1.1 Introduction
Caffeine is the most commonly used psychostimulant worldwide. It is consumed by approximately 85% of the US population with an average intake of 165 mg/day in the form of coffee and caffeinated beverages. Despite the widespread belief that caffeine is not addictive, physical and psychological dependence have been linked to consistent use due to the stimulant's reinforcing effects as well as the desire to ward off withdrawal symptoms and boost attentiveness.
With a higher affinity for the adenosine type 1 receptor (A1R) than for other adenosine receptor types, caffeine is a competitive antagonist of adenosine receptors. Caffeine not only suppresses the A1R in the brain, but it also shortens the cortical silent period (CSP), controls intracellular potassium and calcium levels, and interferes with GABAergic synapses by decreasing inhibitory GABAergic neurotransmission. However, since A2R knockout mice do not experience the arousal effects of caffeine, it is clear that the well-known arousal effect of caffeine is mediated by activation of the adenosine type 2 receptor (A2R). Additional benefits include improving memory, focus, and performance; they also strengthen muscles; control the sleep-wake cycle; affect moods; and alter vision perception.
1.2 Chemistry of Caffeine (mainly Cacao and Coffee)
The ratios of 1,3,7-trimethylxanthine (caffeine), 3,7-dimethylxanthine (theobromine), and traces of 1,3-dimethylxanthine (theophylline) vary between coffee and chocolate. In humans, less than 2% of caffeine is eliminated in urine untransformed within 45 minutes of oral consumption, with the small intestine and stomach absorbing 99% of the caffeine. The majority of caffeine is converted to mono- and dimethylxanthines as well as methylated uracil derivatives in the liver by cytochrome P450 enzymes. More than 95% of caffeine's primary metabolism is carried out by CYP1A2.
The half-lives of the various methylxanthines differ and are dose-dependent, suggesting saturable kinetics of enzymatic metabolism. Caffeine reaches peak plasma concentrations within 1–2 hours of consumption and exhibits a half-life of approximately 2.5–5 hours, with variability between individuals [17, 25]. Paraxanthine’s half-life is similar to that of caffeine (3.1–4.1 hours), whereas theophylline and theobromine have somewhat longer half-lives (6.2–7.2 hours).
Figure-1: The molecular structure of caffeine (1,3,7-trimethylxanthine)
2.1 Caffeine and Neuroplasticity
Growing data suggests that regular coffee and/or chocolate consumption improves cognitive performance under stressful settings and reduces the neurocognitive decline associated with normal ageing and neurodegenerative illnesses.
Acute caffeine use increases memory performance. The Institute of Medicine's Food and Nutritional Board Committee on Military Nutrition Research reported that a dose of 150 mg of caffeine boosts cognitive performance for at least 10 hours, and recommended incorporating caffeine in military rations.
On the other hand, higher alertness after acute caffeine intake mirrors a reduced homeostatic sleep pressure, which is also evident in a reduced depth of sleep. The latter is characterised by attenuated electroencephalographic slow-wave activity (EEG SWA, 0.75 – 4.5 Hz) in non-rapid eye movement (NREM) sleep and shortened slow-wave sleep (SWS). Disrupted sleep homeostasis can cause not only micromorphometric modifications in the mitochondria and chromatin, which contribute to cell death, but also macrostructural changes.
Caffeine interferes with sleep homeostasis by dampening the accumulation of sleep pressure through the antagonism on adenosine A1 and A2A receptors. Evidence in animals shows that acute or long-term caffeine consumption inhibits the long-term potentiation (LTP), neurogenesis and cell proliferation 36 in hippocampus, and can impair learning and memory.
Figure-2 : Areas of the brain, including the hippocampus and medial temporal lobe, showing the effect of caffeine
2.2 Role of A2A Receptors in Neuroplasticity
A2A receptors play a minor function in modulating synaptic plasticity under normal settings, but they are critical in CA1 and CA3 areas when stimulated at high frequencies. A2A receptors function primarily as regulators, altering presynaptic modulation from inhibitory to facilitatory. Optogenetic investigations have revealed that activating A2A receptor signalling in the hippocampus is sufficient to produce LTP in the CA1 while affecting spatial memory ability, whilst activating A2A receptors in the nucleus accumbens enhances locomotor activity. Similarly, selectively inhibiting A2A receptor signalling in the CA3 region of an Alzheimer's animal model restores LTP and rescues memory loss.
While activation of A2A receptors in the hippocampus is sufficient to cause memory deficits, pharmacological or genetic interventions that block A2A receptors improve working memory, reversal learning, and fear conditioning in normal animals, as well as reverse memory impairments in elderly animals and animal models of Parkinson's and Alzheimer's diseases. The continuous presence of increased A2A receptors in diseases characterised by chronic stress and/or neurodegeneration lends credence to the causal relationship between adenosine receptor overactivation and neurological illnesses. Overall, our findings shed light on how coffee and cocoa purines may benefit cognition and prevent age-related memory deterioration.
3.1 Caffeine and Neurological Disorders
Parkinson’s Disease
The highest correlations between the occurrence of neurodegenerative illnesses and methylxanthine use have been observed in cases of Parkinson's disease (PD). According to multiple meta-analyses, drinking coffee in moderation reduces the risk of Parkinson's disease by 24–30%. Studies on men have consistently shown an inverse dose-response relationship between coffee and tea consumption and the prevalence of Parkinson's disease (PD), with a peak effect shown at roughly three cups of coffee per day.
The relationships between methylxanthine intake and the risk of Parkinson's disease (PD) in women, however, are more nuanced when it comes to dosage and hormonal state. Research indicates that women not getting estrogen medication may benefit from low amounts of caffeine in preventing Parkinson's disease (PD); however, those undergoing hormone replacement therapy may be more susceptible to PD at high dosages.
Alzheimer’s Disease
Numerous longitudinal studies have demonstrated an inverse connection between the risk of late-life Alzheimer's disease (AD) and chronic methylxanthine use. Caffeine consumption has been shown in animal experiments to reduce the amount of amyloid plaque in the brain, prevent or improve memory impairment in AD transgenic mice, and improve AD pharmaceutical models. Caffeine and its derivatives may aid Alzheimer's disease (AD) models through mechanisms such as adenosine receptor antagonistic action, cerebral blood flow modulation, increased oxygen consumption, and enhanced generation of cerebrospinal fluid.
Conclusion
In summary, caffeine, which is commonly ingested in the form of coffee and chocolate, has a major impact on cognitive processes and neuroplasticity. While it enhances memory, alertness, and performance, caffeine also disrupts sleep homeostasis and may impair long-term potentiation and neurogenesis in the hippocampus. A2A receptors are essential for mediating these effects, especially when high-frequency stimulation and neurodegenerative illnesses are present. Caffeine may be useful in preventing neurocognitive deterioration as evidenced by long-term studies protecting against Parkinson's and Alzheimer's illnesses. To maximise the positive effects of caffeine while reducing its negative effects, a balanced approach to caffeine use is necessary. The effects of caffeine vary depending on dosage, individual susceptibility, and hormonal status.
References:
Camandola, S., Plick, N., & Mattson, M. P. (2019, January). Impact of coffee and cacao purine metabolites on neuroplasticity and neurodegenerative disease. Neurochemical research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082740/
Vigne, M., Kweon, J., Sharma, P., Greenberg, B. D., Carpenter, L. L., & Brown, J. C. (2023, February 7). Chronic caffeine consumption curbs RTMS-induced plasticity. Frontiers. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1137681/full
Author links open overlay panelMohd Faizal Mohd Zulkifly a b, a, b, c, participants, H. caffeine naïve, AbstractObjectiveWe examined the effects of caffeine, Biabani, M., Cerqueira, V., Concerto, C., Ferreira, D. D. P., Goldsworthy, M. R., Graaf, T. A. de, Guerra, A., Hordacre, B., Huang, Y.-Z., Huang, Y. Z., Islam, N., Karabanov, A., Kraemer, S., … Eggert, T. (2021, March 10). Confounding effects of caffeine on neuroplasticity induced by transcranial alternating current stimulation and paired associative stimulation. Clinical Neurophysiology. https://www.sciencedirect.com/science/article/abs/pii/S1388245721000651?via%3Dihub
Lin, Y.-S., Weibel, J., Landolt, H.-P., Santini, F., Meyer, M., Borgwardt, S., Cajochen, C., & Reichert, C. (2019, January 1). Caffeine-induced plasticity of grey matter volume in healthy brains: A placebo-controlled multimodal within-subject study. bioRxiv. https://www.biorxiv.org/content/10.1101/804047v1.full
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Nield, D. (2023, November 28). Caffeine could have a surprising effect on the brain’s ability to learn. ScienceAlert. https://www.sciencealert.com/caffeine-could-have-a-surprising-effect-on-the-brains-ability-to-learn
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