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| Impact of caffeine on the functional interaction between adenosine and DA receptors. A 1 R and A 2A R, adenosine A 1 and A 2A receptors; D 1 , DA type 1 receptor; D 2 , DA type 2 receptor (adapted from Ferré, 2008).
Source publication
Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemi...
Contexts in source publication
Context 1
... adenosine A 2A receptors are highly expressed postsynaptically in DA rich areas such as neostriatum and accumbens (Acb) (Johansson and Fredholm, 1995;Johansson et al., 1997;DeMet and Chicz-DeMet, 2002;Rebola et al., 2005). In fact, it has been demonstrated that in these areas, there is a functional interaction between DA D 2 and adenosine A 2A receptors (see Figure 1), which are co-localized on enkephalin-containing medium spiny neurons and converge onto the same signal transduction pathways in an antagonistic way ( Ferré et al., 1997Ferré et al., , 2008Fuxe et al., 2003;Ferré, 2008;Beggiato et al., 2014). Similarly, A 1 and D 1 receptors antagonistically interact on substance P-containing medium spiny neurons ( Ferré et al., 1997Ferré et al., , 2008. ...
Context 2
... behavioral effect was supported by changes in an intracellular marker of DA neurotransmission [phosphorylated form of DARPP-32; pDARPP-32(Thr34)] in the striatum ( LópezCruz et al., 2018). Similarly, theophylline reversed the effects induced by this D 2 antagonist in mice tested in the T-maze barrier task (Pardo et al., 2012). Furthermore, several papers have reported that the adenosine A 2A receptor antagonist MSX-3 can reverse the effort-related effects of TBZ across multiple tasks ( Nunes et al., 2013;Randall et al., 2014;Yohn et al., 2015). ...
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Citations
... While moderate caffeine consumption may provide temporary relief from some depressive symptoms and even have potential mood-enhancing effects for some individuals, excessive or poorly managed [88] caffeine intake can exacerbate anxiety [66], disrupt sleep [85], and lead to negative mental health outcomes. It is crucial for individuals with depression [89] to be mindful of their caffeine consumption and its impact on their well-being, as well as to seek professional guidance if necessary, as well as consider any other physical diagnoses present [74]. ...
Caffeine is a popular ergogenic aid that has a plethora of evidence highlighting its positive effects. A Google Scholar search using the keywords “caffeine” and “exercise” yields over 200,000 results, emphasizing the extensive research on this topic. However, despite the vast amount of available data, it is intriguing that uncertainties persist regarding the effectiveness and safety of caffeine. These include but are not limited to: 1. Does caffeine dehydrate you at rest? 2. Does caffeine dehydrate you during exercise? 3. Does caffeine pro- mote the loss of body fat? 4. Does habitual caffeine consump- tion influence the performance response to acute caffeine supplementation? 5. Does caffeine affect upper vs. lower body performance/strength differently? 6. Is there a relationship between caffeine and depression? 7. Can too much caffeine kill you? 8. Are there sex differences regarding caffeine’s effects? 9. Does caffeine work for everyone? 10. Does caffeine cause heart problems? 11. Does caffeine promote the loss of bone mineral? 12. Should pregnant women avoid caffeine? 13. Is caffeine addictive? 14. Does waiting 1.5–2.0 hours after waking to consume caffeine help you avoid the afternoon “crash?” To answer these questions, we performed an evidence-based scientific evaluation of the literature regarding caffeine supplementation.
... 12 Coffee is commonly acknowledged as a prominent dietary source of caffeine; however, it is also present in other beverages such as tea, energy drinks, carbonated soft drinks and in certain fruits and foods that contain cocoa. 13,14 Caffeine is incorporated into the circulation throughout the body following caffeine ingestion 15 and acts as an antagonist for adenosine A1 and A2A receptors. 15 Caffeine can affect metabolism, the cardiovascular and respiratory systems, and neuroinflammatory, neuromodulator, and neuroprotective processes by inhibiting adenosine receptors. ...
... 13,14 Caffeine is incorporated into the circulation throughout the body following caffeine ingestion 15 and acts as an antagonist for adenosine A1 and A2A receptors. 15 Caffeine can affect metabolism, the cardiovascular and respiratory systems, and neuroinflammatory, neuromodulator, and neuroprotective processes by inhibiting adenosine receptors. 16,17 Caffeine has the potential to impede neurodegeneration, increase anxiety, psychomotor acuity by inhibiting NMDA receptors. ...
Aim
Amnesia is a cognitive disorder that may lead to memory loss. Caffeine is a psychoactive substance which have an effect on memory and cognitive functions. This study aimed to assess the association of transient global amnesia (TGA) with dietary intake of caffeine.
Methods
This cross‐sectional study was conducted on the Sabzevar Persian cohort data of 258 patients with TGA and 520 healthy individuals in Sabzevar, Iran. The Nutritional data were gathered in face‐to‐face interviews using a valid Food Frequency Questionnaire. Different models of logistic regression were used to determine the association between TGA and dietary caffeine intake after adjusting the confounders including age, sex, education, job, marital status, physical activity, BMI, and calorie intake.
Results
There was no significant difference in terms of dietary calorie intake of (2279.5 ± 757.9 vs. 2365.5 ± 799.5, p = 0.19), protein (70.79 ± 25.27 vs. 72.94 ± 24.83, p = 0.31), fat (59.97 ± 23.79 vs. 60.13 ± 26.38, p = 0.93), carbohydrate (376 ± 134 vs. 393.1 ± 137.8, p = 0.14), and caffeine (196.4 ± 127.9 vs. 186.3 ± 128.5, p = 0.36) between the groups. No significant association was found between TGA and dietary intake of caffeine (OR: 0.99, 95% CI: 0.99–1.01, p = 0.36). The results did not change after adjusting the confounders.
Conclusions
No significant association was found between TGA and dietary intake of caffeine. Further prospective studies are required to confirm this finding.
... In fact, the presence of this clinical condition is associated with changes in REM (Rapid Eye Movement) and NREM (No Rapid Eye Movement) sleep, impairing sleep time and efficiency (Wang et al. 2016). In contrast, studies with people who have depression suggest a potential protective factor of caffeine (Grosso et al. 2016;Kim and Kim 2018;Wang et al. 2016) due to its non-selective action on adenosine receptors and reduction of dopamine depletion (López-Cruz et al. 2018). However, our results show a significant relationship between caffeine intake and sleep time independently of the presence of this condition. ...
We aimed to evaluate the association between caffeine intake and sleep time in Brazilian adults. This cross-sectional study was conducted with 6,356 participants from the Cohort of Universities of Minas Gerais (CUME Study). Data was collected through an online self-report questionnaire. Of the total, 31.9% of the participants had insufficient sleep. Women were found to sleep less than men (64.1 vs. 35.9%; p < 0.001), as well as being more likely to consume higher doses of caffeine (55.2%, p < 0.001). Coffee (35.7%), dark chocolate (25.2%), milk chocolate (15.2%), and diet soda (11.0%) were the foods that more contributed to caffeine intake. Individuals in the highest quartile of caffeine intake (87.0 - 572.0 mg/day) had a 19% higher prevalence of insufficient sleep compared with the lowest quartile (PR: 1.19; 95%CI: 1.08 - 1.31). Future studies are needed to investigate the genetic and hormonal factors involved in the interindividual response in this population.
... Consuming tea has been proven to lower the chance of developing depression, and it has been suggested that it helps individuals with MDD manage their depression symptoms, anxiety, and sleep problems [42]. Additionally, it has been proposed that CAF can treat depression-related motivational dysfunction [43,44]. CAF is evidently able to block GABA transport through A 1 R blockade and cAMP signaling pathways [45]. ...
This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student-Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABA A receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABA A (α 2 and α 5) subunits than QUR with α 2 , α 3 , and α 5. All these compounds showed stronger interactions with the GABA A receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABA A receptor subunits.
... Caffeine is a non-selective adenosine antagonist for A 1 /A 2A receptors [13]. Epidemiological studies showed that drinking coffee has positive effects on both glucose tolerance and sensitivity to insulin, thus reducing the risk of T2D over long periods of consumption [14,15]. ...
Background/aim:
Recent research suggests that adenosine receptors (ARs) influence many of the metabolic abnormalities associated with diabetes. A non-xanthine benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1 H-inden-1-one (2-BI), has shown to exhibit higher affinity at A1/A2A ARs compared to caffeine. Due to its structural similarity to caffeine, and the established antidiabetic effects of caffeine, the current study was initiated to explore the possible antidiabetic effect of 2-BI.
Methods:
The study was designed to assess the antidiabetic effects of several A1 and/or A2A AR antagonists, via intestinal glucose absorption and glucose-lowering effects in fructose-streptozotocin (STZ) induced diabetic rats. Six-week-old male Sprague-Dawley rats were induced with diabetes via fructose and streptozotocin. Rats were treated for 4 weeks with AR antagonists, metformin and pioglitazone, respectively. Non-fasting blood glucose (NFBG) was determined weekly and the oral glucose tolerance test (OGTT) was conducted at the end of the intervention period.
Results:
Dual A1/A2A AR antagonists (caffeine and 2-BI) decreased glucose absorption in the intestinal membrane significantly (p < 0.01), while the selective A2A AR antagonist (Istradefylline), showed the highest significant (p < 0.001) reduction in intestinal glucose absorption. The selective A1 antagonist (DPCPX) had the least significant (p < 0.05) reduction in glucose absorption. Similarly, dual A1/A2A AR antagonists and selective A2A AR antagonists significantly reduced non-fast blood glucose and improved glucose tolerance in diabetic rats from the first week of the treatment. Conversely, the selective A1 AR antagonist did not reduce non-fast blood glucose significantly until the 4th week of treatment. 2-BI, caffeine and istradefylline compared well with standard antidiabetic treatments, metformin and pioglitazone, and in some cases performed even better.
Conclusion:
2-BI exhibited good antidiabetic activity by reducing intestinal postprandial glucose absorption and improving glucose tolerance in a diabetic animal model. The dual antagonism of A1/A2A ARs presents a positive synergism that could provide a new possibility for the treatment of diabetes.
... Subsequently, the partition was removed, and the mice were E-mail: nonnon7@affrc.go.jp allowed to confront for 2 d (confrontation). Caffeine and theobromine were administered at a nutritionally relevant dose of 6 mg/kg (17,18). To exclude confounding transient effects of methylxanthines, administration was discontinued the day before the confrontational housing stress treatment. ...
Management of chronic psychological stress is important for the prevention of depression, mood disorders, and other related ailments. Recent studies have shown that dietary methylxanthines, such as caffeine and theobromine, exert preventive effects on these ailments. Although the psychological effects of caffeine are well-investigated, those of theobromine are not fully understood. In the present study, the effects of theobromine were evaluated and compared with those of caffeine using a mouse stress model based on confrontational housing. Male mice were kept separately in partition cages (two per cage) to allow the establishment of territories for confrontational housing. The mice were administered caffeine or theobromine daily via oral gavage (6 mg/kg). Thereafter, the partition was removed to induce confrontational stress. We found that theobromine, but not caffeine, suppressed adrenal hypertrophy caused by confrontational stress. Moreover, sociability tests revealed that caffeine and theobromine had different effects on the behavioral changes caused by confrontational stress. Our results suggest that orally administered theobromine suppresses adrenal hypertrophy caused by psychosocial stress and induces different behavioral changes than dose caffeine.
... The association between coffee consumption and depression remains debatable. Caffeine can reverse the dopaminergic system impairments observed in depression; for example, inhibiting the A1 adenosine receptor subunit may boost catecholamines and serotonin (5-HT) levels in the central nervous system (CNS) (Fredholm, 1995;Lopez-Cruz et al., 2018), besides, it is also worth noting that Caffeine increases the release of 5-HT in the limbic system and dopamine (DA) in the prefrontal cortex, producing effects similar to those of antidepressants (Acquas et al., 2002;Szopa et al., 2016). A longitudinal study of 50,776 women in the United States observed a negative correlation between coffee consumption and depressive behaviors after adjusting for age. ...
This cross-sectional study examines the association between coffee and caffeine consumption and depressive symptoms in postpartum women. In total, 821 postpartum women who met the study’s inclusion criteria were interviewed. Data were extracted from the 2007–2018 National Health and Nutrition Examination Survey. Coffee consumption and 11 confounding variables were considered and analyzed as baseline data. Weighted logistic regression models were constructed by adjusting the variables, and the odds ratios of total coffee, caffeinated coffee, and decaffeinated coffee were assessed for their impact on depression status. In addition, subgroup analyses were conducted according to race, breastfeeding status, and postpartum period. The results show that generic coffee and caffeinated coffee intake have a potentially protective effect in postpartum women. Drinking more than three cups of caffeinated coffee may lower the risk of postpartum depression, particularly in the 1–2 year postpartum period and in non-breastfeeding women. The association between decaffeinated coffee consumption and postpartum depression remains unclear.
... This is particularly due to the chemical similarity between caffeine and adenosine, the natural ligand of ARs (Borea et al., 2018). Interestingly, many epidemiological studies supported the beneficial effects of a reasoned daily consumption of caffeine, not exceeding 400 mg/day on cognition, attention or even depression (Haskell et al., 2005;James and Rogers, 2005;López-Cruz et al., 2018). Such broad effect of caffeine to cognition is in line with the impact of caffeine to brain connectivity as recently reported . ...
Adenosine signals through four distinct G protein-coupled receptors that are located at various synapses, cell types and brain areas. Through them, adenosine regulates neuromodulation, neuronal signaling, learning and cognition as well as the sleep-wake cycle, all strongly impacted in neurogenerative disorders, among which Alzheimer's Disease (AD). AD is a complex form of cognitive deficits characterized by two pathological hallmarks: extracellular deposits of aggregated β-amyloid peptides and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated Tau proteins. Both lesions contribute to the early dysfunction and loss of synapses which are strongly associated to the development of cognitive decline in AD patients. The present review focuses on the pathophysiological impact of the A2ARs dysregulation observed in cognitive area from AD patients. We are reviewing not only evidence of the cellular changes in A2AR levels in pathological conditions but also describe what is currently known about their consequences in term of synaptic plasticity, neuro-glial miscommunication and memory abilities. We finally summarize the proof-of-concept studies that support A2AR as credible targets and the clinical interest to repurpose adenosine drugs for the treatment of AD and related disorders.
... Caffeine acts as a competitive antagonist of adenosine receptors, found throughout the body and thought to regulate the sleep-wake cycle (Blaise et al. 2018). As an adenosine receptor antagonist, caffeine increases neuronal excitability, resulting in heightened arousal and attention (López-Cruz et al. 2018). Numerous studies have demonstrated that caffeine administration improves locomotor behaviour and stabilizes mood (Ko et al. 2017). ...
... In rats, caffeine has been demonstrated to decrease sociability levels in the social interaction test (File and Hyde 1979). At high doses, caffeine decreases social interaction in mice and rats, which has been interpreted as an anxiogenic effect (Hilakivi et al. 1989;Baldwin and File 1989;López-Cruz et al. 2018), but lower doses seem to increase social contact (Nadal and Pallares 1993). Research suggests that sleep loss is associated with social withdrawal (Simon and Walker 2018), reduced trust (Anderson and Dickinson 2010), impaired theory of mind (Muzur et al. 2002), and even increased likelihood of hostility and deviant behaviours (Christian and Ellis 2011). ...
Using the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm we developed, the combined effects of chronic sleep deprivation and high caffeine intake on prefrontal cortical synaptophysin expression, neurochemical profiles, and behavioural outcomes in Long-Evans rats were evaluated. The combination of chronic sleep deprivation and high-dose caffeine treatment produced varying degrees of behavioural impairments, depletion of antioxidants, serotonin, and an upregulation of acetylcholinesterase (AChE) activity in the prefrontal cortex. An immunohistochemical assessment revealed a reduction in synaptophysin protein expression in the prefrontal cortex following exposure to high-dose caffeine and chronic sleep deprivation. Overall, our findings support the advocacy for adequate sleep for optimal mental performance as a high intake of caffeine to attenuate the effects of sleep deprivation that may alter the neurochemical profile and synaptic plasticity in the prefrontal cortex, significantly increasing the risk of neuropsychiatric/degenerative disorders.
Graphical Abstract
... It has a wide variety of biological effects with multiple cellular targets in fungi, plants, and humans. In higher animals, caffeine plays beneficial roles in neuronal stimulation accompanied by antidepressant and diuretic effects (López-Cruz et al., 2018). Caffeine is a relatively non-selective drug that affects multiple cellular processes such as cell growth, proliferation, and energy metabolism by triggering calcium mobilization and inhibiting the target of rapamycin (TOR) signaling as well as the DNA damage repair system (Combettes et al., 1994;Ruta and Farcasanu, 2020). ...
Caffeine, a methylxanthine derivative, affects various physiological conditions such as cell growth, proliferation, and energy metabolism. A genome-wide screening for genes required for caffeine resistance in Schizosaccharomyces pombe revealed several candidates, including Pap1 and downstream target genes involved in caffeine efflux. We found that Yap1, a budding yeast AP-1 homolog required for oxidative stress response, has a caffeine tolerance function. Although the Yap1 mutant is not sensitive to caffeine, overexpression of Yap1 renders cells resistant to high concentrations of caffeine. Caffeine sensitivity of mutants lacking two multidrug transporters, Pdr5 or Snq2, is completely recovered by Yap1 overexpression. Among Yap1-dependent target genes, FLR1, a fluconazole-resistant gene, is necessary but not sufficient for caffeine tolerance. Low concentrations of hydrogen peroxide induce Yap1 activation, which restores cell viability against caffeine toxicity. Intriguingly, oxidative stress-mediated cellular adaptation to caffeine toxicity requires Yap1, but not Flr1. Moreover, caffeine is involved in reduction of intracellular reactive oxygen species (ROS), as well as mutation rate and Rad52 foci formation. Altogether, we identified novel reciprocal crosstalk between ROS signaling and caffeine resistance.
