INTRODUCTION:

Caffeine is so widely consumed in the world that a little attention is paid to the fact that in about 80% of the population voluntarily and routinely manipulate their mind pharmacologically. Such a wide spread use suggest s that caffeine has at least some reinforcing effect and that it is well tolerated in habitual doses. Also, being readily available at a low cost and with high social acceptance and incentive ,at least compared to other available drugs, individuals can easily adjust their own dose, time of administration, and dose intervals of caffeine intake according to the perceived benefits and side effects of each dose. Caffeine can be obtained from coffee, tea, energy drinks, and chocolates. Caffeine is the most active compound among the composition(1,2)

PSYCHOTROPHIC EFFECTS OF CAFFEINE:

Caffeine has ‘mental activating’ properties, increasing alertness and energy and reducing sleepiness and fatigue. These effects contribute to increased performance in some context, being particularly apparent in situations of low alertness, such as early morning, sleep deprivation and when sustained performance is demanded. At higher doses in sensitive individuals can induce a condition called caffeinism such as anxiety, restlessness, nervousness, dysphoria, insomnia, excitement which mimic a clinical picture known as mixed mood state.(3,4) caffeine is devoid of important negative consequence on health, performance and social adjustment(5,6) Thus, caffeine has mild to moderate reinforcing effects and has a “therapeutic window” of psycho stimulant properties that may bring about some effect.

ACTION OF CAFFEINE ON BRAIN CIRCUITS:

IN non-toxic doses, the only evident molecular mechanism of action of caffeine seems to be the antagonism of adenosine receptors, mainly of adenosine receptors(7). Caffeine can affect the release of calcium from intracellular stores, interfere with GABA receptors and inhibit 5-nucleotidases and alkaline phosphates, but this requires concentrations of caffeine higher than these required to antagonize adenosine receptors, which are hardly attainable under non-toxic conditions of caffeine consumption.(8-12). A1 and A2A receptors are most abundantly located in the brain, and both have a predominant neuronal localization (13), which is in agreement with the predominant effects of caffeine on brain-related functions. A1 receptor mediated inhibitory system is argued to be responsible by setting a hurdle for plasticity, avoiding the implementation of irrelevant signals in neuronal circuit(14).

The neurophysiologic layoutof the role of the adenosine modulation system in the control of synaptic plasticity leads to 4 predilections related to the expected effects of caffeine on memory performance 1-that the consumption of caffeine might mainly normalize aberrant memory performance rather than enhancing memory performance(15) 2- that caffeine will impact on synaptic transmission through competitive antagonism of excessive activation of A2A receptors, allowing the normalization of synaptic plasticity(16) 3- that the effects of caffeine on the normalization of memory performance might be mimicked by selective antagonist of A2A rather than A1 receptors 4- that the manipulation of A1 receptors might be essentially deleterious for the implementation of novel memory traits since the role of A1 receptors is mostly t control the basal activity of neuronal circuits. Administration of A1 receptor antagonists attenuates memory acquisition but improves memory consolidation(17,18)

EFFECT ON PARKINSONISM:

Parkinson's disease (PD, also known as idiopathic or primary parkinsonism, hypokinetic rigid syndrome (HRS), or paralysis agitans) is a degenerative disorder of the central nervous system mainly affecting the motor system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. The prevalence of Parkinson’s disease is generally estimated at 0.3%of the entire population and about 1% in people over 60 years of age (30). Since the incidence of the disease increases with age, it is likely that the number of people suffering from Parkinson’s will rise steadily in the future. Caffeine, especially A2a receptors antagonism have long been considered as putative strategies to manage Parkinson’s disease andA2a receptor antagonists are currently being pursued as novel non-dopaminergic anti-Parkinson’s drugs (19, 20).

In fact the intake of caffeine is inversely correlated with the incidence of Parkinson’s disease in different cohorts (21-25) and A2a receptor antagonists attenuate motor impairment in different animal models of Parkinson’s disease (26-28). In an animal model of Parkinson’s disease based on the administration of the toxin MPTP, the acute administration of caffeine (0.1-1 mg/kg) prevented the MPTP-induced impairment of the avoidance scores in the training and test sessions of a two-way active avoidance task in rats(29). Of high importance, caffeine-mediated neuroprotection apparently does not develop tolerance after continuous treatment, whereas complete tolerance develops for its motor stimulant effect(31). The complimentary genetic and pharmacological studies provide compelling evidence that caffeine reduces dopaminergic neurotoxicity in animal models of Parkinson’s through the antagonism of adenosine A2a receptors.

EFFECT ON ALZHEIMER’S:

Alzheimer's disease (AD), also known as Alzheimer disease, or just Alzheimer's, accounts for 60% to 70% of cases of dementia. It is a chronic neurodegenerative disease that usually starts slowly and gets worse over time. The most common early symptom is difficulty in remembering recent events (short-term memory loss). As the disease advances, symptoms can include: problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioral issues. As a person's condition declines, she or he often withdraws from family and society.

Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years. The general ability of caffeine to prevent memory deterioration upon different insults, it would be expected that both caffeine and adenosine receptor antagonists should be considered as promising new pharmacological tools to manage the prototypical conditions affecting memory performance in Alzheimer’s. this was first confirmed in a retrospective epidemiological study showing that the incidence of Alzheimer’s was inversely associated with the consumption of coffee in the previous two decades of life.

There is also compelling evidence for a beneficial role of caffeine in animal models of AD [58–60]. Since rodents do not spontaneously develop age-related modifications that resemble AD [61], two parallel strategies have been used to model AD in rodents: the first relies on the use of transgenic mice endowed with different mutations of proteins found to be dysfunctional in AD, namely amyloid β protein precursor (AβPP) and tau [62]; the other relies on the intracerebroventricular administration of soluble amyloid β peptide fragments (Aβ, mainly Aβ1−42), which are proposed to be a causative factor of dementia since their level is the biochemical parameter that correlates better with memory deficits in AD ( 63, 64). In transgenic mice with the Swedish mutation of the AβPP that model several features of AD [65], a six month period of caffeine intake (0.3 mg/ml) alleviated the cognitive deficits found in these mice, as well as the levels of soluble Aβ peptide fragments.

In neuronal cell cultures from these same transgenic mice, caffeine also reduced the production of Aβ1−40and Aβ1−42peptides, whereas propend of ylline attenuated tau phosphorylation also in cultured neurons [66]. Likewise, acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Aβ levels in both brain interstitial fluid and plasma, and long-term oral caffeine treatment to aged AD transgenic mice provides not only sustained reductions in plasma Aβ, but also decreases in both soluble and deposited Aβ in hippocampus and cortex [67]. Caffeine might not only reduce the levels of Aβ peptides but also counteract the noxious effects of these Aβ peptides, thought to be involved in the etiology of AD. Thus, caffeine prevents neuronal damage caused by exposure to Aβ peptide fragments, an effect mimicked by A2A, but not A1, receptor antagonists [68]. Accordingly, the delayed memory deficits observed after the intracerebral administration of Aβ peptide fragments were prevented by either caffeine or selective A2Areceptor antagonists [69,70]. These results further strengthen the idea that caffeine affords beneficial effects on memory performance through its action on A2Areceptors, which were found to be up regulated in cortical regions in animals models as well as in cortical tissue from patients with AD [71,72]. This might be related to the notable finding that caffeine not only allows a prophylactic benefit, but may actually revert the pre-installed memory deficit. Thus, a4–5 week treatment with caffeine (applied through the drinking water) restored performance in 18–19 month old (aged) AβPPsw mice already displaying impaired working memory. Interestingly, in contrast to other noxious brain conditions, it was also observed that there was an up-regulation of A1receptors in afflicted regions which may also control the production of soluble Aβ peptide fragments [72].

However, pharmaceutical studies indicate that the protective effects of caffeine are not mimicked by antagonists of A1receptors but rather by antagonists of A2Areceptors .Recent studies by our group revealed that either the pharmacological or genetic deletion of A2Areceptors prevents the amnesia and synaptic dysfunction caused by administration of Aβ peptides in accordance with the predominant synaptic localization of A2Ain cortical synapses [73]. Since the loss of synapses in cortical regions is the earliest morphological modification in AD (see [74,75]), as well as in mild cognitive impairment [76,77], these results further strength the suggestion that caffeine and A2Areceptor antagonists may be a novel promising prophylactic and/or therapeutic option to manage the precocious phases of AD.

EFFECT ON DEMENTIA:

Dementia is a broad category of brain diseases that cause a long term and often gradual decrease in the ability to think and remember such that a person's daily functioning is affected. Other common symptoms include emotional problems, problems with language, and a decrease in motivation (33). A person's consciousness is not affected. For the diagnosis to be present it must be a change from a person's usual mental functioning and a greater decline than one would expect due to aging (34) These diseases also have a significant effect on a person's caregivers. Alzheimer’s Disease (AD) is the most frequent cause of dementia. It is estimated that between 50-70% of people with dementia suffer from AD.

Caffeinated coffee increased plasma levels of granulocyte-colony stimulating factor (GCSF), which seemed to improve the cognitive performance of AD transgenic mice with the recruitment of bone marrow cells, enhanced synaptogenesis, and increased neurogenesis. Neither a caffeine solution alone nor decaffeinated coffee provided this effect. The authors hypothesize that caffeine might interact with another component in coffee to selectively elevate GCSF (35).

Caffeine may also be active at a different level. In an animal study, the long-term consumption of caffeine in drinking water by rats increased cerebrospinal fluid (CSF) production and cerebral blood flow, which directly affects the production of CSF37. Defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of AD38. This may partly explain the caffeine-induced reduction of brain levels of Aβ peptide although it is not yet known whether this effect also occurs in humans (36, 37).

EFFECT ON BIPOLAR MOOD DISORDER:

Bipolar disorder, also known as bipolar affective disorder (and originally called manic-depressive illness), is a mental disorder characterized by periods of elevated mood and periods of depression. The elevated mood is significant and is known as mania or hypomania depending on the severity or whether there is psychosis. During mania an individual feels or acts abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self harm occurs in 30–40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated.

Caffeine has been classically regarded as an inducer of anxiety at higher doses, typically over 300 mg [38-41], but the consumption of caffeine is poorly correlated with anxiety or anxiety traits [42-44]. Besides dosage, the anxiogenic effect of caffeine is influenced by individual factors, such as preference for caffeine, presence of some anxiety disorders, and genetic background. Doses of 50–100 mg of caffeine are usually sufficient to induce mood effects and in some individuals the effect of 20–30 mg is still clearly noticeable [43]. The presence of specific anxiety disorders influences the perceived effects of caffeine. Earlier studies have found higher sensitivity to anxiogenic effects of high dose caffeine (typically higher than 400 mg) in patients with panic disorder [44], generalized anxiety disorder [45], and to a lesser extent in depressed patients [46]. More recent studies extended these findings to patients with performance social anxiety disorder, but not generalized social anxiety disorder [47] and to first degree relatives of patients with panic disorder [48]. Also, patients with panic disorder who develop caffeine-induced panic attacks have significantly higher non-specific general psychopathology [49].

In contrast, a recent randomized controlled trial showed that caffeine led to clinical response in 7 out of 12patients with treatment-resistant obsessive compulsive disorder (OCD) and a 55% reduction of symptoms core in these responders, which was comparable tod-amphetamine [50]. It should be noted that OCD, although classified as an anxiety disorder, is more related to control of thought and behavior than to fear and worry, as other anxiety disorders. The genetic basis for the anxiogenic effects of caffeine has been investigated. Individuals with the 1976T/T genotypes for A2A adenosine receptors reported greater increases in anxiety after caffeine administration than the other genotypic groups [51].

This genotype (also referred to as 1083 C> T) was associated with less caffeine intake [52] as well as with blood-injury phobia [53] and panic disorder in western population [54], but not in Asians [55].Conversely, caffeine intake at low doses can also reduce anxiety and elevate mood in humans [56].Caffeine cessation over a couple of days may increase anxiety and depression scores in about 10% of volunteers with a moderate daily intake (mean 235 mg perday), and lead to headache in about 50% of volunteers . Also, in one of the few population studies on regular caffeine intake, Smith [57] has shown that consumption of caffeine, even at low doses, was associated with a reduced risk of depression (OR=0.32,CI 0.2–0.5; OR=0.18, CI 0.1–0.3 and OR=0.12,CI 0.1–0.2 for 1–140 mg/day, 141–260 mg/day and>260 mg/day, respectively, compared to those with no caffeine intake). This study was conducted in a nonworking population, which may have higher baseline levels of depression, probably making it easier to identify this effect compared to a working population.

CONCLUSION:

Caffeine is a CNS stimulant and it enhances mood stabilizing effect hence found beneficial in the treatment of central nervous system disorders like Parkinson’s disease, Alzheimer’s disease and Bipolar mood disorder. It has been reported that Coffee Intake of 6 cups /day has drastically reduced the risk of neurological disorder like Alzheimer’s disease. This article will provide a bird’s eye view about the significant beneficial effects of caffeine consumption for management of cognitive disorders.

ACKNOWLEDGEMENT:

The author wish to thank the various peer reviewed indexed journals, database from where the source for compiling the article is utilized.

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Received on 18.05.2015 Modified on 13.06.2015

Research J. Pharm. and Tech. 8(11): Nov., 2015; Page 1582-1587

DOI: 10.5958/0974-360X.2015.00282.6