Caffeine

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• Caffeine
• Nicotine
•   Diani Amaranath Shareen Han

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Caffeine - Content
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Caffeine - Prevalence

• Worldwide, 120,000 tons of caffeine are consumed
  each year
• The highest coffee consuming countries are
  Finland, Sweden, Denmark, Norway and Belgium.
• The average daily consumption of caffeine among
  adults is 200 mg/day in the United States and
  Canada and more than 400 mg/day in Sweden and
  Finland.
• Women metabolize caffeine about 25 faster than
  men
• Why drink coffee?! (most popular source)
• - Need for a stimulant
• - Preference for coffee
• - Knowledge for coffee
• Non-coffee drinkers even get plenty of caffeine
  former coffee drinkers get about 107 mg per day
  and people who have never had coffee get about 91
  mg per day

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Caffeine Comorbidity

• smokers ? ?
• mood disorders
• substance abuse disorders
• Caffeine, drug withdrawal and dependence???

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Caffeine - Symptoms

• Reduce fine motor movement
• Causes insomnia
• Headaches, nervousness and dizziness
• Pupil dilation
• Liver releases sugar into the bloodstream
• Blood vessels near the surface of the skin
  constricts
• Increases heart rate
• Bathroom breaks!!! (diuretic)

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Caffeine - Neuroanatomy

• 
  
• 
  
• Prefrontal Cortex Caudate
  Nucleus

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Caffeine Adenosine

• methylxanthine
• caffeine increases the turnover of many
  transmitters, incl. monoamines (NE, 5-HT) and
  acetylcholines (ACh)
• adenosine-ant. DA , Adrenaline
• adenosine decreases the firing rate of neurons
  and exerts an inhibitory effect on synaptic
  transmission and on the release of most
  neurotransmitters
• acts on the A1 and A2a adenosine receptor
  subtypes
• A1 (at high doses)
• - linked to adenyl cyclase
• - high levels in the hippocampus, cerebral and
  cerebellar cortex and thalamus
• A2a (at low to moderate doses)
• - interaction with D2 receptors
• - almost exclusively located in the striatum,
  nucleus accumbens and olfactory tuburcle

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Caffeine Monoamines

• DA nucleus accumbens ???
• DA prefrontal cortex
• - Mesocortical subsystem
• DA caudate nucleus
• - Nigrostriatal subsystem
• expression of early genes in these areas with
  administration of caffeine
• administer an adenosine A2a agonist, decrease the
  affinity of DA binding to D2 receptors in the
  striatal regions
• caffeine leads to the inhibition and blockage of
  adenosine A2a receptors, leading to a
  potentiation of dopaminergic transmission
• 5-HT later!!!

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Caffeine - Studies

• Withdrawal
• Headaches, feelings of weariness,
• impaired concentration, fatigue, anxiety,
• irritability, increased muscle tension
• onset of caffeine withdrawal effects usually
  occurs 24 h and peaks around 24-48 h (can appear
  within 3-6 h)
• Experiment - Headaches B4 and After Surgery
• - Before and after surgeries, patients are
  usually told to fast for X amount of time
• - For every 100 mg increase in daily coffee
  consumption, the risk of headaches immediately
  before and after surgery is increased by 12-16
  respectively, and also correlates with the
  duration of fasting
• - Risk of headaches reduce with caffeine
  substitutes (pills)
• - Caffeine withdrawal symptoms disappear soon
  after the absorption of caffeine in the blood
• - caffeine withdrawal, headaches and cerebral
  blood flow ???

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Caffeine - Studies

• Tolerance
• Seen in monkeys, mice, cats and squirrels
• Reinforcement threshold for electrical brain
  stimulation
• Tolerance development for animals and humans,
  including the effects of caffeine on blood
  pressure and heart rate, plasma adrenaline and NE
  levels and renin activity
• Some indications of tolerance of caffeine in
  sleep heavy coffee drinkers vs. non-coffee
  drinkers
• No tolerance development for caffeine???
• Limited evidence for tolerance in
  caffeine-induced alertness and wakefulness
• Lack of tolerance of cerebral energy metabolism
  to caffeine subjects had the same metabolic
  increases when administered of 10 mg/kg caffeine
  daily for 15 days (controls were injected with
  saline)
• Tolerance for caffeine remains unclear
• Speculated that if tolerance to caffeine does
  exist it does not involve the adaptive changes in
  adenosine receptors but rather the DA system as a
  result of the chronic adenosine receptor blockage

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Caffeine - Studies

• Reinforcement
• in rats, intravenous self-administration of
  caffeine via a lever (some of these studies, only
  a subset of the subjects pressed the lever)
• in nonhuman primates, self administration was
  sporadic periods of high frequency followed by
  periods of low frequency
• caffeine was able to reinstate an extinguished
  cocaine self-administrating behaviour
• dose dependent 20-25mg reinforcing properties,
  50-100mg decrease, 400-600mg adverse
• - occurs in 100 of heavy coffee drinkers
  (1020-1530 mg/day)
• - occurs in 45 of moderate coffee drinkers
  (128-595 mg/day)

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Caffeine - Studies

• Dependence
• 99 subjects (U.S.)
• 16 of which filled the criteria for caffeine
  dependence
• dependence was not related to the amount of
  caffeine consumed daily
• ranged from 129 to 2548 mg/day, median 360 mg
• of the 16 subjects who were diagnosed as having a
  caffeine dependence
• - 10 had a history of substance abuse disorder
• - 7 had a history of a mood disorders
• these results are concurrent with other findings
  in the past where caffeine use was more prevalent
  in those who also consumed nicotine and alcohol

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Caffeine - Sleep

• Areas that control mood and sleep-
• wake functions are highly sensitive
• to caffeine
• Regions include
• 1. medial raphe (MRAP)
• 2. dorsal raphe (DRAP)
• 3. locus coeruleus (LC)
• i.e. 200 lbs, 1 mg/kg 1 cup of coffee
• 5-HT increase, promotes sleep
• decrease, reduces sleep
• NE increase, reduces sleep, inhibits REM sleep
• lesion LC, abolish muscle tone in REM
  sleep

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Caffeine Sleep (again)

• benefits of sleep
• - restorative properties helps the body
  recover from the activities during the day
• - deprived of stage 4 sleep, people complain
  about being physically tired
• - adaptive for animals who hibernate, are
  nocturnal or diurnal
• shortens the time spent in various phases of slow
  wave sleep (repairing stages of sleep)
• phases of REM sleep is preserved
• prolongs sleep latency
• caffeine withdrawal-induced behavioural changes
  usually last a dew days but the disruption in
  sleep-related signs have been shown to last up to
  30 days after the onset of the withdrawal
  symptoms

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Caffeine Long Term Aversive Effects

• Caffeine dependence
• Infertility (Wilcox, 1988)
• Birth defects
• Weight-loss
• Pancreatic Cancer

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Caffeine Benefits???

• At low to moderate doses
• increases ACh synthesis (LTP and memory)
• alertness (memory)
• ability to concentrate
• speeds up reaction time
• Anacin relieves vascular headaches

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Caffeine Future Studies

• Parkinsons Disease (Ross et al., 2000)
• PD decrease in DA BUT, caffeine increases DA
• 8,004 Japanese American men, 102 developed PD
• PD incidence, correlates negatively with the
  amount of coffee consumption
• Caffeine from other sources
• such as green tea and
• chocolate were also
• associated with a lower
• risk in PD

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A little 4-1-1

• Caffeine does NOT counteract the effects of
  alcohol!!!
• Drug tests include caffeine! Athletes are
  disqualified if their concentration exceeds 12
  micrograms of caffeine per mL of urine.

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NICOTINE
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OVERVIEW

• Epidemiology
• Comorbidity
• Maternal Consequences
• Genetics
• Brain reward circuit
• Neurotransmitters
• Tolerance / Withdrawal
• Treatment
• Long-term effects / Benefits
• Conclusion

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EPIDEMIOLOGY

• Lifetime prevalence - 24
• Highest risk for nicotine dependence occur in the
  first 16 yrs after smoking began
• Gender differences

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COMORBIDITY

• Comorbid with depression and schizophrenia
• Psychiatric comorbidity in adolescents
• Early onset of cigarette smoking and conduct
  problems- increased psychopathology

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Maternal Consequences

• In utero nicotine exposure in animal models
• growth suppression
• disturbances in neuronal pathfinding,
• abnormalities in cell proliferation and
  differentiation
• disruptions in the development of cholinergic and
  catecholaminergic systems.

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Maternal Consequences

• Prenatal exposure to nicotine in humans
• risk of developing ADHD
• low birth weight
• elevated blood pressure
• dysregulation in neurodevelopment
• higher risk for psychiatric problems

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GENETICS

• Family studies
• high vulnerability
• Parental alcoholism and nicotine dependence
• Adult children of alcoholics (ACOA) - high risk
  of developing nicotine dependence (13.3)
• ACOA started regular nicotine use earlier

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Brain Reward Circuit

• Nicotine receptors in the CNS found on
  presynaptic dopaminergic and serotonergic neurons
  in the brain
• Neurons in Substantial Nigra and VTA are
  important in cigarette addiction

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Reward Pathway
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NEUROTRANSMITTERS
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Glutamate / GABA

• Nicotine increases glutamate in the VTA, Nucleus
  accumbens, prefrontal cortex
• Glutamate antagonist
• reduce nicotine self-administration in mice
• GABA agonist
• reduce nicotine self- administration in rats

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Soluble Gases

• Nicotine modulate effects on Nitric Oxide
• increase Nitric oxide indirectly via glutamate
  receptors
• increase in the cortex and hippocampus

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Dopamine

• Increase extracellular dopamine concentration
• inhibit uptake of dopamine through nicotinic
  acetylcholine receptors
• increase release of dopamine in the nucleus
  accumbens

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Dynamics of Addiction
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Tolerance (Addiction Cycle)
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Tolerance

• Repeated exposure to nicotine increase
  nicotinic acetylcholine receptors
• Tolerance builds up during the day
• Night Abstinence regain sensitivity to nicotine
• Smokers use cigarettes to
• regulate amount of nicotine
• stay in the neutral zone
• avoid withdrawal symptoms

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Withdrawal
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Withdrawal Symptoms

• Restlessness
• Irritability
• Anxiety
• Drowsiness
• Impatience
• Confusion
• Impaired concentration

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Withdrawal Symptoms

• Physical signs
• decreased heart rate
• decreased urinary excretion of Epinephrine ,
  Norepinephrine and Cortisol
• gain weight ( 5 pounds)
• absence of anorexic effects of nicotine
• decrease metabolic rate
• craving persist for months to years

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Neurobiology of Withdrawal symptoms

• Central and peripheral populations of nicotine
  acetylcholine receptors involved in mediating
  SOMATIC signs
• Only Central populations of nicotine
  acetylcholine receptors involved in mediating
  AFFECTIVE signs

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Treatment

• Oral nicotine solution
• Nicotine replacement therapy (NRT)
• Bupropoin SR
• reduces withdrawal symptoms and weight gain
• Behavioral Counseling
• Antidepressants - Comorbidity

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Long-term Effects/ Benefits

• Changes in nicotinic acetylcholine receptors
  (nicotine addiction)
• elevation of nerve growth factor
• enhance learning
• protection of neuronal loss
• preventive factor against neurodegenerative
  disease (Alzheimers and Parkinsons disease)
• Cognitive benefits in Schizophrenia

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Future Studies

• Effectiveness of nicotine as treatment for
  neurodegenerative diseases
• Is nicotine dependence a consequence or a cause
  of environmental factors versus biological
  factors