Caffeine Caffeine & Nicotine& Nicotine

Diani AmaranathDiani Amaranath & Shareen HanShareen Han

Caffeine - Content

Item Item Size Caffeine Content(mg)

coffee 150 mL 60-150

coffee, decaf 150 mL 2-5

tea 150 mL 40-80

chocolate milk 150 mL 2-7

Mountain Dew 355 mL 54

Coca Cola 355 mL 46

Diet Coca Cola 355 mL 46

Sprite and 7-UP 355 mL 0

chocolate bar 50 g 3-63

peanut butter cup 51 g 5.6

chocolate chip cookie 30 g 2-5

MIDOL 1 tablet/capsule 32

*ANACIN 1 tablet/capsule 32

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

Caffeine – ”Comorbidity”

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

dependence???

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)

Caffeine - Neuroanatomy

Prefrontal Cortex Caudate Nucleus

http://www2.onu.edu/%7Eksehlhor/lecture.html#mesolimb

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

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!!!

Caffeine - StudiesWithdrawal• 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 ???

Caffeine - StudiesTolerance• 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

Caffeine - StudiesReinforcement• 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)

Caffeine - StudiesDependence • 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

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

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

Caffeine – Long Term Aversive Effects

• Caffeine dependence• Infertility (Wilcox, 1988)

• Birth defects• Weight-loss• Pancreatic Cancer

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

Caffeine – Future Studies

Parkinson’s 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

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.

NICOTINE

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

EPIDEMIOLOGY

• Lifetime prevalence - 24% • Highest risk for nicotine dependence

occur in the first 16 yrs after smoking began

• Gender differences

COMORBIDITY

• Comorbid with depression and schizophrenia

• Psychiatric comorbidity in adolescents

• Early onset of cigarette smoking and conduct problems- increased psychopathology

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.

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

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

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

Reward Pathway

NEUROTRANSMITTERS

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

Soluble Gases

• Nicotine modulate effects on Nitric Oxide

• increase Nitric oxide indirectly via glutamate receptors

• increase in the cortex and hippocampus

Dopamine

• Increase extracellular dopamine concentration

• inhibit uptake of dopamine through nicotinic acetylcholine receptors

• increase release of dopamine in the nucleus accumbens

Dynamics of Addiction

Tolerance (Addiction Cycle)

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

Withdrawal

Withdrawal Symptoms

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

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

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

Treatment

• Oral nicotine solution• Nicotine replacement therapy (NRT)• Bupropoin SR

– reduces withdrawal symptoms and weight gain

• Behavioral Counseling• Antidepressants - Comorbidity

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 (Alzheimer’s and Parkinson’s disease)

• Cognitive benefits in Schizophrenia

Future Studies

• Effectiveness of nicotine as treatment for neurodegenerative diseases

• Is nicotine dependence a consequence or a cause of environmental factors versus biological factors