4. Caffeine D&B Test 2

Caffeine and other Methylxanthines

methylxanthines

caffeine, theophylline and theobromine [ The three have similar molecular structures and similar behavioral and physiological effects.]

most common sources: coffee, tea and chocolate

Starbucks (16floz) - 330mg; Tim Hortons (14floz) - 196 mg; hot chocolate (8floz) - 5-13mg; tea (8floz) - 14-70mg; Coca Cola (12floz) - 34mg.

cup of tea - caffeine plus theophylline,

chocolate - caffeine and theobromine.

Administration, Absorption and Excretion

lipid-soluble

basic, pKa = 0.5, nonionized in all body fluids

oral, peak blood levels at 45-75m

medicinally MXs are given as salts to increase absorption, [e.g. aminophylline; mixture of theophylline and methylenediamine]

readily cross the BBB and placental barrier

about 1% excreted unchanged

CYP1A2 enzyme comes in various forms (fast and slow)

converted to paraxanthine, theobromine and theopylline

half life = 5 hours (range 2.5-7.5, affected by pregnancy, alcohol, smoking, broccoli!)

newborns metabolize slowly

-Peak blood levels of caffeine are reached in about 30 minutes.

-aminophylline-a bronchodilator used to treat asthma

-caffeine does not appear to accumulate in the body over days if it is not consumed after 6:00 p.m.

-The adult pattern of caffeine metabolism is not developed until 7 to 9 months of age

-Caffeine half-life in women is longer during the luteal phase (after ovulation

Half lives are diffferent because different people have more of the fast or slow enzyme. Accellerated by cigarettes and broccoli, slowed by pregnancy and alcohol.

Ceffeine: Neurophysiology

MXs block adenosine receptors, adenosine is a neuromodulator - inhibits release of neurotransmitters

low-levels of adenosine ->alertness

4 adenosine receptors, MXs block A1 and A2a

disinhibits acetylcholine (cognition), glutamate (seizures), norepinephrine (arousal and attention)

these receptors inhibit DA release (therefore MXs increase DA)

participate in the formation of receptor mosaics

e.g. A1-D2 and A2A-D2 contribute to enhanced dopamine transmission in the striatum

caffeine prevents sedation caused by alcohol

caffeinated alcohol drinks have higher consumption levels (both increase DA)

-tends to reduce the spontaneous acitivity of neurons

-if llow levels then your are more likely to be alert

-A2a commonly found in the nucleus accumbens

-...may improve cognition, increase chance of seizure, locus cirrilius.... ne important for arousal and attention

-Both A1 and A2A receptors appear to modulate levels of dopamine in the brain, and, because they block these adenosine receptors, the methylxanthines increase dopamine levels

caffeine neurophysiology cont.

-participate in the formation of receptor mosaics where two or more receptors become attached to each other and consequently influence one another's operation

-A1, A2A, D1, and D2 receptors has been studied in the striatum where they determine dopamine effects by

integrating the activity of dopamine and glutamate

Adenosine reduces spontaneous activity of neurons

rEceptors are found pre and post synaptically and they are distributed widely (found in most areas of the brain)

A2a____- especially in nucleus accumbens

MX increases neural activity levels

Seem to be involved in mosaics especially with the dopamine receptor.

Caffeine:

Other Animals: Discriminative

stimulus properties

discriminative stimulus

will not generalize to other classes of drugs (partial to cocaine and amphetamine with low doses of caffeine)

dopamine and adenosine A1 receptor blockers block discrimination based on low doses.

Caffeine will increase the discriminative effects of

low doses of cocaine. Dopamine receptor blockers will

block the discriminative effects of low but not high doses

of caffeine

Caffeine:

Other Animals: Unconditioned Behaviour

increases spontaneous motor activity at 20-40 mg/kg but decreases activity at 80 mg/kg

LD50 = 200-250 mg/kg [Death may be due to convulsions]

high doses (185 mg/kg) cause automutilation

they can die by bleeding to death, more agression ot themselves not others

Automutilation has been observed in rats when caffeine

was given at a dose of 185 mg/kg for 14 days. The rats

bit their tails and paws, even though they seemed to

retain their normal sense of pain. When a ball of wire

was placed in their cage, they temporarily attacked it

but soon returned to biting themselves. When picked

up, they did not bite the hand of the experimenter, but

they did attack other rats placed with them in a cage

Caffeine

Other Animals: Conditioned Behaviour

pre-exposure to caffeine enhances rate of self-admin of cocaine; also reinstates responding previously maintained by cocaine

relationship probably because caffeine increases catecholamine release and DA activity in reward pathways (same as cocaine)

increase responding for ICSS of MFB

Self-Administration: nonhumans are often reluctant self-administrators.

improved by forced consumption

puts you in a similar state to cocaine use

Caffeine

Humans: Effects on the body

low-moderate doses:

MXs strengthen striated muscles and relax smooth muscles.

reduces threshold for cortisol and endorphin release

-> dilation of the bronchi of the lungs

constriction of blood vessels in brain

reduces headaches

high doses:

increased excitability in spinal cord, convulsions, and rate and depth of breathing - high doses of MX to treat babies born with breathing difficulties.

-By constricting blood flow to the brain, caffeine is able

to reduce headaches caused by high blood pressure. For

this reason, caffeine is found in many over-the-counter headache remedies.

-The regulatory centers of the medulla are also stimulated by high doses, producing an increase in the rate and depth of breathing.

Caffeine

Humans: Subjective Effects

caffeine (20-200 mg) administered to nontolerant subjects described as pleasant

i.v. subjects reported a "high" similar to cocaine.

can induce anxiety in people with anxiety disorders

relaxation, contentment produced by tea just as much due to sensory experience (hot, colour, smell)

we don't take to simply avoid withdrawl symptoms

effects last for ab 8 hrs

Later studies found that participants experience an array of positive effects, such as increases in feelings of well-being, alertness, energy, motivation for work, and self-confidence.

these effects are not simply a matter of alleviating caffeine withdrawal

-There was a dose-related increase in ratings of "liking," "drug effect," "high," and "good effects."

These feelings occurred 2 minutes after injection and

decreased over the following 60 minutes.

Caffeine

Humans: Cognitive

Performance

since it can improve mood and self confidence, that helps (especially when relying on self-reports); also need to make sure effect isn't due to relief from withdrawal

caffeine will improve performance if subjects suffer from fatigue and boredom.

some evidence of improved performance in normal, alert individuals on attention and working memory, reaction time on visual and cognitive tasks (perhaps despite tolerance)

capable of reversing decrements in performance caused

by boredom and fatigue, drugs, caffeine withdrawal,

and the common cold (Lara, 2010). Caffeine improves

attention and speeds both simple and choice reaction

times.

-capable of improving the performance of normal,

alert individuals on attention and working memory

tasks at doses equivalent to a single cup of coffee (Smith,

2009). Improvements have also been seen in reaction

times on visual, cognitive, and verbal reasoning tasks in

regular coffee users who were not experiencing caffeine

withdrawal as well as in non-coffee consumers

Can influence regular usage as well, its not just about reducing withdrawal symptoms 

caffeine

Humans: Sleep

consume before going to bed, sleep less soundly and feel less rested in the morning

stabilizes wakefulness, lowers acoustic threshold, tolerance after 7 days.

might show tolerance after 7 days

Their effect seems to be in increasing the "stability of wakefulness" by increasing the length oftime it takes to fall asleep and reducing total sleep time.

In one study, 300 mg of caffeine increased the latency

of sleep onset from 18 to 66 minutes and reduced total

sleep time from 475 to 350 minutes

caffeine

Humans: Self Adminstration

preference for caffeinated coffee or capsules

can discern amounts as low as 25mg per cup

people more likely to chose coffee if

1) physically dependent

2) report positive subjective effects

3) if the dose is low as opposed to high (100 mg usually decreases the rate of self-administration, and doses in the 400- to 600- mg range are usually avoided.)

4) if tasks (given after capsule) requires vigilance

One such study, conducted with moderate coffee

drinkers, revealed a distinct preference for caffeinated

coffee over decaffeinated coffee. This preference could be

detected in some people at doses as low as 25 mg per

cup

Choice of 3 pills, placebo, caffeine, and amphetamine. Benzodiazepines don't show a preference even if you have high anxiety. Zbut if you give them a task like I will reward you for laying down for 2 hours they will take the amphetamine. If you tell them they need to stare at a computer for 2 hours and you need to quickly signal whenever something happens they will likely choose caffeins, but they wouldn't choose this for a relaxation task. 

Caffeine: Benefits

lower risk for type 2 diabetes (at about 6 cups per day?)

weight loss or gain protection (increases metabolism)

may reduce risk of heart problems, stroke and even mortality (may be because of polyphenol catechins and or flavonoids)

may protect against neurodegenerative diseases (e.g. Alzheimer, Parkinson)

3-5 cups/day -> 65% decreased risk for neurocognitive disorder

-caffeine increases dopamine activity by blocking adenosine receptors.

-prevent weight gain and obesity, because of its ability to increase metabolic activity and increase energy expenditure

-reduced risk of developing Type 2 diabetes, but it is not entirely clear whether this is because of caffeine or some other ingredient in coffee. Other studies that compared caffeinated and decaffeinated coffee found that the decaffeinated coffee also offered some protection against Type 2 diabetes.

not nesceaarily due to the caffeine, it could be due to the other components in the drink blocking the A2A we increase the amount of dopamine and parkinsons is ab low dopamine.

in alheimers is it reduces the beta amyloid plaques

Caffeine: Harmful Effects

at low-moderate doses -> no health effects (about 400 mg per day)

200 mg /day caffeine consumption can retard fetal growth and lowers birth-weight in humans.

research on cardiovascular disease yields mixed results

high doses from energy drinks (which may be consumed in larger quantities) can cause a variety of problems

5-50g of caffeine can lead to death resulting from convulsions or respiratory collapse.

just a correlation not a causal relationship

found in breast milk?

Showed a positive relationship between caffeine consumption and cardiovascular disease, but only in individuals with the “slow metabolizing” form of the CYP1A2 enzyme gene (i.e., the CYP1A2*1F form). These individuals excrete caffeine slowly. While the issue is far from settled, the bulk of recent research has not found an association between caffeine consumption and cardiovascular disease for most people 

Caffeine: Tolerance

adenosine receptors increase in number after chronic caffeine use.

chronic caffeine use in rats can shift the DRC for operant responding to the right by a factor of 6.

behavioural effects on humans greater on nonusers

- tolerance or resistance?

cardiovascular effects (2-5 days), increases in urination (longer or never)

subjective effects of 300 mg tolerate within 4 days.

caffeine: withdrawl

headaches, fatigue, fogginess, anxiousness or agitation.

start within 12 to 28 hours, peak at 20-51 hours, and last 2 to 9 days.

doses of 600 mg/day can produce physical dependence after 6-14 days.

long-term doses of as little as 100 mg. per day will produce physical dependence.

most common symptom is headache

The severity of symptoms is directly related to dose.

U.S. studies have shown that, among coffee consum-

ers who have gone without coffee for 24 hours, 27 to 52%

report experiencing headaches.