BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
CAFFEINE: AN OVERVIEW
By Tina Whiting, Candace Lewis, Brian Godwin, and Erica
Heuer
TABLE OF CONTENTS:
I. Caffeine effects in the brain
II. Behavioral and side effects of caffeine
III. Caffeine: An overview of origins, chemistry, and
neurotransmitter effects.
IV. Caffeine-induced psychological changes & effects
reported by users
I.CAFFEINE EFFECTS IN THE BRAIN:
By Tina Whiting, Humboldt State University
Caffeine acts in a multitude of ways in the brain. The
most recent studies explore the cooperative effects of
adenosine and dopamine, as well as the increase in calcium
in the interstitial fluid and possible accumulation of
cyclic adenosine monophospate. The most popular discussions
of earlier studies of caffeine demonstrate its antagonistic
effects on adenosine receptors. While it has been reported
that adenosine receptors are located throughout the brain,
the various subtypes can be found in very specific areas.
Studies have also shown that caffeine reactions in the brain
are based on the localization of adenosine receptors,
dopamine receptors, and the amount of caffeine.
Historically, the first behavior of caffeine in the
brain to be noticed was the stimulation of the release of
caffeine from intracellular storage sites. (Daly, 1999) In
research done by Garrett and Griffiths (1997) caffeine was
shown to mobilize intracellular calcium by reducing the
calcium uptake and stimulating calcium release. Caffeine
would attach to a calcium channel in this way activating it
and releasing calcium from the "calcium-sensitive"
pool.(Daly, 1999) Due to the importance of calcium
concentrations for the release of neurotransmitters, Garrett
determined, "…mobilization of intracellular calcium has been
proposed as a possible mechanism underlying the behavioral
effects of caffeine" (p.534). However, this determination
was made in vitro and required nearly toxic levels of
caffeine, levels that would rarely be ingested by humans.
(Garrett, 1997; Daly 1999) [See Table 1]
The next effect is the forcing of accumulation of
cyclic adenosine monophospate [cyclic AMP]. This occurs
because caffeine inhibits cyclic nucleotide
phosphodiesterase activity which produces an accumulation of
cyclic AMP. (Garrett, 1997; Myers, 1999) According to the
Pacific Nueropsychiatric Institute "caffeine inhibits
phosphodiesterase breakdown of cyclie 3',-5'-adenosine
monophosphate. (Pharmacology, caffeine, 2) Again, this
occurs only in large quantities that have yet to be
naturally found in vivo. (Myers, 1999) Keep in mind that if
cyclic AMP had a greater than normal concentration in the
synaptic cleft, it would continue to breakdown adenosine
which has a depressant effect on functions in the brain. For
example, adenosine in the central nervous system inhibits
neurotransmitter release and depresses locomotor activity,
however with higher concentrations of cyclic AMP there is
less adenosine so, the effects on the biology of the brain
are an enhanced neurotransmitter release, and stimulated
locomotor activity (Garrett, 1997).
Another way caffeine acts on the brain is indirectly
through the dopamine receptors. As stated by Garrett and
Griffiths (1997), "Although caffeine does not bind directly
to dopamine receptors a number of conflicting reports
suggest that caffeine can either decrease or increase
dopamine release" (p.535). For example, "Caffeine
significantly decreases dihydroxyphenylacetic acid (DOPAC)
levels in the striatum, hypothalamus, and frontal cortex,
but increases DOPAC levels in the nucleus accumbens"
(p.535).
Caffeine also is responsible for significant variations
in caudate dopamine release. (Garrett, 1997) The biphasic
actions of caffeine include: lower doses of caffeine
decrease caudate dopamine release and higher doses of
caffeine increase caudate dopamine release. (Garrett, 1997)
The nucleus accumbens is an area of the brain that is rich
in dopamine receptors and also is affected by caffeine.
Solinas et al. (2002) have stated that caffeine has the
ability to increase extracellular levels of dopamine and
glutamate in the shell of the nucleus accumbens.
In the locomotor area of the brain low to intermediate
doses of caffeine result in an increase in spontaneous
locomotor activity. This effect can be blocked by selective
D1 and D2 receptor antagonists. (Garrett, 1997) This
behavior suggests that stimulant effects of caffeine and
tolerance is mediated by both D1 and D2 dopamine receptor
subtypes. However, the D1 dopamine receptor antagonists do
one of two things, partially block rotational behavior or do
not block rotational behavior at all. The D2 dopamine
receptor does block caffeine induced rotational behavior
(Garrett, 1997). Particularly, there is a negative coupling
in the hippocampal A1 adenosine and D1 dopamine receptors,
thus the adenosine receptors "…exert an inhibitory influence
over the D1 receptors in the hippocampus …(this) has been
cited as a mechanism for the arousal effects of caffeine"
(Damianopoulos, 1999 p.50).
Finally, the most prominent way caffeine interacts with
the brain is through the competitive antagonism (blockade)
of adenosine receptors. Adenosine in the central nervous
system acts as a natural depressant (Garrett, 1997) with
mood-depressing and sleep inducing effects. Adenosine
inhibits the release of neurotransmitters from the
presynaptic cell and modifies the response to the
neurotransmitters in the postsynaptic cell (Daly, 1999).
Currently, there are four known types of adenosine
receptors in the human brain (Fredholm, 1999 p.89). The A1
and A2A adenosine receptors are high affinity (Meyers,
1999). The A3 adenosine receptors are low affinity
(Fredholm, 1999 p.89). However there is variance in
research as to the affinity of the A2B receptor, Fredholm
(1999) states, "Although A2B and A3 receptors are unlikely
to be important, A1 and A2A receptors are activated at the
low basal adenosine concentrations measured in resting rat
brain" (p.89). In contrast Myers (1999) states, "As
antagonists of adenosine at both high-affinity (A1) and low-
affinity receptors…" (p.20).
The A1 adenosine receptors are inhibitory to adenylate
cyclase and calcium; yet they are stimulatory to potassium
channels, and phophoinositide breakdown (Daly, 1999). The
A2A and A2B adenosine receptors are stimulatory to adenylate
cyclase (Daly, 1999). The final adenosine receptor, A3 is
similar to the A1 receptor in one respect; it is also
inhibitory to adenylate cyclase (Daly, 1999).
Central adenosine receptors affected by typical human
caffeine exposure are present in nearly all brain structures
(Lorist, 2003). [See Table 2] Adenosine A1 receptors are
most prominent in the hippocampus, cerebral and cerebellar
cortex, and particularly in the thalamic nucleus (Fredholm,
1999). A mapping technique utilizing mRNA has shown A1 and
A2 receptors located on the nerve terminals (Fredholm,
1999). Evidence also suggests that there are little to no
A2A receptors outside the striatum. (Lorist, 2003). However
A2A receptors are found in areas of the brain that are
dopamine rich such as the nucleus accumbens and tuberculum
olfactorium (Fredholm, 1999).
In a study conducted by Solinas, Ferre, Zhi-bing,
Darez-Kubicha, Popoli, and Goldberg (2002), caffeine
demonstrated the ability to block certain adenosine
receptors such as A1 and A2A, and A2B receptors. Caffeine
binds to the highly receptive adenosine receptors sites
which thwart adenosines typically sedating effects. Thus
the stimulating results of caffeine are directly related
only as a secondary effect of adenosine antagonism (Pacific
Nueropsychiatric Institute, Fredholm et al.). It has been
argued that the stimulatory effects of caffeine are directly
related to the blockade of the A2A adenosine receptors in
striatopallidal neurons (Lorist, 2003).
Garrett showed in 1997 that the A2 adenosine receptor
and the D2 dopamine receptor appear to be colocalized
postsynaptically on striatal neurons particularly the "A2
adenosine receptor mRNA in GABAergicenkephalin straital
neuron" (p.535). These demonstrate functional interactions
in the striatum (Garrett, 1997). Functional evidence also
shows that A1 adenosine receptor agonist inhibit D1 dopamine
receptor mediated which increases adenylate cyclase activity
(Garret, 1997). Thus studies from Garrett (1997) and
Solinas et al. (2002) have demonstrated "Caffeine enhances
dopanminergix activity, presumably by competitive antagonism
of adenosine receptors that are colocalized and functionally
interact with dopamine receptors" (p. 538).
Other effects of the brain chemistry of caffeine
include neurotransmitter modulation affect (Myers, 1999) and
a reduction of hypnotic effect (Yacoubi, 2003). Early
studies of neurotransmitter modulation showed no effect on
the cerebral norepinephrine concentrations; however an
increase in the rate of turnover and synthesis of
norepinephrine has been demonstrated (Myers, 1999).
Naturally occurring dietary caffeine has been shown to
increase the concentrations of serotonin and tryptophan,
while other studies have shown the postsynaptic availability
of serotonin is decrease by caffeine which affects sleep
mechanisms and motor function (Myers, 1999). Caffeine
effects on amino acids demonstrate an increase in glutamate
and a decrease in GABA and glycine (Myers, 1999). Caffeine
has demonstrated the ability to increase extracellular
levels of dopamine and glutamate in the nucleus accumbens
(Solinas et al., 2002) Yacoubi (2003) did research on mice
to access the effects of caffeine on an ethanol-induce
hypnosis. The research demonstrated that caffeine reduced
the hypnotic state via the A2A adenosine receptors.
At the time of Daly's' research there had been only one
extended study on the habitual ingestion of caffeine.
Chronic effects of caffeine in the brain include an increase
in the amount of A1 adenosine receptors by 15 to 20%, though
they do not appear to up-regulated (Daly, 1999; Van Soeren,
1998). However, the A2A adenosine receptors were unaltered
(Daly, 1999). Also the levels of striatal D1 and D2
dopamine receptors were unaltered and the density of calcium
channels increased by 18% (Daly, 1999). The most studied
long term effect of caffeine consumption is the tolerance to
it. Though studied in rats, there was an "insurmountable
tolerance" to caffeine (Daly, 1999 p.5). A constant supply
of caffeine in the body does lead to a certain tolerance
that is attained by the body creating more adenosine
receptor sites (Spiller, 1998).
REFERENCES:
Daly, J. W., Shi, D., Nikodijevic, O. & Jaconson, K.A.
(1999). The Role of
Adenosine Receptors in the Central Action of Caffeine. In
B.S. Gupta &
U. Gupta (Ed.). Caffeine and Behavior; Current Views and
Research
Trends (pp. 1 – 16). Washington D.C. CRC Press.
El Yacoubi, M., Ledent, C., Parmentier, M., Costentin, J. &
Vaugeois, J. (2003) Caffeine
Reduces Hypnotic Effects of Alcohol through Adenosine A2a
Receptor Blockade.
Neuropharmacology, 45, 977-985. Retrieved March 2, 2005. from
Science Direct
Database.
Fredholm, B. b., Battig, K., Homen, J., Nehlig, A., & Zvartau,
E. (1999) Actions of
Caffeine in the Brain with Special Reference to Factors That
Contribute to Its
Widespread Use. Pharmacological Review, 51. 87-96. Retrieved
February 10,
2005. from PsychINFO database.
Garrett, B. E. & Griffiths, R.R. (1997) The Role of Dopamine in
the Behavioral Effects
of Caffeine in Animals and Humans. Pharmacology Biochemistry and
Behavior,
57, 533-541. Retrieved February 28, 2005, from PsychINFO
database.
Myers, J. P., Johnson, D. A., McVey, D. E., (1999).
Caffeine in the Modulation
of Brain Function. In B.S. Gupta & U. Gupta (Ed.).
Caffeine and
Behavior; Current Views and Research Trends (pp. 1 – 16).
Washington
D.C. CRC Press.
Pacific Nueropsychiatric Institute. (2005). Pharmacological
Effects. Retreived March 2,
2005, from Pacific Nueropsychiatric Institute Website:
http://www.pni.org/psychopharmacology/drugs_recreational/caffein
e/caffeine.html
Solinas, M., Ferre, S., Zhi-Bing, Y., Karcz-Kubicha, M., Popoli,
P., & Goldberg, S.R.
(2002). Caffeine Induces Dopamine and Glutamate Releases in the
Shell of the
Nucleus Accumbens. The Journal of Neuroscience, 22.6321 – 6324.
Retrieved
March 2, 2005. from PsychInfo database
Spiller, G. A.,(1998). Basic Metabolism and Physiological
Effects of the
Methylxanthines. In G. Spiller (Ed.) Caffeine (pp. 225 –
232). Washington
D.C. CRC Press.
Van Soeren, M. H.; Graham, T. E. (1998) Effect of Caffeine on
Metabolism, Exercise Endurance, and Catecholamine Responses
After Withdrawal. The
American Physiological Society. 1493 – 1501. Retrieved March 2,
2005. from
Science Direct database
II. BEHAVIORAL AND SIDE EFFECTS OF CAFFEINE
By Candace Lewis, Humboldt State University
Caffeine is the most consumed psychoactive drug in the world
(Solinas et al, 2002). Caffeine has been known to have many
side effects on hour external behavior and our internal
physiological behavior. We use caffeine in our lives to
sometimes stay awake to study or just get through the day.
Caffeine decreases the blood flow to the brain by
constricting the blood vessels but can also increase blood flow
after continuous intake that may cause headaches (Kalat, 2004).
Caffeine has a tendency to block adenosine (A1-, A2A-, A2B-,
A3), which increases throughout the day to allow us to sleep and
then decreases as we sleep which allows us to wake. Thus, if
caffeine blocks adenosine we are unable to sleep when feeling
the urge or wanting to sleep, which may cause us to decrease our
caffeine intake.
Caffeine acts to antagonize adenosine receptors, which then
affects cell populations because it counteracts many adenosine
effects. The caffeine mainly has an effect on the A2a adenosine
receptors which then elevates the energy metabolism in the brain
and also causes a decrease in cerebral blood flow
(Cameron,et.al, 1990; Ghelardini, et.al, 1997; Nehliget.al,1992;
Neuhauser-Berthold et.al, 1997). Along with caffeine affecting
the adenosine it also has an effect on GABA receptors and the
release of dopamine (Nehlig et.al, 1992).
Caffeine not only blockades adenosine it also releases
intracellular calcium, inhibits phosphodiesterases and blockade
or regulatory sites of GABAa-receptors (Gupta and Gupta, 1999).
Withdrawal symptoms of caffeine are headache, drowsiness,
fatigue and lethargy (Gupta and Gupta, 1999).
Dopamine and glutamate neurotransmission is modulated by
adenosine in the striatum. Adenosine A1 in the nerve terminals
inhibits dopamine and glutamate from being released. Caffeine
has an effect in this system by antagonizing of adenosine, which
can then stimulate neurotransmitters to release dopamine and
stimulate dopamine receptors (Solinas et al, 2002). A study
done on rats showed that caffeine increased extracelluar
concentrations of dopamine and glutamate in the shell of the
nucleus accumbens (Solinas et al, 2002). These results of
dopamine and glutamate in the shell of the nucleus accumbens
might be related to the psycho stimulant effects of caffeine
(Solinas et al, 2002).
Studies show that Dopamine2 receptors are needed for
caffeine activation in the brain (Zahniseret al, 2000).
Adenosine receptors, dopamine receptors and GABA have been shown
in studies to be involved in behavioral hyperactivity due to
caffeine intake which then induces locomotor activation
(Zahniser, et.al., 2000). Mice that have been injected with
caffeine in studies have shown to be more active than mice that
were injected with saline instead of caffeine due to the
activation of Dopamine2 receptors (Zahniser, et.al., 2000).
The same study showed that caffeine-induced locomotion was
mediated by the dopamine receptors that were being released to
block the caffeine (Zahniser, et.al., 2000).
Studies have been done to test changes in ACh in the
hippocampus in rats, which would then slow the blockade of
presynaptic adenosine receptors, by caffeine. When ACh was
paired with choline there was a synergistic effect that raised
the ACh concentrations, thus the blockade of adenosine (Gupta
and Gupta; 1999).
The inhibitions of transmitter release from the presynaptic
cell and limit of the activity evoked membrane depolarization on
postsynaptic cell are due to A1 receptors (Rudolphi et.al,
1992). A2 receptors are found in dopamine receptor rich areas
of the brain and A1 receptors are in many areas of the brain but
are found in large quantities in the neocortex (Fastbom, 1987;
Goodman, 1982). Caffeine binds with the A1 receptors, which
then prevents inhibition thus causing excitation (Lesk and
Womble, 2004).
Caffeine in the central nervous system raises
cerebrovascular resistance. In rats it has been shown that the
rates of local cerebral blood flow (LCBF) decreases in the areas
where it usually increases metabolism. In humans the cerebral
blood flow also decreases but only by 20-30% and there are no
decreases in any other regions (Gupta, Gupta; 1999). During
these tests it showed that with the decreases in the cerebral
blood flow that the patients (rats and humans) had an increased
anxiety rating after the intake of caffeine (Gupta and Gupta,
1999).
Other studies have been done on rats with stress responses
to coffee on the hippocampal serotonin and dopamine levels.
Coffee affects the brain in many ways such as it acts as a
stimulant on the central nervous system, it increases the levels
of serotonin and dopamine in the hippocampus and striatum. The
hippocampus is mainly responsible for food intake, emotion and
memory. Dopamine and serotonin is also released from the
hippocampus when rats are exposed to restraint stress (Yomato,
2002). Studies on rats showed that when injected with some type
of caffeine product while being restrained and then when
released showed high levels of dopamine and serotonin but after
an hour and forty minutes the levels of dopamine and serotonin
went back to normal levels (Yomato et al, 2002). While the
rats were being restrained the study found that the
coffee/caffeine had suppressed the amount of serotonin that was
released from the rats hippocampus (Yomato et al, 2002).
Studies have been done on caffeine drinks such as Red Bull
and Rock Star to show the effects they have on the human and
animal brain. Studies have shown that caffeine can interact
with the neurotransmitters of the brain, which causes
spontaneous firing rates of the cortical neurons (Specterman et
al, 2005).
Caffeine has been shown by previous studies to increase
alertness, increase visual vigilance and improve cognitive
functioning (Fagan et al, 1998; Smith et al, 1992; Stein et.al,
1996; Loke and Meliska; 1984). Reaction time is also decreased
in individuals who consume large amounts of caffeine (Leiberman
et al, 1987).
A number of studies on caffeine and memory have shown that
caffeine enhances memory performance. They have also shown that
caffeine improves delay recall, recognition memory, semantic
memory and verbal memory (Stein et al, 1996; Warburton, 1987;
Bowyer et.al, 1983; Jarris, 1993). Studies that showed an
increase in performance in tasks such as short and long term
memory retrieval, reading speed and encoding efficiency was due
to caffeine having cholinergic properties (Greenburg and
Shapiro, 1987). However, even though there have been studies
that show positive effects of caffeine there have been other
studies that have shown the opposite effects, saying that
caffeine decreases memory and recall (Gupta and Gupta, 1999).
Seeing that different studies have gotten opposite results other
studies have been done to understand this and what was found was
that the amount of recall and memory that an individual can
exhibit with caffeine was due to the memory of the individual
before (Andersen and Revelle, 1983).
People who chronically experience headaches usually take
medications that have some type of caffeine, which causes the
same effect that acetaminophen, would have. Those who suffer
headaches from caffeine withdrawal can usually be relieved by in
taking a small amount of caffeine (Nahlig, Daval, and Debry,
1992). During caffeine withdrawal headaches, in high caffeine
consumers usually have headaches in the frontal regions of the
brain. These headaches are due to the increase of cerebral
blood flow. After these consumers have taken in some type of
caffeine their cerebral blood flow decreases after about thirty
minutes and then becomes normal again after approximately two
hours (Couturier, Hering, and Steiner, 1992). Through these
studies the brain and cerebral blood flow never adjust or evolve
to caffeine intake (Gupta and Gupta, 1999).
Neurological changes are considered to be the central part
of developing a dependence on drugs, which could then eventually
lead to an outbreak in consumption of caffeine-containing
beverages (Solinas et al, 2002).
In a study done to show if people who are habitual coffee
drinkers become tolerant to caffeine showed that in both
habitual and nonhabitual coffee drinkers when caffeine was
infused into the system their sympathetic nerve active and blood
pressure increased. In nonhabitual coffee drinkers their
systolic blood pressure increased and did not in habitual
drinker thus indicating that habitual coffee drinkers may
develop a tolerance to caffeine (Corti et.al, 2003). In the
study decaffeinated and caffeinated coffee was tested and showed
that decaffeinated coffee also increased the sympathetic nerve
activity and blood pressure as did with caffeinated coffee in
nonhabitual coffee drinkers. The study also showed that the up
regulation of adenosine receptors is the reason for caffeine
tolerance but there may be other substances that may contribute
to the effects of coffee (Corti et.al, 2003).
Caffeine has a large effect on adenosine receptors in the
brain and can cause many different types of reactions from
increased stress, anxiety, alertness, insomnia (due to large in
take of caffeine), and effects on the hippocampus and can even
have some dependence effects. The effect that caffeine has on
people is different for each person. One person may have no
effects to caffeine and another person may have strong effects.
However, caffeine does affect your brain no matter what your
tolerance to it may be.
REFERENCES:
Anderson, K. and Revelle, W. (1983). The interactive effects of
caffeine and task demands on visual search task. Person.
Indivi. Diff. 4, 127
Bowyer, P., Humphreys, M. and Revelle, W. (1983). Arousal and
recognition memory: The effects of impulsivity, caffeine and
time on a task. Person. Indivi. Diff. 4, 41
Cameron, O.G., Modell, J.G., and Harinharan, M. (1990).
Caffeine and human cerebral blood flow: A positron emission
tomography study. Life Science 47, 1141
Corti,R., Binggeli,C., Sudano,I., Spieker,L., Ruschitzka,F.,
Luscher,T., Noll,G., Hanseler,E., Chaplin,W. (2003). Caffeine
and Coffee Tolerance. American Heart Association: Circulation.
108 (6).
Couturier, E.G.M., Hering, R. and Steiner, T.J. (1992). Weakened
attacks in migraine patients: caused by caffeine withdrawal?.
Cephalagia, 12, 99
Fagan, D., Swift, C.G., and Tiplady, B. (1998). Effect of
caffeine on vigilance and other performance tests in normal
subjects. Journal Psychopharmacology 2,19
Ghelardini, C., Bartolini, A., and Galeotii, N. (1997).
Caffeine induces central cholineigic analgesia. Arch.
Pharmacol., 356, 590
Greenberg, W., and Shapiro, D. (1987). The effects of caffeine
and stress on blood pressure in individuals with and without
family history of hypertension. Psychophysiology, 24, 151
Jarris, M. (1993). Does caffeine intake enhance absolute levels
of cognitive performance? Psychopharmacology. 110, 45
Leke, W.H., Meliska, C.J. (1984). Effects of Caffeine use and
ingestion on a protracted visual vigilance task.
Psychopharmacology. 84, 54
Lesk,V., Wombel,S. (2004). Caffeine, Priming, and Tip of the
Tongue: Evidence for Plasticity in the Phonological System.
Behavioral Neuroscience 118(3).
Lieberman, H.R., Wurtman, R.J., Emde, G.G., and Roberts, C.
(1987). The effects of low doses of caffeine on human
performance and mood. Psychopharmacology. 92,308
Nehlig, A., Daval, J.L., and Debry, G. (1992). Caffeine and the
Central Nervous System: Mechanisms of action, biochemical,
metabolic and psychostimulant effects. Brain Res. Rev., 12, 99.
Neuhauser-Berthold, Luhrmann, P.M., Verwied, S.C., and Beine,S.
(1997). Coffee consumption and total body water homeostasis as
measure by fluid balance and bioelectrical impedance analysis.
Ann. Nutr. Metab. 41, 29
Smith, A.P, Kendrick, A.M., and Maben, A.L. (1992). Effects of
breakfast and caffeine on performance and mood in the late
morning and after lunch. Neuropsychobiology 26,198
Solinas,M., Ferre,S., You,Z., Karcz-Kubicha,M., Popoli,P., and
Goldberg,S. (2002). Caffeine Induces Dopamine and Glutamate
Release in the Shell of the Nucleus Accumbens. Journal of
Neuroscience 22(15).
Specterman,M., Kuppuswamy,A.B., Strutton,P.H., Cately,M., and
Davey,N.J. (2005). The effect of an energy drink containing
glucose and caffeine on human corticospinal exitability.
Psychololgy and Behavior 83(5).
Stein, M.A., Bender, G.B., Phillips, W., Leventhal, B.L. and
Krasowski,M. (1996). Behavioral and cognitive effects of
methylxanthines: A meta-analysis of theophyline and caffeine.
Arch. Pediatric Adolescent Med. 150, 284
Warburton, D.M. (1995). Effects of caffeine on cognition and
mood without caffeine abstinence. Psychopharmacology 119,66
Yamato,T., Yamasaki,S., Misumi,Y., Obata,M.K., and Aomine,M.
(2002). Modulation of the stress response by coffee: an in vivo
microdialysis study of hippocampal serotonin and dopamine levels
in rat. Neuroscience letters 332(2).
Zahniser,N., Simosky,J., Mayfield,R.D., Negri,C., Hanaia,T.,
Larson,A., Kelly,M.A., Grandy,D.K., Rubinstein,M., Low,M.J., and
Fredholm,B.B. (2000). Functional Uncoupling of Adenosine A2a
Receptors and Reduced Response to Caffeine in Mice Lacking
Dopamine D2 Receptor. Journal of Neuroscience 20(16).
III. CAFFEINE: AN OVERVIEW OF NATURAL ORIGINS, CHEMISTRY, AND
NEUROTRANSMITTER EFFECTS.
By Brian Godwin, Humboldt State University
INTRODUCTION:
Caffeine is the most-widely consumed psychoactive
substance by human beings throughout the world (Reid, 2005).
This report will detail its natural origins, chemical
structure (as well as those of similar substances), and the
methods and dosages in which it is rendered into its usable
form. Additionally, this report will detail caffeine's various
biological pathways within the human body, including access to
the brain and various neurotransmitter pathways.
NATURAL ORIGINS:
Caffeine is a chemical that occurs naturally in over 100
plant species throughout the world (Steffen, 2000). Perhaps
the most widely recognized of these plants is the coffee tree,
whose small seed (commonly referred to as a "bean") is roasted
and then crushed into a fine powder (Weinberg and Bealer,
2001). Caffeine also occurs naturally in cocoa beans, tea
leaves, kola nuts, and gurana seeds, and mate. Some of these
plants, such as tea, actually bear a distinct, but similar
chemical to caffeine (i.e. theophylline); these chemicals will
be discussed further in the chemistry section (Steffen, 2000).
CHEMICAL COMPOSITION AND STRUCTURE:
Caffeine is chemically known by two names. The first is
1,3,7 -trimethylxanthine; the second is 3,7,-Dihydro-1,3,7-
trimethyl-1H-purine-2,6-dione. Historically, caffeine has also
gone by the name of methyltheobromine, as well as thein
(Weinberg and Bealer, 2001). The chemical formula of caffeine
is C8 H10 N4 O2. The molecular weight for this chemical is
194.19 atomic units. Its composition is as follows: 49.5
percent carbon, 5.2 percent hydrogen, 28.9 percent nitrogen,
and 16.5 percent oxygen. Caffeine melts from a solid hexagonal
crystal at 238 degrees Celsius (Karch, 1993).
Caffeine is a methylated purine derivative and is
classified as an alkaloid. An alkaloid is a class of organic
compounds composed of carbon, hydrogen, and nitrogen; oxygen
is usually found amongst these compounds. The term "alkaloid"
refers to compounds that can be extracted from plants, and
whose salts can be crystallized. Other alkaloids include
cocaine, serotonin, and the hallucinogenic compound, LSD. A
purine is a base compound, consisting of a six-membered and
five-membered nitrogen containing ring fused together; other
examples of purines include adenine and guanine, two bases
found in human DNA (Angstadt, 1997). The term "methylated"
refers to the fact that hydrogen atoms upon the compound have
been replaced with a methyl (CH3) compound (Methylation,
2005).[See figure 3]
PREPARATION, INGESTION, AND DOSING:
Caffeine is often served within hot beverages, such
as coffee or tea. In the case of the latter, the coffee bean
is ground up into a coarse powder, which is used as a filtrate
for hot water (Weinberg and Bealer, 2001). Hot water can also
be passed through tea leaves. At hot temperatures, such as
those found within serving temperatures of coffee and tea,
provide for the complete solubility (Weinberg and Bealer,
2001). Caffeine can also be found in solid food substances
such as chocolate and gurana fudge (Steffen, 2000).Certain
soft drinks and so-called "energy" drinks also contain
caffeine additives (Reid, 2005). All of the above substances
are ingested orally. The percentage of caffeine in the above
substances varies. In coffee, for example, caffeine composes
1.34% of the drink by weight; in tea, this number is 3.24%
(Weinberg and Bealer, 2001). Chemical extraction of caffeine
from roasted coffee beans yields between 8 and 20 milligrams
(mg) of caffeine per gram (g) of coffee beans (Karch, 1993).
Human consumption varies across demographic
characteristics, especially nationality. In the Scandinavian
countries, such as Norway and Denmark, the average daily
consumption of caffeine for a 60-70 kilogram (kg) subject 7.0
milligrams (mg) per kilogram of body mass; in American and
United Kingdom subjects, this daily average is between 2.4
mg/kg and 4.0 mg/kg of body mass. In Denmark, the mean daily
intake for children under the age of 18 years is 2.5 mg/kg of
body mass, and in the United States, this number is 1.0 mg/kg.
(Nehlig, 2000)
There is considerable variation amongst persons in
terms of bodily concentrations of caffeine (Weinberger and
Bealer, 2001). In an experiment in which the participants each
consumed 568 milliliters (ml) of coffee, peak blood levels of
caffeine were reached between 15 and 45 minutes after
ingestion; the amount of caffeine present per liter of blood
was 5.3 micrograms (Marks and Kelly, 1973, as cited in Karch,
1993). The half-life of caffeine in the body varies as well:
in healthy adults, the half-life of caffeine is 3.5 hours on
average, in pregnant women, the half life of caffeine up to 18
hours, and in term infants, the half life of caffeine is 82
hours. Additionally, other substance use factors, such as the
ingestion of alcohol or tobacco products can significantly
impact the half-life of caffeine within human blood. (Weinberg
and Bealer, 2001). Eventually, the caffeine is metabolized
by the liver, where, according to Weinberg and Bealer (2001),
it is either "demethylated" into dimethylxanthine and
monoethylxanthine, or oxidized and converted into uric acid,
and eventually excreted in the urine.
NEUROLOGICAL PATHWAYS OF CAFFEINE:
Caffeine acts upon the human central nervous
system (Spiller, 1998). The central nervous system encompasses
the brain and the spinal cord (Kalat, 2001). Caffeine is
designated as a stimulant drug; according to Kalat, stimulants
produce "…excitement, alertness, elevated mood, decreased
fatigue, and sometimes increased motor activity (2001, p.
70)." Indeed, many people report using caffeine, often in the
form of coffee or other beverages, as a means of staying alert
during activities requiring intense concentration (Reid,
2005). Additionally, caffeine also works as a vasoconstrictor
within the brain, causing the blood vascular to constrict
whilst increasing the overall heart rate (Kalat, 2001). The
subsequent vasodilation occurring upon withdraw of caffeine
from the brain may be responsible for the severe headaches
endured by habitual users (Spiller, 1998)
The following sections will detail the effects of
caffeine upon the neurotransmitters adenosine, dopamine, and
serotonin, respectively:
CAFFEINE AND ADENOSINE:
Over the years, there have been competing reports
of the action of caffeine upon brain physiology (in example,
see Weinberg and Bealer, 2001). Theories included caffeine as
means of increasing calcium secretion of neurons, as calcium
is a necessary agent for nervous impulse transmission (Myers,
Johnson, and McVey, 1999). Another theory posited that
phosphodiesterase became inhibited by caffeine (Spiller,
1999). At the present time, both of these theories have been
more or less abandoned, mainly along the lines that the
dosages required of caffeine to activate these systems are so
large that ingestion would most likely yield lethal effects
(Weinberg and Bealer, 2001; see also Nehlig, 2000).
Researchers now look to the neuromodulator adenosine as the
molecule that plays a direct role in the neurological effects
associated with caffeine (Weinberg and Bealer, 2001).
Caffeine works directly upon the neuromodulator
adenosine as an antagonist (Daly et al, 1999). An antagonist
is a chemical that blocks the effect of a neurotransmitter
(Kalat, 2001). During metabolic activity, adenosine
monophosphate breaks down into adenosine. Adenosine inhibits
the brain's arousal system by binding to receptors in the
basal forebrain, an area responsible for wakefulness. As a
person goes about the day, adenosine accumulates; at high
enough levels, the adenosine inhibits the arousal centers and
induces sleepiness. (Kalat, 2001)
Caffeine binds with presynaptic adenosine receptors
(Daly et al, 1999). The primary molecular sites for the action
of caffeine are A1 and A2a receptors; these are high affinity
and low affinity receptor, respectively (Myers, Johnson, and
McVey, 1999). Adenosine mediates the release inhibition of
various neurotransmitters, including serotonin, dopamine,
glutamate, GABA, and acetylcholine. These neurotransmitters
are instrumental themselves in mediating alertness, sleep
cycles, attention, and memory, to name a few (Weinberg and
Bealer, 2001). The next two sections will briefly discuss the
inhibition of adenosine upon the neurotransmission of
serotonergic and dopaminergic pathways.
CAFFEINE AND THE DOPAMINERGIC PATHWAYS
Dopamine is a catecholamine neurotransmitter,
meaning that it is composed of a catechol and an amine group
compound (Kalat, 2001). Dopamine is often found in
reinforcement and reward pathways, hence its designation as a
"pleasure" molecule (Kalat, 2001). In a study involving rats,
caffeine was administered to two different dopaminergic
pathways (Nehlig, 2000). Regarding the first of these
pathways, the nigrostriatal dopaminergic system, caffeine was
found to activate a structure known as the caudate nucleus,
inducing dopamine release by modifying the spontaneous
electrical activity of the neurons within this structure.
Dopamine release in the nigrostriatal system accounts for the
stimulant effects of caffeine on locomotor activity (Nehlig,
2000).
The second dopaminergic pathway in the Nehlig
study, the mesolimbic dopaminergic system, has been studied as
a possible site for the formation of a physical dependency on
caffeine; it should be noted, though, that the issue of
caffeine and dependence is somewhat controversial (2001; see
also Weinberg and Bealer, 2001, and Spiller, 1999). This
system originates in the ventral tegmental area of the
midbrain, "…projects into the nucleus accumbens, and
terminates in the medial prefrontal cortex ( Nehlig, 2000,
p.50)." The nucleus accumbens is divided into a core and a
shell unit. The medioventral shell is thought to be a key
component of emotional, motivational, and reward functions;
the laterodorsal core regulates somatomotor functions. Other
stimulants, such as nicotine and cocaine, selectively
activate dopamine release within the shell; caffeine, however,
does not display any similar stimulation of dopamine release
at a normal dosing level of 0.5 to 5 mg/kg. In fact,
activation of the nucleus accumbens occurs only at high doses
(i.e 10 mg/kg), an amount 4 to 5 times greater than the
average adult American's daily consumption. (Nehlig, 2000)
CAFFEINE AND SEROTONERGIC PATHWAYS
Serotonin is a 5-HT indoleamine neurotransmitter;
amongst other attributes, serotonin is known for its influence
upon arousal and sleep activity (Kalat, 2001). Serotonergic
neuron cell groupings play a part in the regulation of sleep,
mood, and general well being (Nehlig, 2000). At low-to-medium
doses, caffeine stimulates electrical activity in reticular
formation neurons, as well as lowering electrical activity in
the thalamus, a site known to be connected with caffeine-
induced arousal (Nehlig, 2000). Serotonin availability is also
reduced by medium levels of caffeine, which in turns reduces
the sedative effects of the neurotransmitter at the
postsynaptic level (Myers, Johnson, and McVey, 1999). This can
lead to an interference of the sleep cycle, as well as changes
in motor function (Nehlig, 2000). Additionally, caffeine has
been shown to induce serotonin release in the cerebellum and
cerebral cortex (Spiller, 1998).
CONCLUSION:
Caffeine and its methylxanthine relatives compose
the most widely used psychoactive substances in the world.
This widely available drug can be found in beverages such as
coffee and tea, and in foods like chocolate. Much research
exists describing its chemical and molecular properties, as
well as its human dosing information. Caffeine works directly
upon the neuromodulator adenosine; this effect subsequently
influences the neurotransmission of hormones and
neurotransmitters, such as dopamine and serotonin. As more
research unfolds regarding neurological physiology and
chemistry, the scientific community will no doubt discover
many more facets of the workings of caffeine.
WORKS CITED
Angstadt, C. (1997). Purines and pyrimidine metabolism.
Retrieved March 6, 2005 from Net Biochem
website:http://wwwmedlib.med.utah.edu/NetBiochem/pupyr/pp.htm.
Daly, J., Shi, D., Nikodijevic, O., and Jacobson, K. (1999).
The role of adenosine receptors in the central action of
caffeine. In B. Gupta and U. Gupta (Eds.), Caffeine and
behavior: Current views and research trends (p.1-16). New
York: CRC Press.
Kalat, J. (2001). Biological psychology,7th ed.. Belmont:
Wadsworth-Thompson.
Karch, S. (1993). The pathology of drug abuse. Boca Raton: CRC
Press.
Methylation (2005). Retrieved March 6, 2005 from Wikipedia,
the Free Encyclopedia website:
http://en.wikipedia.org/wiki/Methylation.
Myers, P., Johnson, D., and McVey, D. (1999). Caffeine in the
modulation of brain function. In B. Gupta and U. Gupta (Eds.),
Caffeine and behavior: Current views and research trends
(p.17-30). New York: CRC Press.
Nehlig, A. (2000). Caffeine effects on the brain and behavior:
a metabolic approach. In H. Parliament, C.Ho, and P.Schieberle
(Eds.), Caffeinated beverages: Health benefits, physiological
effects, and chemistry (p.46-53). Washington, D.C: American
Chemical Society.
Spiller, G. (1998). Basic metabolism and physiological effects
of the methylxanthines. In G. Spiller (Ed.), Caffeine (p.225-
231). New York: CRC Press.
Steffen, D.(2000). Chemistry and health benefits of
caffeinated beverages: symposium overview. In H. Parliament,
C.Ho, and P.Schieberle (Eds.), Caffeinated beverages: Health
benefits, physiological effects, and chemistry (p.2-8).
Washington, D.C: American Chemical Society.
Reid, T. (2005). Caffeine: What's the buzz? Why we love
caffeine. National Geographic, 207, 1, p.2-33.
Weinberg, B., and Bealer, B. (2001). The world of caffeine:
The science and culture of the world's most popular drug. New
York: Routledge.
CAFFEINE-INDUCED PSYCHOLOGICAL CHANGES:
To many people, caffeine seems like more of a necessity
to start the day, or keep the day going, rather than a
potentially harmful drug; however, most do not realize the
long-term physiological changes that can occur as reported by
several users. According to National Geographic, consumers
spend 30 million dollars every year on caffeine tablets and
roughly 50 billion dollars on caffeinated soda.
Caffeine is a drug and as such makes changes the bodies. When
people consume food or drink with caffeine in it the body
responds by a raise the blood pressure, exciting the central
nervous system, endorses urine formation, and speed up the
action of the heart and lungs. (Microsoft, 2003)
There are lots of reasons people use caffeine to get through
daily life, to stay away, to get ride of migraine and for
weight loss. Caffeine helps reduce migraines by reducing
blood flow in the vessels and thereby reduces the pain felt by
migraines. Caffeine can also heighten the effects of
painkillers like an aspirin. Caffeine widening airways
passages which helps relieve asthma. (Microsoft, 2003)
Caffeine has lots of immediate positive side effects such
as energizing, mood lifting, and pain relieving. However most
people today do not stop and think about the long-term
correlational effects of usage. Studies have found a possible
relationship between caffeine use and kidney, bladder,
fibrocystic breast disease, pancreatic cancer, osteoporosis
and birth defects. Caffeine increases a person's blood
pressure which given long term uses can cause an increase
likely-hood of heart disease. More research needs to be done
on exactly what caffeine cause. There is clear evidence that
shows caffeine is bad for you at normal uses levels this is
why U.S. Food and Drug Administration does not include
caffeine on its "generally recognized as safe" (GRAS) list.
(Microsoft, 2003)
Caffeine is a psychoactive drug and as such when consumed,
there are physiological changes that occur such as mood and
increase energy. People have explained this a "buzz." Users
like the way the buzz makes them feel. Other users feel a
sense of normalcy using the drug, which also makes it possible
for them to get through their daily life. (Ieid, T.R., 2005)
Caffeine is the most widely used drug in the world, yet
abuse of the drug is rare because people stop using when they
feel jittery and unable to function in a clear mental state.
Jittery is a feeling of anxiousness, most likely due to an
increase in blood pressure. Like other drugs, the amount of
caffeine needed to become jittery is dependant on the person's
body weight, i.e. children consume less amounts of caffeine
than adults and feel the same effects because of their low
body weight. (Ieid, T.R., 2005)
Digital imagery of the brain shows that a heavy caffeine
user's brain on caffeine looks the same as a person's brain
that is a light caffeine user not on caffeine at that
particular time. In other words, a heavy caffeine user needs
caffeine to have their brain function somewhat normal. (Ieid,
T.R., 2005)
There has been no direct relationship between death and
caffeine use, however there is a case in Ireland, of an 18-
year old basketball player who drank large quantities of Red-
Bull and died suddenly on the basketball court. Due to this
incident, the government of Ireland formed a committee to look
into the matter. They found "no serious risk for consumption
of caffeinated energy drinks- at moderate levels." Per the
committee's recommendation there have been warning labels
placed on containers. Other countries have laws in place, yet
the United States does not have such laws in action. (Ieid,
T.R., 2005)
EFFECTS REPORTED BY CAFFEINE USERS:
Caffeine has become a widely used, socially acceptable
drug for many different reasons. College students use caffeine
to stay awake to study and young adults use the substance to
party all night long. A 29-year old said, "By four or five in
the morning, you are totally blotto [intoxicated]. That's
where Red-Bull comes in. I drink these two tins, it's like
drinking a pint of speed." The common office worker starts out
the day with a cup of coffee and has a soda at lunch not
knowingly putting caffeine into their body, because without
it, they are tired and unable to work to their full potential.
(Ieid, T.R., 2005)
Daily users report that when they don't have caffeine,
they get headaches, feel tired, and have general lack of
energy. This was explained earlier why this happens on a
biological level. Caffeine has a circular effect on the body.
A person becomes dependent on caffeine after several days of
use. Their body needs caffeine to prevent headaches and other
reported side effects. (Ieid, T.R., 2005)
People use the drug because of its socially
acceptableness, its availability and how it makes people feel.
People report increase energy, increase happier moods and an
increase in alertness. People also report an increase for the
need of urination after moderate consumptions of caffeine.
(Design, 2005)
People need caffeine because of insufficient sleep, which
could be largely contributed to the use of caffeine. Humans
are stuck in a viscous cycle of having caffeine all day long,
waking up and the affects of caffeine are worn off so they
need more caffeine to jump start their morning. (Ieid, T.R.,
2005)
Most people today will tell you that caffeine is a drug,
yet they still use that substance because of the effects
achieved through the usage.
References
Caffeine. (2003). Microsoft Encarta Reference Library 2003. ©
1993-2002 Microsoft Corporation.
Coffee -- Healthy Tonic for the Liver? (2005). National Coffee
Association.
http://www.coffeescience.org
Design, M. (2005). What is the Buzz?. from National
Geographic Society. Web site:
http://magma.nationalgeographic.com/ngm/0501/sights_n_sounds/m
edia1.html
Ieid, T.R. (2005). Caffeine: It's the world's most popu-.
National Geographic, January 2-32
Parliament, Ho and Schieberle (2000). Caffeinated Beverages:
Health Benefits, Physiological Effects and Chemistry.
Washington, D.C.: Oxford University Press.
Go back to the beginning
Copyright © 2005, Dr. John M. Morgan, All rights
reserved -
This page last edited 1-3, 2005
If you have any feedback for the author, E-mail me
