What Knock-Out Animals Tell Us About the Effects of Caffeine

Chen, Jiang‐Fan; Yu, Liqun; Shen, Hai‐Ying; He, Jincai; Wang, Xiaotong; Zheng, Ran

doi:10.3233/jad-2010-1403

Cited by 30 publications

(18 citation statements)

References 59 publications

(72 reference statements)

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“…It is assumed that at the concentrations typically consumed by humans caffeine acts as CNS stimulant mainly by acting as a competitive antagonist of A 1 and A 2A adenosine receptors (Fredholm et al 1999; Chen et al 2010). Here, we propose an additional complementary mechanism that may explain the effects of caffeine in a cellular and molecular model of learning and memory.…”

Section: Discussionmentioning

confidence: 99%

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Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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Caffeine has cognitive‐enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor‐independent form of LTP (CAFLTP) in the CA1 region of the hippocampus by promoting calcium‐dependent secretion of BDNF, which subsequently activates TrkB‐mediated signaling required for the expression of CAFLTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAFLTP, a process that requires cytosolic free Ca2+. Consistent with the involvement of IRS2 signals in caffeine‐mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2−/− mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3‐kinase (PI3K) pathway. These findings indicate that TrkB‐IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

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Section: Discussionmentioning

confidence: 99%

“…It has been suggested that, at the concentration typically consumed by humans, caffeine may act mainly by inhibiting adenosine receptors in the CNS (Fredholm 1995). By functioning as a competitive antagonist at A 1 and A 2A adenosine receptors, it leads to diminished endogenous adenosinergic tone (Fredholm et al 1999; Chen et al 2010). …”

Section: Introductionmentioning

confidence: 99%

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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“…Psychostimulantinduced augmentation of dopaminergic activity causes hyperlocomotion in rodents, a quantifiable response that is widely used experimentally to study susceptibility to psychotic symptoms (41 (10,43,44), adenosine is expected to exert a regulatory influence on amphetamine-induced psychomotor behavior. In line with these receptor-receptor interactions, reduced adenosinergic tone in Adk-tg mice is expected to exert a stimulatory influence on dopamine receptors, which is also considered the primary mechanism underlying the motorstimulant effect of the mixed A 1 R/A 2A R antagonist caffeine (45). Consistent with this interpretation, Adk-tg mice were hyperactive in a novel environment (25) and showed impaired LI (Figure 2), a widely established model of schizophrenia closely linked to striatal hyperdopaminergia (46).…”

Section: Adk-tg Mice -An Effective Mouse Model Of Adenosine Hypofunctmentioning

confidence: 99%

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Shen¹,

Singer²,

Lytle³

et al. 2012

J. Clin. Invest.

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An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A 2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia. IntroductionDespite extensive research over half a century, schizophrenia remains a major health concern, affecting more than one percent of the population. Two hypotheses, those of dopaminergic hyperfunction (1) and glutamatergic hypofunction (2), are widely accepted conceptual frameworks for understanding the pathophysiology of schizophrenia and for the development of drugs for the treatment of either dopamine-related or glutamate-related symptoms of the disease (2, 3). This study addresses a third hypothesis, the "adenosine hypothesis of schizophrenia," which has recently been proposed as a novel concept to integrate the dopaminergic hyperfunction and glutamatergic hypofunction hypotheses (4).The purine ribonucleoside adenosine modulates neurotransmission through activation of 4 types of G protein-coupled adenosine receptors (ARs), A 1 R, A 2A R, A 2B R, and A 3 R, which exert spatially distinct functions within the brain on presynaptic and postsynaptic sites (5, 6). Presynaptically, adenosine regulates the release of both dopamine and glutamate (7,8), whereas the output of dopaminergic and glutamatergic neurotransmission is regulated by heterodimerization of ARs with dopamine and glutamate receptors (9, 10). Through these mechanisms adenosine exerts upstream control over both dopaminergic and glutamatergic signaling. Consequently, any disruption in adenosine homeostasis is expected to affect those 2 transmitter systems, which play fundamental roles in the pathophysiology of schizophrenia. This regulatory function of adenosine might provide a missing link for the functional integration of the dopamine and glutamate hypotheses. Conventional antipsychotic

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“…Genetic constitutional knockout animals for the different adenosine receptors suggest that the psychostimulant and arousal effects are mainly mediated by the A 2A adenosine receptor (11)(12)(13). However, these data cannot readily be extrapolated to the human condition because there are substantial interspecies differences with regard to the cerebral distribution and concentration of adenosine receptor subtypes.…”

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confidence: 95%

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

et al. 2012

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Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. 18 F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ( 18 F-CPFPX) has been established as a highly selective and affine PET ligand for the A 1 adenosine receptor (A 1 AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A 1 AR by caffeine using 18 F-CPFPX and PET. Methods: Fifteen subjects (age range, 24-68 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V T ) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V T of the A 1 AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%-44% of 18 F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Halfmaximal displacement was achieved at a plasma caffeine concentration of 67 mM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A 1 AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that 18 F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

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What Knock-Out Animals Tell Us About the Effects of Caffeine

Cited by 30 publications

References 59 publications

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

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What Knock-Out Animals Tell Us About the Effects of Caffeine

Cited by 30 publications

References 59 publications

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

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Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET