• Incas used coca leaves as money.

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• Psychomotor stimulants include drugs such as
  amphetamine, methylphenidate and cocaine.
• Therapeutic use
• Amphetamines used for treatment of Narcolepsy,
  Obesity, Attention Deficit Disorder
• Cocaine has no therapeutic use but has been used
  in the past as a local anaesthetic/vasoconstrictor
  (to control bleeding)

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Current Use

• In 1997, an estimated 1.5 million Americans (0.7
  percent of those age 12 and older) were current
  cocaine users, according to the 1997 National
  Household Survey on Drug Abuse (NHSDA).

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EARLY NON-TRADITIONAL COCA USES

• Drinks, teas, wines
• Local anesthesia
• Psychiatric uses
• Coca-Cola

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COCAINE
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CRACK

• Smokable form of cocaine.
• Rapid, short-lived high.
• Price reduction

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COCAINE / AMPHETAMINES

• PHYSIOLOGICAL RESPONSES
• Increased alertness, motor hyperactivity,
  tachycardia, vasoconstriction, hypertension,
  bronchiodilation, increased body temp., pupillary
  dilation, increased glucose availability
• PSYCHOLOGICAL EFFECTS
• Immediate euphoria, giddiness, enhanced
  self-consciousness, forceful boastfulness (30
  min.)
• Mild euphoria mixed with anxiety (60-90 min.)
• Racing thoughts, rapid speech, incoherent,
  appetite suppression which rebounds, fatigue is
  decreased which rebounds, conscious awareness
  heightened followed by depression, DESIRE FOR
  MORE (hours)
• Toxicity and Psychosis hypervigilance,
  paranoia, impulsive, bizarre hallucinations,
  aggressive or homicidal, hyperthermia, stroke,
  heart attack
• MOST USERS CANNOT DISTINGUISH BETWEEN EFFECTS OF
  COCAINE AND AMPHETAMINE

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Cocaine High Dose Effects

• Increased intensity of moderate dose effects
• Aggression
• Cause of death from overdose is often
  cardiovascular problems strokes, heart attacks
• Cause of death from overdose is sometimes
  convulsions all local anaesthetics do this

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Cocaine Chronic Use

• Tolerance occurs to most effects
• Binge pattern of use
• Dependence major withdrawal symptom is
  depression
• Craving/desire for drug persists long, long,
  long after last use
• Formication feeling that bugs are crawling
  under the skin
• Paranoid psychosis
• Sensitization stereotypy and psychotic effects

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Phase 2 Withdrawal 1-10 weeks
Phase 1 Crash 9 hours 4 days
Phase 3 Extinction Indefinite
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Cocaine Pre-birth Exposure

• Infants show unusual behaviours
• Dont respond to holding, cuddling
• More irritable
• Children less than normal on alertness,
  attention, intelligence

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Cocaine toxicity

• As of today, no data convincingly demonstrate
  that cocaine destroys any part of the brain
• Substantial data suggest that cocaine changes
  how some parts of brain function may be
  permanent
• The major life-ending and health-related
  problems associated with cocaine use are a
  consequence of life-style
• Potentiates effects of AIDS virus in brain

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Cocaine Mechanism

• Increases the amount of dopamine in synapses
• Blocks the transporter (uptake pump) that
  removes dopamine from synapses

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Mechanism of action

• Increases the amount of dopamine in synapses
• Blocks the transporter (uptake pump) that
  removes dopamine from synapses
• True also for noradrenaline and serotonin

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Cocaine increases the amount of dopamine in
synapses Blocks the transporter (uptake pump)
that removes dopamine from synapses
                                   
 
Tyrosine hydroxylase
DA
Ca
Action potential
DA
DA
MAO
DA
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Amphetamine has additional mechanismsreverses
re-uptake pump, blocks MAO
MAO
DA
DA AMPH
DA
MAO
DA
X
DA
MAO
DA
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Dopamine

• Dopamine is very abundant in brain areas
• Nucleus accumbens
• Striatum (caudate/putamen)
• Pre-frontal cortex
• Dopamine apparently modulates many kinds of
  nerve activity in the brain

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• Nucleus accumbens
• Is part of the reward pathway in the brain
• One function is to coordinate motivation with
  movement
• One function is to signal when what is happening
  is different from what is expected

• Striatum
• One function is to regulate initiation of
  movement (voluntary activity)
• Is part of the brain system that controls
  movement

• Prefrontal cortex
• Is part of the decision-making/evaluation system
  of the brain
• Excessive activity of dopamine synapses in this
  area is associated with paranoid schizophrenia

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• Cocaine blocks dopamine reuptake transporter.
• Problems
• Other blockers do not produce the same effects
• Other neurotransmitters involved
• Mice with deletion of the DA transporter gene
  still self-administer cocaine
• Why?

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Psychostimulants differ from natural rewards in
effects on dopamine release
1st experience Food DA increase in
accumbens Cocaine DA increase in accumbens
2nd experience Food No DA increase in
accumbens Cocaine DA increase in accumbens
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WAYS OF USE

• Chewing leaves (Mambiar)
• Slowly absorbed
• Very low blood levels
• Snorting
• Cocaine hydrochloride
• Intravenous
• High concentration to brain
• Smoking (Crack)
• From lungs to brain, more rapid dependence than
  IV

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Drug to brainRoutes of administration
Intranasal (snorting)
Oral
Stomach/GI tract
Mucous Membrane
Blood
Liver
Blood-brain barrier
SLOW
Blood
FAST (RUSH)
Lungs
Intravenous
Inhalation (smoking)
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Why pharmacokinetics may be important in
determining abuse liability

• Less time for the body to adapt to the drug to
  oppose its effects
• If drug taking is influenced by conditioning
  process, easier to form associations with
  discrete stimuli if reinforcer event is precisely
  timed
• Ditto for instrumental conditioning

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COCAINE AND OTHER DRUGS

• Research has revealed a potentially dangerous
  interaction between cocaine and alcohol. Taken in
  combination, the two drugs are converted by the
  body to cocaethylene. Cocaethylene has a longer
  duration of action in the brain and is more toxic
  than either drug alone. While more research needs
  to be done, it is noteworthy that the mixture of
  cocaine and alcohol is the most common two-drug
  combination that results in drug-related death.

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Cocaine Self-Administration Dose Response Curve
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Psychostimulants and conditioned reinforcement
Hill (1970) put forward hypothesis of the action
of psychomotor stimulant drugs, that they enhance
the effects of conditioned reinforcers since both
retard extinction. Robbins et al (1983
Psychopharm 80 113-119 ) reported experiment in
which rats were given pairings of a visual
stimulation with presentation of water, and
subsequently trained to operate a lever to switch
on the visual stimulus in the absence of water,
i.e. for the conditioned reinforcer. Pipradol
facilitated this responding Blocked by 6-OHDA
lesions of accumbens
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Amphetamine facilitates conditioned reinforcement
Taylor Horger, Psychopharmacology 142 31-40
(1999)
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Conditioned Activation of Brain
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Amphetamine facilitates conditioned reinforcement

• Amphetamine is a reward in its own right
• Amphetamine facilitates the ability of
  environmental cues associated with rewards to
  control behaviour
• Repeated amphetamine use results in increased
  effects on conditioned reinforcement
• Effects mediated by nucleus accumbens