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Thread: Caffeine And Its Physiological Effects

  1. #1
    CAFFEINE AND ITS PHYSIOLOGICAL EFFECTS





    Caffeine, probably the most widely used drug, is a potent pharmacological and psychotropic agent. The white, bitter-tasting, crystalline substance was first isolated from coffee in 1820. The origins of the words, caffeine and coffee, reflect the spread of the beverage into Europe via Arabia and Turkey form North-East Africa, where coffee trees were cultivated in the 6th century. Coffee began to be popular in Europe in the 17th century, and plantation had been established in Indonesia and the West Indies by the 18th century. Nowadays, it is a regular component of the diet for most people. Caffeine is considered as a cheap drug that could be found in many nature sources such as tea, chocolate, and cocoa.

    What happen to the caffeine when it is ingested, and what are its consequences? In addressing these questions, there have been many contributors spent much time to prove that caffeine has been shown to behave as an adenosine antagonist to stimulate motor activity, mood and behavior. This antagonist behavior is the basis for an increase in cholinergic and dopaminergic behavior after caffeine intake. Beside of that, the acute administration of caffeine has been reported by several laboratories to elevate brain level of serotonin (5-HT) and 5-hydroxyindoleacet ic acid (5-HIAA). This increase of serotonin may be associated with the improvement in good mood. Recent studies also show the higher caffeine intake to a lower suicide risk. In this paper, I will investigate the caffeine at a biochemical level and relate its effects on physiological behavior of human with information from the recent research.

    For many years, the mechanism of caffeine was not yet clear. However, it was thought that the mechanism involves the response of hormone signals. When hormones cannot penetrate the cell directly, they bind to the hydrophilic surface of the cell membrane and activate adenylate cyclase, and enzyme that catalyzes ATP to cyclic AMP,a secondary messenger hormone. Most of these hormones are catecholamines. This process, in turn, leads to cyclic AMP's activation of protein kinases, which then active, catalyze a cascade of enzyme phosphorylation. The cascade leads to the releasing of other hormones which are responsible for physiological effects in brain.

    In early studies, caffeine was thought to inhibit phosphodiesterase, an enzyme which is responsible for degrading cAMP. This inhibition leads to an increase of cAMP, which is known to have the effects on excitatory neurotransmitters such as norepinephrine and dopamine. Therefore, caffeine would lead to higher activity of the excitatory neurotransmitter causing the stimulatory effects psychomotor (Glass et al. 1996). However, substantial inhibition of phosphodiesterases requires millimolar concentrations of caffeine, roughly 100 times the caffeine levels in the brain after ingestion of typical doses in man. Furthermore, some inhibitors of phosphodiesterase are 100-1000 times more potent than caffeine lack behavior effects.

    The most important neurobiological effects of caffeine is its activity as an antagonist of the adenosine receptor. Recently, a variety of evidence has accumulated suggesting strongly that adenosine may mediate the behavioral influences of caffeine. Adenosine is an intermediary in a wide range of metabolic pathways and is a consitituent of ATP and nuclei acids. Administration of adenosine can produce sedation, bradycaardia, hypotension, hypothermia, and attenuation fo the responses of the heart, vaculature, and adipose tissue to sympathetic stimulation. Adenosine has a variety of actions on central neurons. In most instances it inhibits its spontaneous neuronal firing. The inhibitory actions of adenosine seem in large part to be presynaptic due to the inhibition of release of excitatory neurotransmitters, though there are also postsynaptic effects.

    The localization of adenosine receptor has been approached by autoradiography. By applying this technique, researchers have been able to map in detail the location of adenosine receptors in the central nervous system. There are marked differences in the concentration of adenosine receptors in different brain areas. The highest densities occur in specific areas such as the molecular layer of the cerebellum, the molecular and polymorphic layers of the hippocampus and dentate gyrus. This implies that the function of adenosine receptor is to inhibit the presynaptic release of granule cell excitatory neurotransmitter, which is thought to be glutamic acid. We also found adenosine receptors in the superior colliculus. Thus, presumably adenosine could act in the superior colliculus by inhibiting release of the excitatory transmitter from optic nerves. From these information, the researchers have agreed upon that caffeine blocks the presynaptic inhibitory action of adenosine, causes an increase in excitatory neurotransmitter release, and results in stimulation of psychomotor activity. Chronic caffeine consumption also increases the number of adenosine receptors in the brain that is possibly due to the body's attempt to compensate for caffeine's antagonist effects (Glass et al. 1996). Adenosine can increase the accumulation of cyclic AMP in brain by a mechanism that does not involve conversion of adenosine to cyclic AMP, but rather an action on extracellular receptors. The effects of adenosine on the enzyme adenylate cyclase, which synthesizes cyclic AMP, reveal two distinct subtypes of adenosine receptors A1 and A2. The enhancing actions of adenosine on adenylate cyclase occur at micromolar concentration via A2. Through A1 receptors, adenosine at nanomolar concentrations inhibits adenylate cyclase activity. Beside structural differences in these subtypes, both are stereospecific for binding adenosine derivatives. Adenylate cyclase is an important G-protein coupled enzyme necessary for second messenger production. Recent studies have been shown that A1 adenosine receptors have increased after chronic caffeine intake while the A2 subtype remained unchanged (Kaplan et al.1995). This increase in A1 adenosine receptors was followed with an increase in the inhibitory effects on motor activity when adenosine analogs were added.

    Chronic caffeine use also alters the regular release of other neurotransmitters in the brain such as dopamine and catecholamine. The antagonist effects of caffeine at the presynaptic adenosine receptor could allow for increased activity of these neurotransmitters. An example of this is the increased cholinergic activity in the hippcampus following caffeine ingestion ( WWW1). Studies have indicated a relationship between increased cholinergic activity with arousal, behavior consistent with the presence of caffeine. The psychostimulant effects of caffeine, such as decreased fatigue and increase wakefulness can be traced to this cholinergic pathway. This suggest that adenosine may also normally regulate the arousal and sleep-wake behavior.

    Dopamine has been proposed to mediate some of the behavior effects of caffeine. Caffeine has been shown to enhance dopaminergic activity by competitive antagonism at adenosine receptors and interact functionally with dopamine receptors. Thus, caffeine may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors leading to stimulating dopaminergic activity.

    There has also been frequent speculation on the relation ship between adenosine A2 receptor and dopamine D2 receptor. The dopamine is a neurotransmitter that associated with the brain's motor regulation, cognition, and reward-pleasure centers. The caffeine acts behaviorally by blocking adenosine receptors enhance dopaminergic function. In reverse, intake of adenosine analogs seems to decrease the stimulatory effects of the dopaminergic activity. Similar to the actions caused by dopamine antagonists, caffeine intake increases motor activity. The enhance of stimulatory effects of cocaine is thought to be due to the increase in dopaminergic function. Recently is has been shown that infusions of adenosine into rats at rates that increase plasma adenosine only very slightly result in considerable reductions in blood pressure. Caffeine antagonizes this effects very potently. This raises the possibility that most or all the ability of caffeine to raise blood pressure relates to antagonism of adenosine. Caffeine as an antagonist at the adenosine receptor would be expected to counteract this effect directly.

    Caffeine has frequently been studied for its effects on norenephrine neurons in brain. Early reports by Berkowitz et al. (1970) indicated that caffeine injections enhances norepinephrine synthesis and turnover. The increase in turnover suggested to the investigators that caffeine enhanced norepinephrine release from nerve terminals. The hypothesis mechanism by which caffeine stimulates norepinephrine neurons in brain is that the caffeine may increase the firing rate of norenephrine- containing neurons in brain, thereby leading to increase in both norenephrine synthesis and turnover.

    Caffeine also influences catecholamine neurons in the peripheral as well as the central nervous system. It may cause these peripheral effects directly, by some action on the end organ itself, indirectly, via the release of catocholamine and its interaction with end organ (Kaplan et al. 1995). It stimulates the release of catecholamines from both the adrenal gland and sympathetic nerves. The predictable consequences of an increase in sympathetic activation and catecholamine release should include increased gluconeogenesis, lipolysis, and metabolic rate.

    The acute administration of caffeine has been reported by several laboratories to elevate brain levels of serotonin (5-HT) and 5-hydroxyindoleacet ic acid (5-HIAA), which is primary metabolite of serotonin. The effects are observed both in whole brain and in such brain regions as the brainstem and cerebral cortex. The mechanism by which caffeine injection elevates brain levels of 5-HT is thought that caffeine might somehow induce tryptophan hydroxylase, or it might elevate brain levels of tryptophan, which would then lead indirectly to a stimulation of 5-HT synthesis. It seems likely that a multiplicity of known and unknown factors may contribute to the caffeine-induced rise in brain tryptophan, because of the relatively high doses required to obtain this effect. A rise in tryptophan levels enhances 5-HT synthesis rate by increasing the degree of substrate saturation of tryptophan hydroxylase, the enzyme that catalyzes the rate-limiting step in 5-HT formation. An explanation for this occurrence could be that the tryptophan hydroxylase reached its saturation level by the excessive tryptophan, or may be this enzyme could be regulated by biochemical mechanisms to decrease its activity and synthesize less 5-HT synthesis and degradation to 5-HIAA. Overall, caffeine raises the level of brain 5-HT which is opposite to the depressive behavior and instilling pleasure and arousal.

    Many caffeine users experience caffeine dependence. In the DSM-IV, substance dependence can be identified with tolerance and withdrawal. Tolerance refers to the body "getting used" to a drug with its repeated taking. It is difficult to study the tolerance of human subjects to the various effects of caffeine because nearly everyone in our society uses caffeine regularly in one form or another. Withdrawal symptoms experienced with cessation of use, and the substance is taken in order to avoid or relieve withdrawal symptoms. Some people that stop using caffeine will have a headache, fatigue, irritability, dysphoria, and craving for coffee. Withdrawal symptom experienced may be caused by serotonergic activity. An increase in the number of 5-HT receptors after chronic caffeine intake may reduce the depressive symptoms. Withdrawal also occurs as caffeine cessation leading to symptom of irritability, nervousness, and headaches. Serious headaches associated with withdrawal symptoms are usually alleviated with caffeine intake itself (Glass et al. 1996). Caffeine withdrawal is caused by a hypersensitivity to adenosine because of the increased number of adenosine receptors from caffeine consumption. The headaches are induced by intense drop in blood pressure since adenosine is known as a vasodilator (Kaplan et al. 1995).

    With evidence suggesting that low level of 5-HT and increased 5-HT receptors correlating to symptoms of depression and suicide, there have been many recent studies attempted to perform a survey of 90,000 women who have chronic use of caffeine in 10 years. The results revealed an inverse relationship between coffee intake and risk of suicide. There were fewer suicides among coffee drinkers than non-drinkers. This survey involved people from various ethnic, ages, and other health factors. Many heavy coffee drinkers are revealed participating in less-healthy activities such as smoking and drinking, therefore having more potential to have higher risk of suicide. The results that coffee drinkers are less prone to suicide are consistent with the increasing level of 5-HT in brain. Regular coffee drinkers also reported improved mood and decreased irritability because of the result in increasing level of 5-HT from caffeine intake (WWW1).

    Tolerance occurs as an increase in number of adenosine receptors created by caffeine use requires more of this drug to block the greater number of receptors. Thus, heavy caffeine consumers are usually least affected by the stimulant properties of the drug. Biochemical studies showed that caffeine in the non-tolerant condition reduced GABAergic activity in cerebral cortex, corpus striatum, cerebellum, and pons-medulla. Tolerance to caffeine pushed up the GABAergic activity to the control value in all these regions of brain. From the present study the scientists concluded that development of tolerance to caffeine id dependent on the dosage of caffeine, and the reduction of central GABAergic activity in the caffeine-nontoleran t condition pushed up and restored the locomotor activity to the control level on the development of tolerance to caffeine (WWW1).

    In conclusion, caffeine today are the world's most widely consumed mind altering substances, and people are as curious as ever about what they are and how they work. There is still much to learn about its effects at the molecular and physiological level. However, from researches and experiments scientists do seem to agree upon the mechanism that caffeine is an adenosine receptor antagonist. It blocks the inhibitory effects of adenosine causing the increase in release of certain neurotransmitters such as norepinephrine and dopamine. Acetylcholine was found to be inhibited by adenosine A1 receptors in the hippocampus. Increase cholinergic activity has been known to affect the cortex and can account ffor the psychostimulant effects of caffeine. This includes arousal, decreased fatigue, and decrease for sleep. Caffeine also blocks the inhibitory actions of the adenosine A2 receptor leading to the effect on motor generation pathway. Another neurotransmitter that I mention in this paper is 5-HT in the brain. Caffeine may not be omnipotent in raising 5-HT, however, since studies have shown that frequent and highly concentrated doses of caffeine can actually depress production of 5-HT due to the saturation of 5-HIAA. Low level of 5-HT associates with depression and suicide. Therefore, caffeine may have potential to prevent these symptoms due to its effects on raising the level of 5-HT. These physiological and behavior effects, however, depend on the amount of ingested. A small amount, probably less that 500mg, may enhances psychomotor performance, improving the work output, and help staying arousal. If the mount is more than 500mg, it may cause anxiety, restlessness, insomnia, and elevated body temperature. And if someone ingested with the amount more than 10grams, then it will have serious effects on health such as seizures from over-stimulation of the Central Nervous System, tachycardia and cardiac arrhythmia. Recent surveys have shown that the effects of caffeine overdose usually occur from taking pills containing caffeine. Highly overdose may cause people died from seizure, or heart attack. However, chronic caffeine consumption seems to have a little harm to health at a moderate level. Yet, in fact, it provides a pleasurable feeling and motivation of work for users are the beneficial consequences of these substances, although it is known to cause the withdrawal symptoms and signs of tolerance. Americans are thought to consume an average of 3-10mg caffeine per kilogram of their body weight everyday (WWW1)
    I M What i Call i m "i m Loaded hell"
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  2. #2
    great post! For me, when I drink coffee early in the morning... I tend to have insomnia for 2 nights in a row.

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