Journal of Alzheimer's Disease - Volume 20, issue s1

Authors: Mendonça, Alexandre | Cunha, Rodrigo A.

Article Type: Editorial

DOI: 10.3233/JAD-2010-01420

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S1-S2, 2010

Authors: Ribeiro, Joaquim A. | Sebastião, Ana M.

Article Type: Review Article

Abstract: Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, …cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine. Show more

Keywords: Adenosine, Alzheimer's disease, anxiety, caffeine, cognition, Huntington's disease, migraine, Parkinson's disease, schizophrenia, sleep

DOI: 10.3233/JAD-2010-1379

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S3-S15, 2010

Authors: Chen, Jiang-Fan | Yu, Liqun | Shen, Hai-Ying | He, Jin-Cai | Wang, Xiaotong | Zheng, Rongyuan

Article Type: Review Article

Abstract: Caffeine is well known for its complex pharmacological actions, in part reflecting the multiple molecular targets of caffeine. The adenosine receptors are the primary extracellular targets of caffeine. Since caffeine has similar affinity for several adenosine receptors, it has been difficult to determine which receptor subtypes mediate caffeine's effects using pharmacological tools. The development of genetic mutant mice deficient in adenosine receptors and other signaling molecules has allowed targeted inquiry into the molecular targets by which caffeine elicits its biological effects on behavior and gene expression. This review summarizes recent work using genetic knockout models to elucidate the mechanisms of …caffeine action in the brain. This review focuses on insights into caffeine action from genetic knockout models on: (1) the molecular basis for caffeine's effects on psychomotor activity; (2) the involvement of adenosine receptors in caffeine-mediated arousal and cognitive effects; and (3) a novel approach using knockout animals coupled with microarray profiling to validate multiple molecular targets of caffeine in striatal gene expression. Show more

Keywords: Adenosine A2A receptor, adenosine A1receptor, caffeine, arousal, DARPP-32, psychostimulation

DOI: 10.3233/JAD-2010-1403

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S17-S24, 2010

Authors: Costenla, Ana Rita | Cunha, Rodrigo A. | de Mendonça, Alexandre

Article Type: Review Article

Abstract: Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) for 3 weeks, displayed a concentration of caffeine of circa 22 μM in the hippocampus. It is known that selective adenosine A1 receptor antagonists facilitate, whereas selective adenosine A2A receptor antagonists attenuate, long term potentiation (LTP) in the hippocampus. Although …caffeine is a non-selective antagonist of adenosine receptors, it attenuates frequency-induced LTP in hippocampal slices in a manner similar to selective adenosine A2A receptor antagonists. These effects of low micromolar concentration of caffeine (30 μM) are maintained in aged animals, which is important when a possible beneficial effect for caffeine in age-related cognitive decline is proposed. Future studies will still be required to confirm and detail the involvement of A1 and A2A receptors in the effects of caffeine on hippocampal synaptic plasticity, using both pharmacological and genetic approaches. Show more

Keywords: A1 receptors, A2A receptors, adenosine, aging, caffeine, long-term potentiation, hippocampus, synaptic plasticity

DOI: 10.3233/JAD-2010-091384

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S25-S34, 2010

Authors: Ferré, Sergi

Article Type: Review Article

Abstract: Caffeine is the most consumed psychoactive drug in the world. It is a non-selective adenosine receptor antagonist that in the brain targets mainly adenosine A1 and A2A receptors. The same as classical psychostimulants, caffeine produces motor-activating, reinforcing and arousing effects. This depends on the ability of caffeine to counteract multiple effects of adenosine in the central ascending neurotransmitter systems. Motor and reinforcing effects depend on the ability of caffeine to release pre- and postsynaptic brakes that adenosine imposes on the ascending dopaminergic system. By targeting A1 –A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors …in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A –D2 and A1 –D1 receptor heteromers. Arousing effects of caffeine depend on the blockade of multiple inhibitory mechanisms that adenosine, as an endogenous sleep-promoting substance, exerts on the multiply interconnected ascending arousal systems. Those mechanisms include a direct A1 -receptor mediated modulation of the corticopetal basal forebrain system and an indirect A2A -receptor mediated modulation of the hypothalamic histaminergic and orexinergic systems. Show more

Keywords: Adenosine A1 receptor, adenosine A2A receptor, ascending arousal systems, caffeine, dopaminergic system, local modules, receptor heteromers

DOI: 10.3233/JAD-2010-1400

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S35-S49, 2010

Authors: Pelligrino, Dale A. | Xu, Hao-Liang | Vetri, Francesco

Article Type: Review Article

Abstract: While the influence of caffeine on the regulation of brain perfusion has been the subject of multiple publications, the mechanisms involved in that regulation remain unclear. To some extent, that uncertainty is a function of a complex interplay of processes arising from multiple targets of caffeine located on a variety of different cells, many of which have influence, either directly or indirectly, on cerebral vascular smooth muscle tone. Adding to that complexity are the target-specific functional changes that may occur when comparing acute and chronic caffeine exposure. In the present review, we discuss some of the mechanisms behind caffeine influences …on cerebrovascular function. The major effects of caffeine on the cerebral circulation can largely be ascribed to its inhibitory effects on adenosine receptors. Herein, we focus mostly on the A1 , A2A , and A2B subtypes located in cells comprising the neurovascular unit (neurons, astrocytes, vascular smooth muscle); their roles in the coupling of increased neuronal (synaptic) activity to vasodilation; how caffeine, through blockade of these receptors, may interfere with the "neurovascular coupling" process; and receptor-linked changes that may occur in cerebrovascular regulation when comparing acute to chronic caffeine intake. Show more

Keywords: Adenosine, arteriole, astrocyte, calcium, neurovascular coupling, synapse, vasodilation

DOI: 10.3233/JAD-2010-091261

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S51-S62, 2010

Authors: de Carvalho, Mamede | Marcelino, Erica | de Mendonça, Alexandre

Article Type: Research Article

Abstract: We review the electrophysiological studies concerning the effects of caffeine on muscle, lower and upper motor neuron excitability and cognition. Several different methods have been used, such as electromyography, recruitment analysis, H-reflex, transcranial magnetic stimulation (TMS), electroencephalography and event-related potentials. The positive effect of caffeine on vigilance, attention, speed of reaction, information processing and arousal is supported by a number of electrophysiological studies. The evidence in favor of an increased muscle fiber resistance is not definitive, but higher or lower motor neuron excitability can occur as a consequence of a greater excitation of the descending input from the brainstem and …upper motor neurons. TMS can address the influence of caffeine on the upper motor neuron. Previous studies showed that cortico-motor threshold and intracortical excitatory and inhibitory pathways are not influenced by caffeine. Nonetheless, our results indicate that cortical silent period (CSP) is reduced in resting muscles after caffeine consumption, when stimulating the motor cortex with intensities slightly above threshold. We present new data demonstrating that this effect is also observed in fatigued muscle. We conclude that CSP can be considered a surrogate marker of the effect of caffeine in the brain, in particular of its central ergogenic effect. Show more

Keywords: Caffeine, cortical silent period, lower motor neuron, muscle, transcranial magnetic stimulation

DOI: 10.3233/JAD-2010-1377

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S63-S69, 2010

Authors: Koppelstaetter, Florian | Poeppel, Thorsten D. | Siedentopf, Christian M. | Ischebeck, Anja | Kolbitsch, Christian | Mottaghy, Felix M. | Felber, Stephan R. | Jaschke, Werner R. | Krause, Bernd J.

Article Type: Review Article

Abstract: Caffeine has been consumed since ancient times due to its beneficial effects on attention, psychomotor function, and memory. Caffeine exerts its action mainly through an antagonism of cerebral adenosine receptors, although there are important secondary effects on other neurotransmitter systems. Recently, functional MRI (fMRI) entered the field of neuropharmacology to explore the intracerebral sites and mechanisms of action of pharmacological agents. However, as caffeine possesses vasoconstrictive properties it may interfere with the mechanisms underlying the functional contrast in fMRI. Yet, only a limited number of studies dealt with the effect of caffeine on measures in fMRI. Even fewer neuroimaging studies …examined the effects that caffeine exerts on cognition: Portas and colleagues used fMRI in an attentional task under different levels of arousal (sleep deprivation or caffeine administration), concluding that the thalamus is involved in mediating the interaction of attention and arousal. Bendlin and colleagues found caffeine to stabilize the extent of neuronal activation in repetitive word stem completion, counteracting the general task practice effect. Recently, Koppelstaetter and colleagues assessed the effect of caffeine on verbal working memory demonstrating a modulatory effect of caffeine on brain regions (medial frontopolar and anterior cingulate cortex) that have been associated with attentional and executive functions. This review surveys and discusses neuroimaging findings on 1) how caffeine affects the contrast underlying fMRI techniques, particularly the blood oxygen level dependent contrast (BOLD fMRI), and 2) how caffeine operates on neuronal activity underlying cognition, to understand the effect of caffeine on behavior and its neurobiological underpinnings. Show more

Keywords: Caffeine, functional magnetic resonance imaging (fMRI), higher cognitive functions, working memory

DOI: 10.3233/JAD-2010-1417

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S71-S84, 2010

Authors: Nehlig, Astrid

Article Type: Review Article

Abstract: The effects of caffeine on cognition were reviewed based on the large body of literature available on the topic. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on working memory, and caffeine appears to rather improve memory performance under suboptimal alertness …conditions. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. At low doses, caffeine improves hedonic tone and reduces anxiety, while at high doses, there is an increase in tense arousal, including anxiety, nervousness, jitteriness. The larger improvement of performance in fatigued subjects confirms that caffeine is a mild stimulant. Caffeine has also been reported to prevent cognitive decline in healthy subjects but the results of the studies are heterogeneous, some finding no age-related effect while others reported effects only in one sex and mainly in the oldest population. In conclusion, it appears that caffeine cannot be considered a `pure' cognitive enhancer. Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties. Show more

Keywords: Alertness, attention, caffeine, cognition, learning, memory, mood, performance

DOI: 10.3233/JAD-2010-091315

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S85-S94, 2010

Authors: Cunha, Rodrigo A. | Agostinho, Paula M.

Article Type: Review Article

Abstract: Caffeine, the most widely consumed psychoactive drug, enhances attention/vigilance, stabilizes mood, and might also independently enhance cognitive performance. Notably, caffeine displays clearer and more robust beneficial effects on memory performance when memory is perturbed by stressful or noxious stimuli either in human or animal studies. Thus, caffeine restores memory performance in sleep-deprived or aged human individuals, a finding replicated in rodent animal models. Likewise, in animal models of Alzheimer's disease (AD), caffeine alleviates memory dysfunction, which is in accordance with the tentative inverse correlation between caffeine intake and the incidence of AD in different (but not all) cohorts. Caffeine also …affords beneficial effects in animal models of conditions expected to impair memory performance such as Parkinson's disease, chronic stress, type 2 diabetes, attention deficit and hyperactivity disorder, early life convulsions, or alcohol-induced amnesia. Thus, caffeine should not be viewed as a cognitive enhancer but instead as a cognitive normalizer. Interestingly, these beneficial effects of caffeine on stress-induced memory disturbance are mimicked by antagonists of adenosine A2A receptors. This prominent role of A2A receptors in preventing memory deterioration is probably related to the synaptic localization of this receptor in limbic areas and its ability to control glutamatergic transmission, especially NMDA receptor-dependent plasticity, and to control apoptosis, brain metabolism, and the burden of neuroinflammation. This opens the real and exciting possibility that caffeine consumption might be a prophylactic strategy and A2A receptor antagonists may be a novel therapeutic option to manage memory dysfunction both in AD and in other chronic neurodegenerative disorders where memory deficits occur. Show more

Keywords: A2A receptors, adenosine, aging, Alzheimer's disease, caffeine, chronic stress, memory

DOI: 10.3233/JAD-2010-1408

Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S95-S116, 2010