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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.
The widely-consumed psychostimulant, caffeine (1,3,7-trimethylxanthine), displays a broad array of actions on the brain. There are multiple targets of caffeine, giving rise to a high level of complexity that can confound experimental efforts to understand caffeine influences in the brain. Despite such “impediments”, a substantial body of literature has been accumulated in recent years that has provided some insights into the mechanisms of caffeine influence in the brain, with important clinical/translational implications. One example of the latter would be Alzheimer's disease (AD), as supported by evidence suggesting a positive influence of long-term caffeine intake on cognitive function in patients, especially memory and learning (e.g. ). One possible contributing factor to the onset and progression of cognitive impairment in AD, is vascular dysfunction. In particular, this relates to pathologic changes in cerebral vascular tissue linked to accumulation of amyloid-β peptide (Aβ) in and around cerebral blood vessels, resulting in a condition labeled cerebral amyloid angiopathy (CAA). Some of the characteristics of CAA that are thought to contribute to exacerbation of AD pathology include impaired neurovascular coupling, cerebral hypoperfusion and hypercontractility, loss of cholinergic innervation, blood-brain-barrier damage, and microvascular ruptures [2–5]. Of some relevance to the present discussion, Arendash and co-workers  recently published compelling data showing that chronic caffeine consumption was associated with reductions in cerebral Aβ levels, and cognitive improvement in AD mice. Since increased presence of Aβ may impair cerebral vascular function (see above), it is tempting to postulate that caffeine could limit the severity of CAA and, perhaps, mitigate cognitive decline, via a vasculoprotective effect. However, such a mechanism remains to be established. Thus, in the remainder of this review, no further consideration will be given to caffeine-modulated vascular-AD linkages. Instead, we will focus primarily on acute and chronic caffeine influences on hemodynamic function, with some emphasis on neurovascular coupling (functional hyperemia).
Caffeine influence on cerebral perfusion is likely to involve its interactions with targets in vascular cells (e.g., smooth muscle; endothelium) as well as non-vascular cells (e.g., neurons; astrocytes; microglia). The literature points to at least 4 targets of caffeine in the brain – adenosine receptors, cyclic nucleotide phospodiesterases, ryanodine receptors, and GABAA receptors. With exception of the ryanodine receptors (activation), caffeine's influence on the above targets is inhibitory. Realistically, within the range of daily human caffeine consumption, among the caffeine-sensitive entities listed above, only the adenosine receptors may have any relevance, since caffeine possesses 1–2 orders of magnitude less potency toward the other targets listed . Thus, the present review will focus only on caffeine effects on adenosine receptors and the implications of that interaction with respect to neurovascular coupling in particular.
The tight coupling between neuronal activity and blood flow is fundamental to brain function. When a specific brain region is activated, cerebral blood flow increases in a temporally and spatially coordinated manner, thereby improving substrate (glucose, O2) delivery to meet local metabolic demands. Multiple signaling pathways have been shown to contribute to neurovascular coupling (reviewed in [8–11]). However, there appears to be a considerable degree of overlap in the mechanisms promoting the vasodilation accompanying increased neural activity, suggesting interactions among the signaling pathways. That complexity of the neurovascular signaling process, to a large degree, arises from the participation of multiple cells, principally neurons, astrocytes, and vascular cells (smooth muscle and endothelium), collectively termed the “neurovascular unit”. Astrocytes, in fact, may represent the linchpin in transducing increased synaptic activity to local vasodilation. The important physiologic function of astrocytes in sensing neuronal activity and in turn regulating the tone of cerebral arterioles has been addressed by a number of investigators [8–11]. Astrocytic endfeet extensively ensheath cerebral microvessels, to the extent that direct neuronal contacts to cerebral arterioles are sparse. Thus, astrocytes physically link neurons and their synapses with the vasculature, and are in a strategic position to convey neuronal signals to the blood vessels. As an example, neuronal activation can evoke increases in astrocytic [Ca2+], which in turn may trigger certain enzymes or cell membrane channels to generate or release vasoactive compounds. In this review, owing to its relevance to caffeine influences, we consider only one such vasodilating pathway, one that is related to adenosine. Clearly, there are other astrocytic Ca2+-linked vasodilating mechanisms, for example, involving K+ or arachidonic acid-derived mediators [8–11]. The overall importance of astrocyte Ca 2+ regulation to the neurovascular coupling process is reflected in the impairment of that process following inhibition of certain astrocyte Ca2+-related pathways [12, 13].
Increased synaptic activity has been linked to initiation of a propagated signal between astrocytes. Thus, a signal originating at the site of increased neural (synaptic) activity can be transmitted, over multiple astrocytes, to perivascular glial endfeet and elicit changes in arteriolar tone. Calcium, as reflected in the appearance of a “Ca2+ wave” capable of traversing multiple astrocytes, appears to be a vital component in this signaling process. Other factors that may play important roles in the transmission of a neuronally-initiated vasodilating signal, via astrocytes, include excitatory neurotransmitters (e.g., glutamate), K+, and ATP released by activated neurons (see ). There is evidence that ATP binds to purinergic receptors on neighboring astrocytes. These receptors are termed metabotropic purinergic receptors (labeled P2Y in Fig. 1) by virtue of their linkage to phospholipase C activation, inositol trisphosphate generation, and the well-described release of Ca2+ from intracellular stores (e.g. ). This appears to play an important role in initiating and propagating the Ca2+ wave. The appearance of ATP in the extracellular compartment also leads to rapid formation of adenosine. This is due to the ubiquitous presence of ecto-nucleotidases on astrocytic, vascular, and neuronal surfaces in the brain [15–19], particularly ecto-nucleoside triphosphate diphosphohydrolase-1 (E-NTPDase-1) and ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), which mediate direct ATP to AMP conversions; and ecto-5’-nucleotidase, which catalyzes the subsequent formation of adenosine from AMP. In considering neurovascular coupling and the neurovascular unit, one cannot ignore the contributions from the pial arterioles that lie upstream from the parenchymal arterioles. Thus, although local dilation of parenchymal arterioles is important in adjusting nutrient supply to neuronal needs, that response could be ineffective in the absence of dilation in the pial arterioles. Indeed, during increased activity of cortical neurons, overlying pial arterioles dilate, despite the lack of any direct contact with activated neurons. In a recent report, we showed that astrocytes provide a key link between increased neuronal activity in the brain parenchyma and the remote arteriolar relaxation represented by pial arterioles .
The role of adenosine and its receptors in the coupling of increased neuronal/synaptic activity to dilation of arterioles and arteries, and how caffeine might influence that important physiologic response, is the central theme of this review. To facilitate the following discussion of this rather complex process, we have created two cartoons representing neurovascular coupling in the absence (Fig. 1) and presence (Fig. 2) of acute caffeine exposure. In constructing these cartoons, a number of simplifying assumptions were made regarding the interplay among the major components of the neurovascular unit (synapse, astrocyte, and arteriole), adenosinergic mechanisms, and the targets of caffeine. Those assumptions, along with their rationale, supporting evidence, and caveats are summarized in Table 1.
Adenosine receptors, also referred to as purinergic P1 receptors, consist of four known subtypes (A1, A2A, A2B, and A3). These receptors are coupled to either Gi/o (A1 and A3) or Gs (A2A and A2B) proteins, which, upon engagement with adenosine, results in inhibition or enhancement of adenylyl cyclase activity, respectively. Among the adenosine receptors, the A1 receptor is the most regionally widespread in the brain. Evidence indicates that the A1 receptor is enriched in synaptic membranes in relation to other cellular elements , which is consistent with its purported neuromodulatory role. A prime example of that role is the ability of A1 receptor activation to restrict presynaptic neurotransmitter release . Furthermore, A1 receptor agonists have been reported to have a far greater effect toward restricting glutamate vs GABA release, indicating that presynaptic A1 activation is primarily anti-excitatory . Although some cerebrovascular presence of A1 receptors has been documented , its functional significance is unclear, since direct applications of A1 ligands do not affect cerebral arterial/arteriolar tone . The A1 receptor is expressed in astrocytes [25,26]. However, results from in vitro models (primary cultures, acutely isolated astrocytes, or brain slices) have not yielded consistent findings. That is, A1 receptor activation has been associated with PLC-linked intracellular Ca2+ elevations in some situations , but repression of Ca2+ influx in others (e.g. ). The A3 receptor also is expressed in brain tissue, but with a limited distribution . Although some expression of A3 receptors has been found in brain blood vessels , like the A1 receptor, it does not appear to be associated with any direct hemodynamic function . The A3 receptor has also been detected in astrocyte in vitro preparations , and may be involved in the regulation of astrocyte intracellular Ca2+ .
The high affinity, A2A, and low affinity, A2B, receptors are expressed in cerebral resistance vessels (see, for example ). Despite its lower adenosine affinity, recent findings  suggested that the A2B receptor plays a significant role in physiologic cerebral vasodilation. Some have speculated that the A2A and A2B receptors are differentially distributed within the cerebral arterial/arteriolar system, with A2A receptors predominating in the upstream pial arterial/arteriolar segments and A2B having greater influence in the downstream intraparenchymal segments . However, others have reported a substantial A2A receptor participation in adenosine-induced dilations in rat brain parenchymal arterioles . Irrespective of segmental localization, adenosine engagement of the vascular A2 receptors promotes vasodilation. Like A1 receptors, A2A receptors are found in presynaptic structures, but with a more limited regional distribution compared to A1 receptors . In rodents, the A2A subtype exhibits the highest expression in the striatum, in keeping with its association with dopamine-rich structures, with comparatively low abundance (relative to A1) in the cortex and hippocampus (e.g. ). Nevertheless, the existence of A2A receptors in the cortex is not insignificant, in light of evidence that glutamate release in rat cortical synaptosomes is enhanced by A2A receptor activation [32,33]. In contrast to the hippocampus  and striatum , the possibility of a cortical A1/A2A colocalization has not been confirmed via immunohistochemistry. Nevertheless, the presence of both A1 and A2A receptors in cortical synaptic structures can be inferred from findings that evoked glutamate release from cortical synaptosomes exhibits a marked sensitivity to manipulations of A1 and A2A receptor function [32, 33]. One postulated manifestation of colocalization is the “heteromeric” A1/A2A arrangement . Thus, the higher levels of extracellular adenosine that are likely to be associated with conditions of elevated neuronal activity are thought to favor increased A2A receptor function . The activated A2A receptor can, in turn, effect an inhibition of A1 receptor function, via a mechanism involving protein kinase C, rather than PKA [36, 37]. The A2A receptor effect could also include a more conventional PKA-dependent mechanism that involves elevated presynaptic Ca2+ entry . The end result of these A2A receptor-related actions is enhancement of glutamate release. Experimental evidence, obtained in synaptosomal preparations of rat cortex, hippocampus, and striatum, support an A2A receptor crosstalk repression of A1 receptor synaptic function that occurs across multiple cerebral structures [36,37].
With respect to A2B receptors, evidence indicates a rather sparse neuronal presence in the brain [38,39]. Although A2B receptors are reasonably well-expressed in astrocytes and cerebral vascular cells [8,22,24,40], in view of the low affinity of A2B receptors toward adenosine, any functional relevance may be limited to conditions of elevated extracellular adenosine presence, as may be found during higher neuronal activity states. The model depicted in Fig. 1 represents such a state. Therefore, A2B receptors on astrocytes and vascular smooth muscle are given consideration (see also Table 1).
In astrocytes, at least two functions for A2A receptors have been identified (see Fig. 1). Both of these functions are likely linked to activation of adenylyl cyclase and enhanced cAMP-dependent protein kinase (PKA)-mediated phosphorylation. The first involves restriction of glutamate uptake, via inhibition of the astrocytic GLT-1 transporter . The second A2A receptor function relates to PKA-mediated release of Ca2+ from astrocytic stores . This not only can contribute to trans-astrocytic signaling (i.e., the “Ca2+ wave”), but also promote Ca2+-dependent glutamate and ATP efflux (e.g. [41,43–45]). This will yield further elevations of glutamate and ATP in the synaptic cleft, potentiating neurotransmission [25,40] and providing more ATP for extracellular adenosine generation. It also has been suggested that adenosine engagement of astrocytic A2B receptors may provide a “boost” for the astrocytic Ca2+ wave during neural activation states (see review by Koehler et al. ). The A2 receptor-associated potentiation of astrocytic signaling, provided by a more robust Ca2+ wave, will ultimately enhance release of astrocytic ATP in the vicinity of arterioles. The ATP can then be rapidly converted to adenosine, which interacts with arteriolar smooth muscle A2 receptors. The subsequent Gs-mediated activation of smooth muscle adenylyl cyclase will increase intracellular cAMP levels and activate PKA (and, perhaps, cGMP-dependent protein kinase [PKG] ), which in turn, can phosphorylate targets within the smooth muscle cells. One target is K+ channels , leading to K+ efflux, thereby promoting smooth muscle hyperpolarization and reduced intracellular Ca2+ levels. Another key group of phosphorylatable targets are myosin light chain phosphatase, myosin light chain kinase, and RhoA, with the result being a reduced sensitivity of contractile proteins to Ca2+ [46,48]. It should be emphasized that the signaling scheme provided by Fig. 1 applies both to local dilation of parenchymal arterioles, involving a single astrocyte, or upstream pial arteriolar dilation involving Ca2+/ATP (and perhaps K+) – linked communication over multiple astrocytes (see [11,20]).
It is of some interest to note that if one replaces the vascular smooth muscle cell in Fig. 1 with another synapse, interactions of adenosine with its receptors in that synapse could lead to synaptic depression. Such a process might be found in the “heterosynaptic depression” model proposed by Cunha . Thus, an astrocytic Ca2+ wave, arising as the result of synaptic activation at one locus, will ultimately result in the release of ATP and subsequent generation of adenosine at a remote astrocytic site. If that adenosine contacts an arteriole, vasodilation (neurovascular coupling) will occur. If another synapse is contacted instead, synaptic depression could occur. One might speculate that a possible contribution to that heterosynaptic depression could arise not only from the presence of A1 receptors presynaptically, but also from the presence of A1 and A2A receptors on post-synaptic membranes of these distal synapses. Post-synaptic A1 and A2A receptors are thought, if anything, to be associated with attenuation of post-synaptic excitation (e.g., glutamatergic [22,49]). Thus, adenosine-related attenuation of post-synaptic function at remote (and even proximal) synapses could act to limit the spread of electrical activity from extending much beyond the area of initial activation. This might be viewed as an efficient way to ensure sufficient perfusion and substrate delivery to active neurons while limiting the amount of electrical “noise” (see Table 1). However, it merits mention that distribution of adenosine receptors between pre-and post-synaptic membranes may exhibit regional variations. For example, for A2A receptors, evidence suggests post-synaptic localization being favored in the striatum, while a distribution favoring the presynaptic membrane appears to be the case in the cortex . How such differences might affect heterosynaptic depression remains to be determined.
A scheme summarizing acute caffeine effects on neural activation-evoked arteriolar dilation is presented in Fig. 2. A number of the simplifying assumptions listed in Table 1 relate specifically to caffeine influences. First, we assumed a roughly equivalent caffeine potency toward blocking A1, A2A, and A2B receptors . However, despite that similarity, the A2B receptors, owing to their low adenosine affinity, may be affected by caffeine only under conditions of enhanced neuronal (synaptic) activity, where endogenous adenosine levels are likely to be elevated. Since Fig. 2, like Fig. 1, depicts an increased synaptic activity state, caffeine influences on A2B receptors are included. Second, possible contributions from A3 receptors are not considered. This is due to limited A3 receptor distribution in the brain  and an apparent caffeine inhibitory potency toward the A3 receptor that is lower by approximately one order of magnitude, in relation to the other 3 receptors . Third, we postulated that caffeine effects toward A1 receptors primarily involve preventing presynaptic manifestations of A1 receptor activation (i.e., the capacity to restrict neurotransmitter release); although post-synaptic A1 receptor blockade is given some consideration . Fourth, when examining the effects of caffeine-mediated blockade of A2A receptors on arteriolar responses during neuronal activation states, we took into account pre- and post-synaptic, astrocytic, and vascular smooth muscle A2A receptor sites (see earlier). For A2B receptor-related influences of caffeine on arteriolar tone, under conditions of increased synaptic activity, it seems reasonable to limit the focus to blockade of astrocytic and smooth muscle A2B receptors.
Nevertheless, in the context of neurovascular coupling, the assumption of an A1 receptor effect of caffeine being largely confined to presynaptic elements is bolstered by findings that topical application of the A1 receptor antagonist, DPCPX, actually potentiates pial arteriolar dilations evoked by sciatic nerve stimulation in rats . This might be explained on the basis of an A1 receptor-linked repression of neurotransmitter (e.g., glutamate) release, during increased axonal activity, acting as a “brake” on synaptic function. The upshot of this is that A1 receptor blockade will be accompanied by enhanced synaptic activity. In fact, there appears to be a significant A1 receptor-related tonic inhibition of synaptic transmission . This could account for the well-known arousal effects associated with caffeine consumption. However, caffeine-induced arousal was reported to be absent in A2A receptor knockout mice . Although this seems to imply an important role for A2A receptor inhibition in the arousal response to caffeine, those findings have been questioned in a recent report . On the other hand, acute caffeine administration in rats constricts pial arterioles  and lowers CBF in rats  and human subjects [56,57]. This could be explained by the caffeine-induced loss of a basal A2 receptor-associated vasodilating “tone”. The importance of a vascular (presumably A2 receptor) site for the vasoconstrictive actions of caffeine is underscored by findings showing that direct application of caffeine was accompanied by a ~70% reduction in adenosine-induced dilation of isolated rat brain arterioles . The acute effects of caffeine on vascular tone and CBF not only may be related to the presence of A2A and A2B receptors on vascular smooth muscle, but also on astrocytes. Thus, especially under conditions of elevated synaptic activity, blockade of astrocytic A2 receptors could disrupt Ca2+ signaling mechanisms, diminishing ATP release, and reducing the amount of adenosine to which arterioles are exposed. Furthermore, one also cannot ignore effects arising from caffeine blockade of A2A (and A1) receptors on synaptic membranes. During enhanced axonal activity, A2A receptor-mediated facilitation may override A1 receptor-mediated repression of glutamate release from nerve endings . In the presence of caffeine, which blocks both receptors, it is difficult to predict what the net effect on glutamate release will be. Caffeine-associated blockade of astrocytic A2A receptors, as depicted in Fig. 2, may favor net glutamate uptake into astrocytes, reducing glutamate levels in the synaptic cleft. Thus, there is a measure of uncertainty regarding the net effect of caffeine on activation of post-synaptic glutamate receptors. Adding to the uncertainty, caffeine will also block post-synaptic A1 and A2A receptors . Since this could remove adenosine-associated inhibitory influences on glutamate-related post-synaptic function, the overall net effect could be enhanced post-synaptic activity. It is tempting to speculate that caffeine blockade of post-synaptic adenosine receptors might enhance the post-synaptic electrical response to glutamate during states of elevated neural activity. This might lead to a greater spread of electrical “noise” beyond the initial site of increased axonal firing, perhaps contributing to increased heterosynaptic activity and caffeine-related arousal. Thus, the ability to maintain or increase neural activity, in the face of direct vasoconstrictive actions (caffeine blockade of VSM A2 receptors) is consistent with findings showing neurovascular “uncoupling” in rats and humans given acute caffeine treatment [54,56,64].
Although there is agreement among studies, with respect to the vasoconstrictive, CBF-lowering actions of acute caffeine treatments, the effects of chronic caffeine exposure on cerebral perfusion cannot be easily generalized. There are a number of factors one might consider regarding cerebrovascular regulation in conjunction with chronic caffeine use. Certainly, adenosine-linked factors merit prime consideration. This includes (but is not limited to), changes in adenosine receptor expression and agonist sensitivity associated with caffeine tolerance. One example is the upregulation of platelet A2A receptor expression observed in human subjects following chronic caffeine exposure . One could also consider how variations in adenosine receptor distribution, within the cerebral arterial system and the other components of the neurovascular unit, may impact on caffeine effects. A number of publications appearing over the past two decades point to cerebral A1 (but not A2A) receptor upregulation and sensitization in rodents in association with chronic caffeine intake (reviewed in ). Consistent with a lack of influence of chronic caffeine intake on A2A receptor function, one study in rats revealed that the tolerance that develops toward the striatal motor stimulant effects of caffeine, with chronic caffeine intake, could not be recapitulated with prolonged administration of a selective antagonist of A2A receptors . However, the results of other investigations showed seemingly opposite effects of chronic caffeine treatment. Thus, an enhanced A2A receptor ligand binding in the striatum was reported in one study , while a downregulation of striatal A2A mRNA and protein expression was observed in another . Adding to the uncertainty, Arendash and co-workers  reported no changes in A2A and A1 expression in hippocampus and frontal cortex of mice following chronic caffeine intake. While this might reflect regional selectivity in adenosine receptor responses to chronic caffeine exposure, it should be noted that the results in the latter study were obtained in AβPP transgenic mice, and, thus, should be viewed with some caution.
Another potentially interesting aspect of the role of adenosine receptors in caffeine tolerance development relates to the postulated presence of presynaptic A1-A2A receptor heterodimers in the brain , as touched upon earlier. In one postulated scenario , at least in the striatum, receptor tolerance to chronic caffeine exposure affects A2A more than A1 receptors. This relative enhancement of A2A receptor function could affect further inhibition of caffeine-repressed A1 receptors. In this way, chronic caffeine exposure would favor a greater A2A over A1 receptor function and enhanced presynaptic activity, as opposed to caffeine-naïve rats. It might be speculated that such a scheme could be associated with a partial recovery of the repressed neurovascular coupling accompanying acute caffeine exposure. However, this co-localization of adenosine receptors is not uniformly distributed among brain regions and may simply function as a limited local “fine-tuning” mechanism [30,31,34]. Furthermore, the potential impact of A1-A2A receptor heterodimerization as a facilitator of neurovascular coupling may only be manifested in higher brain activation states . In summary, there remains a high level of uncertainty surrounding this issue, and further study is clearly warranted.
However, none of the studies cited above provided evidence regarding expression or functional changes in vascular-specific adenosine receptor populations. Based upon the earlier discussion, it is difficult to envisage chronic caffeine effects that do not involve vascular smooth muscle A2 receptors (see ). Indeed, it has been suggested that the increased CBF that occurs in human subjects within 24 h of caffeine withdrawal results from adenosine binding to a more sensitized population of receptors or a greater abundance of cerebral arterial receptors (see [65,66] for references). Due to the lack of evidence supporting any direct adenosine A1 receptor effects on cerebral arteriolar tone , one might ascribe the apparent “upregulation” of adenosine receptor function to vascular A2 receptors. Furthermore, in human subjects, a partial (or incomplete) tolerance to acute caffeine-related CBF reductions was found in association with chronic caffeine intake [66, 67]. While this could be a reflection of A2A receptor up-regulation (as postulated by Addicott et al. ), in the absence of any data regarding A2 receptor expression or ligand affinity in cerebral arteries and arterioles, one cannot eliminate the possibility that these chronic caffeine effects may be related to adenosine receptors residing in astrocytes or neurons. One also cannot ignore the role of altered abundance of non-adenosinergic receptor populations. For example, increased expression of brain tissue acetylcholine, serotonin, and GABAA receptors has been documented in the mouse in conjunction with chronic caffeine ingestion [59,68]. As such, there is the possibility that chronic caffeine effects on neurovascular coupling (or vascular function in general) may arise from altered expression of nonadenosinergic receptors, or even ion channels [59,68], residing in one or more of the cellular elements of the neurovascular unit. These and related issues will make interesting subjects for future experimentation.
In conclusion, caffeine can have multiple effects on cerebral arteries and arterioles, resulting in a complex influence on brain perfusion both under resting (basal) conditions and during states of increased synaptic activity (neural activation-induced hyperemia). At the levels of caffeine achieved in the circulation and brain during normal human consumption, caffeine is known to exert measurable effects on CBF. Those effects can be largely attributed to actions toward adenosine receptors and not other potential targets of caffeine, such as phosphodiesterases and ryanodine receptors. Both animal and human studies have indicated that acute caffeine exposure leads to constriction of cerebral vessels and reduced CBF, as well as diminished neurovascular coupling. It can be postulated that those effects of caffeine likely arise from inhibitory actions on A1, A2A, and A2B receptors distributed among the cellular components of the neurovascular unit – namely, neurons, astrocytes and vascular smooth muscle. The principal site of acute caffeine influence on A1 receptors is likely presynaptic nerve endings. Yet, if this were the only target of caffeine to affect neurovascular coupling, one should observe an enhanced cerebral vasodilating response to neural/synaptic activation, as was reported by Meno et al.  in the presence of an A1 receptor antagonist. Since caffeine suppresses neurovascular coupling (e.g., in the cortex ), it is probable that this reflects caffeine actions toward A2A receptors, and, perhaps to a lesser extent, A2B receptors. The A2 receptors contributing to the caffeine effect are likely to be found in multiple cellular sites. Indeed, A2A receptors have been identified in presynaptic, post-synaptic, astrocytic, and vascular smooth muscle sites; whereas A2B receptors are, at the least, expressed in astrocytes and vascular smooth muscle cells.
Attempts to understand the effects of chronic caffeine intake on cerebral hemodynamics have been confronted with more uncertainty. A principal problem here arises from a lack of consensus with respect to changes in the expression and/or adenosine sensitivity of A1 vs A2 receptors in association with prolonged exposure to an antagonist, like caffeine. While we cannot ignore A1 receptor changes, there is some indirect evidence to suggest that vascular A2A receptors might selectively upregulate during chronic caffeine exposure. This could explain the repeated observation that acute caffeine withdrawal from chronic caffeine ingestion is associated with an increase in CBF – one that is directly proportional to the daily caffeine intake immediately preceding the onset of abstinence (e.g. ). However, further experimentation is clearly warranted. Such experimentation could include, in animal models, a simple verification of whether there is at least a trend toward normalization of an acutely depressed neurovascular coupling in the presence of continuous caffeine intake. In association with such studies, one might consider the use of conditional knockouts to characterize the participation of adenosine receptors associated with specific cellular elements within the neurovascular unit.
This work was supported by grant number HL088259 from the NIH (DAP); the American Heart Association (HLX); and the Juvenile Diabetes Research Foundation (FV).
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=247).