An update on the mechanisms of the psychostimulant effects of caffeine

“The blockage of adenosine to the neurons causes the sleep promoting effects of adenosine to stop, resulting in the neurons speeding up instead of slowing down (Ferre 2008).”

“Similarly, in mammals, caffeine is a competitive antagonist of inhibitory adenosine A1 and A2 receptors, which in turn leads to activation via increased dopaminergic and glutamatergic activity (64).”

“Prolonged administration of an adenosine A2A receptor antagonist does not induce tolerance to its motor stimulant effect, suggesting that caffeine tolerance may be dependent on blockade of A1, rather than A2A, receptors (Ferre, 2008).”

“Caffeine improves cognition [1]; however, it also affects sleep [3].”

“Quercetin, like caffeine, has been shown to be an adenosine A1 receptor antagonist in vitro (1), which is at least partially responsible for the psychostimulant and ergogenic effects of caffeine (1, 5, 7, 9).”

“The blockage of adenosine to the neurons causes the sleep promoting effects of adenosine to stop, resulting in the neurons speeding up instead of slowing down (Ferre 2008).”

“The psychomotor stimulant effects of caffeine are due to antagonism of adenosine's inhibitory actions on the striatal D 2 transmission (Ferre 2008).”

“The broad caffeine intake associated with common beverages, together with the impact of xanthines on biomedical research, prompted many studies that have focused on specific caffeine effects rather than using it as a tool to antagonize ARs (Daly 2007; Ferré 2008).”

“Caffeine affects brain function mainly by its antagonist action on the adenosine A2A receptor and, therefore, plays a role in the modulation of dopaminergic transmission.(30,33) The antagonist effect of caffeine on adenosine also might imply nondopaminergic mechanisms, such as modulation of the release of acetylcholin…”

“dopamine, glutamate, and acetylcholine [4,5].”

“Furthermore, evidence is accumulating suggesting that the chronic consumption of caffeine mostly acts by antagonizing A2A rather than A1 receptors [107,108], as first suggested by Daly and Fredholm [58].”

“Genetic association studies focused on candidate genes related to the pharmacokinetic and pharmacodynamic properties of caffeine have identified genes encoding cytochrome P-450 (CYP)1A2, as the primary enzyme involved in caffeine metabolism [3,4].”

“Caffeine is the single most widely consumed psychoactive ingredient (Ferre 2008).”

“Importantly, caffeine has been shown to stimulate dopaminergic activity by removing the negative modulatory effects of adenosine at dopamine receptors.(28) Studies suggest that dopamine release in the nucleus accumbens shell may be a specific neuropharmacological mechanism underlying the addictive potential of caffein…”

“2006) and postsynaptic A1 receptors that form heteromers with D1 receptors in the GABAergic striato-nigral neuron (Ferré et al. 1997; Ferré 2008).”

“Caffeine has been described to have the ability to influence dopaminergic neurotransmission and potentiate dopamine receptor-mediated behavioral responses, such as locomotion and cognitive functions (Ferré, 2008; Xie et al., 2007).”

“Regarding the dopaminergic involvement in schizophrenia, it is noteworthy that activation of adenosine A2A receptors reduces the affinity of dopaminergic D2 receptors for dopamine, being the probable mechanism underlying the antipsychotic-like profile of adenosine agonists [213], the hyperdopaminergic effect of caffei…”

“Dose-dependent effects of caffeine on behaviour Short-term effects of caffeine consumption include enhanced mood and alertness (Ferré, 2008; Kaplan et al., 1997; Lorist and Tops, 2003), improved exercise performance (Doherty and Smith, 2004), increased blood pressure (Riksen et al., 2009), improved…”

“Caffeine is an adenosine receptor antagonist; it reduces inhibition of neural firing by large through an increased turnover of noradrenaline in the brain (Smith et al., 2003; Ferre, 2008).”

“Second, caffeine, as a nonspecific adenosine A1/ A2A receptor antagonist, generates psychostimulant effects through modulating dopaminergic transmission(Ferre, 2008; Morelli et al., 2010), and major metabolites of caffeine act on adenosine receptors in the brain (Morelli et al.”

“A2ARs may control the migration of GABA neurons Chronic consumption of caffeine exerts its central action mostly via its antagonistic action onA2ARs (27, 28).”

“The psychoactive function of caffeine is mediated via the non-selective antagonistic action on A1/A2A receptors.(144) How A1/A2A receptors regulate depression-like behaviour remains unclear.”

“It has been hypothesized that the allosteric interactions between A2AR and D2R agonists within the A2AR-D2R heteromer provide a mechanism responsible not only for the depressant effects of A2AR agonists, but also for the psychostimulant effects of adenosine A2AR antagonists and the nonselective adenosine receptor anta…”

“Quercetin, like caffeine, is an adenosine-A1-receptor antagonist, at least in vitro (Alexander), and the delay in fatigue that occurs with caffeine results at least in part from its ability to block adenosine receptors in the brain (Davis et al., 2003; Ferre, 2008).”

“Another major argument to dismiss this hypothesis is the observation that chronic caffeine mostly affects central adenosine A2A receptors (A2AR) [35, 61], which do not seem Fig.”

“[3,22]) Particularly influential were the experiments with A2A receptor knockout (A2AKO) mice, which showed a lack of motor-activating effects of caffeine [49].”

“Caffeine actions on A1 and A2A adenosine receptors (Ferré, 2008), has promoted its study as an alternative preventive or therapeutic tool for parkinsonian symptoms (Prediger, 2010).”

“Finally, caffeine can increase excitatory neurotransmitters through modulating dopaminergic transmission((11)) and facilitate the release of acetylcholine and serotonin((12)).”

“CAFF acting through AdoR on dopaminergic neurons could stimulate dopamine synthesis or release through protein kinase A dependent mechanisms similar to the A2A receptor in mammals (4).”

“Caffeine, 1,3,7-trimethylxanthine, is the world’s most consumed psychoactive substance (Ferre´, 2008).”

“Furthermore, the modest effects of caffeine are consistent with reports indicating that caffeine, despite its some-what mixed pattern of binding to adenosine receptors, does show some degree of preference for adenosine A1 receptors over A2A receptors [23].”

“The highest dose of theobromine decreased alertness and increased response times on the ANT task.”

“Caffeine has complex effects in the central nervous system, largely mediated by antagonism of adenosine A2a and A1 receptors, including an increased turnover of several monoamine transmitters, such as serotonin, dopamine, and noradrenaline (Fredholm et al. 1999; Ferre 2008; Ferre et al. 2008).”

“…effects of adenosine analogues and for the psychostimulant effects of selective adenosine A2AR antagonists and the non-selective adenosine receptor antagonist caffeine, with implications for several neuropsychiatric disorders (Ferré et al., 2004, 2008; Ferré, 2008; Bonaventura et al., 2015).”

“…in the A2AR-D2R heteromer, a reduction in the affinity of agonists for the D2R, contradicts the hypothesis of a key role of allosteric interactions within the A2AR-D2R heteromer as a main mechanism involved in the opposite behavioral effects of A2AR agonists and antagonists (Ferré, 2008, 2016).”

“This A2A/D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine [56].”

“Caffeine is well known to have psychostimulant effects [35].”

“CREB phosphorylation then increases transcription of immediate early genes such as c-fos and other genes like preproenkephalin (Ferré, 2008).”

“itor at concentrations higher than the physiological conditions (Ferré, 2008).”

“neurotransmission [374].”

“It is generally believed that caffeine exerts psychostimulant effects acting as a nonselective adenosine A1 receptor (A1R) and A2A receptor (A2AR) antagonist (Fredholm and Persson 1982; Nehlig et al., 1992; Fredholm and Lindstrom, 1999; Fisone et al., 2004; Ferré, 2008).”

“A2A receptor reduces affinity for dopamine D2 receptors [123, 124]”

“Chronic administration of caffeine does not affect seizure susceptibility as strongly as acute administration[3,16–26,29,30,45,46,49,57], suggesting the development of tolerance to A1- and A2Areceptor blockade by caffeine.[45,54,56,58,64,100,104] Chronic or acute administration of caffeine did not affect the sensitivi…”

“Caffeine, a commonly used central nervous system stimulant (Nicholson & Stone, 1980; Nehlig et al., 1992; Ferre, 2008), is an important pharmacological research tool for studying the involvement of adenosine receptors in cognitive function (Kopf et al., 1999; Dall’ Igna et al., 2004).”

“Several studies have indicated that caffeine exerts its psychostimulant effects acting as a nonselective adenosine A1R and A2AR receptor antagonist (Fredholm and Persson, 1982; Nehlig et al., 1992; Fredholm and Lindström, 1999; Fisone et al., 2004; Ferré, 2008).”

“Caffeine also stimulates dopaminergic activity by removing the negative modulatory effects of adenosine at dopamine receptors.(112) Caffeine was first demonstrated to be effective for treatment of apnea of prematurity (AOP) in the 1970s by Aranda et al.”

“Gi-coupled A1 and Gs-coupled A2A adenosine receptors have received the most attention for their regulation of synaptic physiology in recent years [95, 107, 108].”

“Caffeine is present in a range of beverages (eg, tea, coffee, soft drinks, energy drinks) and in some foods (eg, chocolate) and is the most consumed psychoactive ingredient worldwide (24).”

“At normal dietary concentrations, caffeine produces a mild neurostimulant effect by antagonizing adenosine, thus disinhibiting neuronal firing throughout the brain (for review, see Nehlig 1999; Ferre 2008).”

“…A1R could be involved in the pathogenesis of PLMS in RLS. Postsynaptic A1R form heteromers with D1R and their activation or blockade leads to a respective selective decrease or increase in D1R-mediated activation of D1R-expressing striato-nigral neurons (Ferré et al., 1997; Ferré, 2008, 2010).”

“This finding is consistent with both the neurostimulant and arousal enhancing effects on caffeine primarily via the dopamine (Ferre, 2008; Pelligrino et al., 2010) and histaminergic arousal (Ferre, 2008) systems respectively.”

“Due to caffeine’s low affinity for phophodiesterases, its in vivo action, particularly its psychostimulant effect, is thought to be mediated through its inhibitory effects on adenosine receptors (Ferré, 2008).”

“The activation of A2ARs can reduce D2R affinity and function, which may potentially underlie the antipsychotic-like profile of adenosine agonists [56], the hyperdopaminergic effect of caffeine [53, 56] and the exacerbation of psychotic symptoms by caffeine in schizophrenic patients [132].”

“…adenosine receptor antagonist with similar in vitro affinities for A1 receptors (A1R) and A2AR (Fredholm et al., 1999), the main adenosine receptors involved in memory normalization (Cunha and Agostinho, 2010) and in the motor-activating, reinforcing and arousal effects of this drug (Ferré, 2008).”

“interacts with the central dopaminergic systems via antagonism of endogenous adenosine (135).”

“In addition, y, Park Place, Cardiff University, license. there is also evidence showing that caffeine has secondary effects on other neurotransmitter systems including dopamine, acetylcholine and noradrenaline (Ferre, 2008; Fredholm et al., 1999; Latini and Pedata, 2001).”

“Blockade of the A2A receptor by caffeine inhibits the sleeppromoting effect with adenosine levels increasing across the hours of wakefulness (Davis et al. 2003; Ferré 2008; Huang et al. 2007; Landolt 2008; Sturgess et al. 2010).”

“Caffeine supplementation can improve short-term (5–10 min) endurance performance (Jackman, Wendling, Friars, & Graham, 1996; Wiles, Bird, & Hopkins, 1992) via enhanced voluntary muscle activation (Ferré, 2008; Kalmar, 2005), reduced rating of perceived exertion (RPE) and pain perception during exercise (Ganio, Klau, C…”

“For the most part, its enhancing effects are attributed to the antagonism of adenosine A2A receptors (A2ARs)—ligands of which, like adenosine, bind to induce sleepiness—which may explain the psychostimulatory effects of caffeine (Ferré, 2008a).”

“Nonselective adenosine antagonists such as caffeine act as minor stimulants and are commonly consumed by humans drinking coffee, tea, and “energy drinks” (Antoniou et al. 2005; Ferré 2008; Ferré et al. 2008a; Reissig et al. 2009).”

“In addition, current evidence suggests that the psychostimulant and reinforcing effects of caffeine may be the result of increased activity of dopaminergic neurotransmission, perhaps via adenosine–dopamine interactions (Powell et al., 2001; Ferré, 2008).”

“…adenosine binds to adenosine receptors, adenylyl cyclase and Ca2 + channels are activated, consequently activating the cAMP-PKA signalling pathway, which induces the phosphorylation of dopamine, inhibiting its release, leading to many downstream biological changes in the brain and the CNS , [112].”

“Pharmacological mechanisms underlying caffeine effects are primarily via a nonselective antagonism of adenosine receptors, with A1 and A2A receptors as preferential targets (Fredholm et al., 1999; Ferre, 2008).”

“The psychostimulant effect of caffeine on the central nervous system (CNS) is primarily due to the antagonism of adenosine receptors A1 and A2A (Ferré, 2008; Fredholm, Bättig, Holmén, Nehlig, & Zvartau, 1999).”

“The anatomical and functional interactions between the adenosine and dopamine receptors in the striatum have been recently reviewed [8-10].”

“Caffeine causes a diverse range f pharmacological effects that are time- and concentrationependent and reversible (Ferre et al., 2008; Ferre, 2008; Bode Abbreviations: SR, serine/arginine-rich; ACTN, alpha actinin; KLF6, Krüppel-like actor 6; EMT, epithelial-mesenchymal-transition; HIF-1 , hypoxia…”

“Caffeine exerts pharmacological actions at diverse sites, both centrally and peripherally, due mostly to antagonism of endogenous adenosine, with A1 and A2A receptors appearing to be the primary targets (Ferré, 2008).”