Caffeine Tamie Miura Psychology 760 San Diego State

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Caffeine

• Tamie Miura
• Psychology 760
• San Diego State University

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• Introduction
• Mechanism of action
• Properties of adenosine
• Pharmacodynamics of caffeine
• Pharmacokinetics of caffeine
• Effect of caffeine on neurotransmitters
• Studies on the behavioral effects of caffeine
• Tolerance
• Withdrawal and physical dependence
• Health concerns and therapeutic uses

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Caffeine

• Caffeine is often considered the most widely
  consumed stimulant in the world.
• Roughly about 80 of adults in the United States
  drink coffee or tea daily.
• Intake of caffeine also occurs from ingesting
  chocolate, cold and headache medicines and
  appetite suppressants.
• Every year in the U.S. consumers spend around 30
  million dollars on caffeine tablets and 50
  billion dollars on caffeinated soda
• Benowitz, 1990

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Amount of Caffeine Consumption

• Beverages / Food
• Cup of coffee 65-120 mg caffeine
• Espresso 1oz shot 40 mg
• Cup of tea 40-60 mg
• Can of soda 30-60 mg
• Red Bull (8.3oz) 80 mg
• Hersheys milk chocolate almond bar (6oz) 25mg
• Over the counter medicines
• No-Doze 100 200 mg
• Midol 20-100 mg
• Excedrin 30-65 mg
• Benowitz, 1990
• Total consumption of caffeine per person per day
  is estimated at
• 210 to 238 mg (Barone and Roberts, 1996)

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Chemical Properties

• Caffeine, an alkaloid of the methylxanthine
  family.
• Similar compounds included in the methylxanthine
  family are theophylline and theobromine

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Mechanism of Action

• Three main hypotheses
• 1. Mobilization of intracellular calcium
• Biphasic effect on intracellular calcium levels
• Toxic amounts of caffeine
• 2. Inhibition of phosphodiesterase
• Inhibition of enzyme that breaks down cyclic
  adenosine monophosphate (cAMP)
• Toxic amounts of caffeine
• 3. Antagonism of inhibitory presynaptic adenosine
  receptors
• Caffeine blocks adenosine receptors
• Resulting in the inhibition of the breakdown of
  cAMP
• Blocking the inhibitory effects of adenosine
• Nehlig et al., 1992

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Properties of Adenosine

• Adenosine is an endogenous inhibitory
  neurotransmitter or neuromodulator that acts on
  adenosine receptors located throughout the body
• Reduction in firing rate of neurons
• Inhibition of synaptic transmission
• Inhibition of neuronal release of many
  neurotransmitters (i.e. acetylcholine,
  norepinephrine, dopamine, serotonin, and
  glutamate)

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Subclasses of Adenosine Receptors

• Two Main subclasses
• A1 receptors high affinity for adenosine
• Located throughout the brain (hippocampus,
  thalamus, cerebral and cerebellar cortex)
• A2 receptors low affinity for adenosine
• Located mainly in the striatum, basal ganglia and
  nucleus accumbens
• A2a and A2b

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Antagonism of Adenosine Receptors

• Caffeine competitively binds to both A1 and A2a
  adenosine receptors thereby inhibiting the
  actions of adenosine resulting in an increase
  in the release/turnover of many neurotransmitters
  like monoamines and acetylcholine.
• Nehlig et al., 1992 Nehlig et al., 1999

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Pharmacodynamics
Garrett and Griffiths 1997
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Chronic Consumption of Caffeine During
Development on the Density of Adenosine Receptors

• Study by Guillet and Kellogg 1991
• Doses of caffeine given to rat pups during
  development
• 20mg/kg (postnatal day 2) and 15mg/kg (postnatal
  days 3-6)
• Density of adenosine receptors examined across
  different ages (14 90 postnatal days)
• Significant increase in specific binding after
  neonatal exposure to caffeine in the cortex,
  cerebellum, and hippocampus due to an increase in
  A1 receptors.
• Changes in A1 receptors lasted for several weeks
  after cessation of caffeine

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Chronic Consumption of Caffeine During
Development on the Density of Benzodiazepine
Receptors

• Research by Boulenger and Marangos 1989
• Mice pups were given a diet enriched with
  caffeine for 15 days
• No increase in benzodiazepine receptors, after
  chronic oral administration of caffeine.
• Controlled environment and housing to minimize
  stress
• Contradictory results on chronic caffeine
  consumption and the density of benzodiazepine
  receptors
• Stress rather than caffeine-enriched diet induces
  an upregulation of benzodiazepine receptors
• 5 10 times higher concentration of caffeine
  required to produce an antagonistic effect on
  benzodiazepine receptors than adenosine receptors

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Pharmacokinetics

• Absorption
• Gastrointestinal tract and stomach
• Rapid rate, peak blood level in 30-60 min.
• Crosses lipid-membrane (not water soluble)
• Distribution
• Diffuses throughout the organism and crosses BBB
• Including placenta and placental BBB
• Nehlig et al., 1999 Fredholm et al., 1999

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Pharmacokinetics

• Metabolism
• Metabolized through liver biotransformation
  initially by demethylation into
  dimethylxanthines.
• Dimethylxanthines are pharmacologically active
  and may add to the effects of caffeine
  consumption in humans.
• This process is unique to humans, no other animal
  species metabolizes caffeine in a similar way
• Half life of caffeine
• Three to eight hours varies with age and other
  external factors
• Newborns cannot metabolize caffeine, mainly
  eliminated by excretion
• Half life 80 /_ 23 hours
• Smokers, half life is reduced up to 50
• Pregnant women and those taking oral
  contraceptive, half life up to 15 hours longer
• Nehlig et al., 1999 Fredholm et al., 1999

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Effects of Caffeine on Neurotransmitters

• Caffeine modifies the release and turnover of
  several neurotransmitters by inhibiting
  presynaptic adenosine receptors.
• serotonin, acetylcholine, glutamate,
  norepinephrine, and dopamine
• Caffeine may also act at postsynaptic receptors.
• The threshold necessary for caffeine to induce
  changes in neurotransmitter function is an
  prominent area currently being explored to better
  understand the effects of caffeine on
  neurotransmission.

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Caffeine and Serotonin

• Increased in vitro serotonin concentrations in
  the brain stem, cerebral cortex, and cerebellum
• Inconsistent results on the impact on the rate of
  release, uptake, synthesis and turnover
• Decreased serotonin accessibility postsynaptically

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Caffeine and Acetylcholine

• Increased Ach release from the cerebral cortex
• 15 and 30 mg/kg I.P. in anesthetized rats
• Increased Ach turnover in the hippocampus
• Intracerebral injections of theophylline
• Relatively unexplored area

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Caffeine and Amino Acids

• Increased amount of glutamate in the whole brain
  of mice
• Decreased amounts of GABA and glycine,
  specifically posterior region of the brain
• Dose of caffeine
• .5 mg/ml in drinking water for 7 days then
• 1.0 mg/ml for 14 days

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Caffeine and Catecholamines

• Norepinephrine (noradrenaline) increased rate of
  synthesis and turnover
• Increase firing rate of noradrenergic neurons in
  the locus coeruleus
• Exact mechanism of how caffeine activates
  norepinephrine neurons is not clear
• Epinephrine (adrenaline) increased circulating
  rate
• Dopamine
• Inconsistent findings increased, decreased and
  no change in rate of synthesis and turnover
• Animal model (rat) caffeine inhibits firing rate
  of dopamine neurons in the ventral tegmental area
  that projects to the mesolimbic and mesocortical
  areas no significant change in the firing rate
  of dopamine neurons in the substantia nigra that
  projects to the caudate nucleus

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Caffeine and Dopamine

• Indirect action on dopamine receptors through
  caffeines antagonistic effect on adenosine
  receptors
• A2 adenosine receptors are co-localized
  postsynaptically with D2 dopamine receptors on
  striatal neuronal cells and extends to the core
  and shell of the nucleus accumbens
• Revealing direct evidence for a central
  functional interaction between the two receptors
• Stimulation of A2 receptors with a selective A2
  agonist decreases the affinity of D2 receptors
  for dopamine
• Fredholm et al., 1999

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The Behavioral Effects of Caffeine

• Motor activity
• Vigilance
• Attention
• Learning and memory
• Mood
• Arousal

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Caffeine and Locomotor ActivityStudy by Solinas
et al. 2002

• Animal model
• I.P. injections of caffeine
• 3 mg/kg 10 mg/kg 30 mg/kg 100mg/kg
• Total motor activity after I.P. injection
  resulted in a dose response curve that had an
  inverted u-shape
• Significant motor activity with caffeine doses of
  10 and 30mg/kg 3 and 100mg/kg are ineffective

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Effects of Caffeine on Dopamine and Glutamate
Release

• Study by Solinas et al., 2002
• In vivo study where probes were implanted in the
  shell or core of the nucleus accumbens in adult
  Sprague-Dawley rats
• 10 and 30 mg/kg doses of caffeine induced
  significant increase in extracellular
  concentrations of dopamine and glutamate in the
  shell of the nucleus accumbens
• 30 mg/kg dose of caffeine significantly increased
  level of dopamine in the core of nucleus accumbens

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Caffeine and Motor ActivityGarrett and Holtzman
1996

• Animal Model
• Rotational behavioral experiment
• Animals with unilateral nigrostriatal lesions
• Doses of caffeine 10-100 mg/kg
• 30 mg/kg produced peak contralateral rotational
  behavior
• Locomotor activity experiment
• Doses of caffeine 3100 mg/kg
• 10 30 mg/kg produced peak increases in
  locomotor activity
• Both motor behaviors were affected in a biphasic
  manner by caffeine
• Two different mechanisms by which caffeine
  affects rotational and locomotor activity

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Caffeine and Vigilance

• 16 Human subjects
• 28 hrs of sleep deprivation
• Subjects given a 400mg dose of caffeine and two
  subsequent 100mg doses of caffeine
• ½ hour after first dose of caffeine a 2 hr march,
  followed by sandbag pilling tasks
• Second day treadmill run to exhaustion
• Subjects that received caffeine performed the
  sandbag pilling task in a significantly shorter
  amount of time than the placebo group
• Caffeine group had significantly longer time
  until they reached exhaustion compared to placebo
  (25 longer treadmill run)
• McLellan et al., 2004

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Caffeine and Learning and Memory

• Inconclusive results on the relationship of
  caffeine and learning and memory abilities
• Some studies have shown improvements in learning
  and memory
• Fewer errors and decreased latency in maze tasks
• Others have shown no change in performance
• Researchers agree that caffeine does influence
  attention levels, vigilance, and exploratory
  behavior which may impact the learning process

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Caffeine and Mood

• Low doses of caffeine are associated with
  affecting ones mood in a positive manner.
• Subjective reports of changes in energy,
  imagination, efficiency, increased
  self-confidence and feeling of well being.
• High doses of caffeine (over 200mg) may produce
  feelings of insomnia, anxiousness, nervousness
  and restlessness

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Caffeine and Sleep

• Human Study
• 200mg of caffeine
• Prolonged onset of sleep (33 min.)
• Decreased quality of sleep (self report)
• Regular coffee drinkers have relatively mild
  effects of caffeine on sleep compared to
  non-habitual coffee drinkers
• Nehlig et al., 1992

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Tolerance to the Effects of Caffeine

• A change in the sensitivity of a subject to an
  agent after continuous exposure has occurred, in
  which larger doses are needed to produce the
  original effect
• Tolerance to various behavioral effects of
  caffeine have been shown extensively in animal
  studies, relatively few human studies
• Tolerance occurs quiet rapidly in animals
• Animal Model
• Rats had more than 50mg/kg of caffeine per day
  available in their drinking water (7 days total)
• After a week, the rats were given a series of
  doses of caffeine (3-100mg/kg) and locomotor
  activity was assessed
• Non exposed rats had a 50 increase in locomotor
  activity when given a single 3.0mg/kg dose of
  caffeine
• Rats previously exposed to caffeine did not have
  an increase in locomotor activity more than by
  25 and this occurred at the higher caffeine dose
  levels
• Finn and Holtzman 1986

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Tolerance to the Effects of Caffeine

• Human Studies
• Tolerance to the effect of caffeine on blood
  pressure, heart rate and diuresis have been found
  to develop within a few days of caffeine
  consumption
• Tolerance to certain behavioral effects of
  caffeine have also been demonstrated
• Anxiety, jitteriness, nervousness, insomnia

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Mechanism of the Development of Tolerance

• An increase in the number of adenosine receptors
  may contribute to the sedative effects on
  activity observed in both animal and human
  studies after caffeine consumption has stopped
• Increased sensitivity to endogenous adenosine
• Adaptive changes in adenosine receptors doesnt
  explain the development of tolerance to stimulant
  action of caffeine in cases of locomotor activity
• Compensatory changes in the dopaminergic system
  resulting from chronic antagonism at adenosine
  receptors may play a role in the development of
  tolerance to caffeine
• Dews et al., 2002 Nehlig et al., 1999

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Caffeine Dependence and Withdrawal

• Withdrawal symptoms usually occur if tolerance
  has developed and the presence of withdrawal
  symptoms after discontinuation of a substance
  generally defines physical dependence
• Withdrawal symptoms have been reported within
  12-24 hours after termination of caffeine intake
• And generally peaks around 20-48 hours after
  cessation of caffeine
• Benowitz 1990

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Withdrawal Continued

• Caffeine withdrawal Human studies
• Increases cerebral blood flow
• Headaches, irritability, sleepiness, lethargy,
  impaired mental function, weakness, hand or limb
  tremors, dysphoria, restlessness, nausea and
  anxiety
• Caffeine withdrawal Animal studies
• Decreased locomotor activity
• Decreased operant behavior
• Changes in sleep
• Dews et al., 2002 Nehlig et al., 1999

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Caffeine Related Disorders

• Caffeinism A condition due to an excessive
  intake of caffeine resulting in
• diarrhea, elevated blood pressure, rapid
  breathing, heart palpitations, and insomnia.
• Caffeine-Related Disorders listed in the DSM
• Caffeine intoxication
• Caffeine induced anxiety disorder
• Caffeine induced sleep disorder

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Caffeine and Health Concerns

• Conflicting findings on any association between
  caffeine and impaired health.
• Moderate consumption of caffeine does not seem to
  pose health risks
• Dose response relationship between the amount of
  coffee consumption and the risk of cardiovascular
  disease
• Elevated levels of total and LDL cholesterol
  (more than 2-3 cups per day)
• A correlation reported between caffeine
  consumption in pregnant individuals and lower
  newborn birth weights
• Neonatal do exhibit withdrawal symptoms born to
  mother who consume a large amount of caffeine
  during pregnancy
• High doses of caffeine shown to elicit mental
  disturbances like anxiety, restlessness,
  nervousness, and insomnia (exacerbates in
  individuals who are more sensitive to anxiety and
  may produce panic attacks at high doses, but not
  in healthy controls)
• Benowitz 1990 Nawrot et al., 2003

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Therapeutic Uses for Caffeine

• Treatment of apnea in newborns
• Caffeine helps regularize breathing
• Treatment of migraine headaches when combined
  with aspirin