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Potential therapeutic interest of adenosine A
2A
receptors in
psychiatric disorders
Rodrigo A. Cunha
1
, Sergi Ferré
2
, Jean-Marie Vaugeois
3
, and Jiang-Fan Chen
4
1 Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra,
Portugal
2 National Institute on Drug Abuse, I.R.P., N.I.H., D.H.H.S., Baltimore, MD, USA
3 Neuropsychopharmacology of Depression Unit, CNRS FRE 2735 (IFRMP), Institute for Biomedical
Research, University of Rouen, France
4 Department of Neurology, Boston University School of Medicine, USA
Abstract
The interest on targeting adenosine A
2A
receptors in the realm of psychiatric diseases first arose
based on its tight physical and functional interaction with dopamine D
2
receptors. However, the role
of central A
2A
receptors is now viewed as much broader than just controlling D
2
receptor function.
Thus, there is currently a major interest in the ability of A
2A
receptors to control synaptic plasticity
at glutamatergic synapses. This is due to a combined ability of A
2A
receptors to facilitate the release
of glutamate and the activation of NMDA. Therefore, A
2A
receptors are now conceived as a
normalizing device promoting adequate adaptive responses in neuronal circuits, a role similar to that
fulfilled, in essence, by dopamine. This makes A
2A
receptors a particularly attractive target to manage
psychiatric disorders since adenosine may act as go-between glutamate and dopamine, two of the
key players in mood processing. Furthermore, A
2A
receptors also control glia function and brain
metabolic adaptation, two other emerging mechanisms to understand abnormal processing of mood,
and A
2A
receptors are an important player in controlling the demise of neurodegeneration, considered
an amplificatory loop in psychiatric disorders. Current data only provide an indirect confirmation of
this putative role of A
2A
receptors, based on the effects of caffeine (an antagonist of both A
1
and
A
2A
receptors) in psychiatric disorders. However, the introduction of A
2A
receptors in clinics as anti-
parkinsonian agents is hoped to bolster our knowledge on the role of A
2A
receptors in mood disorders
in the near future.
Keywords
adenosine; A
2A
receptor; caffeine; mood disorders; psychiatric diseases; anxiety; depression;
schizophrenia; attention deficit hyperactivity disorder; ADHD
INTRODUCTION
Psychiatric disorders are currently defined on the basis of behavioural modifications found in
patients. Behavioural analysis essentially provides trends suggesting modified behavioural
patterns in comparison with a standardised population, which in itself display intra- and inter-
subject heterogeneity. There is currently no clear bio-marker to support the modified
behavioural patterns. This might be one of the reasons justifying the difficulty in categorising
psychiatric disorders, in spite of the tremendous effort in the refinement of neuropsychological
tests.
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Published in final edited form as:
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This reality also makes it difficult to appreciate the relevance of novel molecular targets to
develop drugs aimed at managing psychiatric conditions. In fact, the decision on pursuing a
given molecular target to develop novel therapeutics is expected to be based on a strong
scientific rational. This normally derives from the pathological changes that are characteristic
of the disease conditions being targeted. In the case of brain disorders, one should ideally
identify what brain areas are primarily affected and what are the main biochemical and/or
neurochemical traits pathognomonic of the disease. For instance, it would be of great help
deciding if the disease is mostly associated with neuronal or glial deficit. In case it would be
mostly neuronal, one could seek for the brain circuits primarily affected, and the neurochemical
systems suffering the most significant imbalance; if a glial deficit would be evident, then one
could attempt defining if the disease results from a metabolic drift or if neuroinflammation
deregulation plays a role. Finally, the issue of neurogenesis defaults as a possible cause of
disease should also be considered. It is this general information that ultimately provides the
scientific rationale to select any particular molecular target to develop novel therapeutic
strategies.
In the case of psychiatric disorders, it is currently not possible to apply any solid anatomical
or neurochemical rationale to sustain pursuing any particular molecular target for the
development of novel drug-based therapeutic strategy. In fact, none of the questions listed
above have received a clear answer in the case of the most common psychiatric disorders.
Taking as examples the case of depressive disorders (the plural reflecting the idea that they are
multiple defined clinical entities), the brain areas affected are rather broad and too many
biochemical and/or neurochemical (or morphological) traits have been reported to allow any
of them to be considered pathognomonic of these ‘diseases’ [1–5]. Different groups place
different emphasis on whether ‘depression’ is primarily due to neuronal or glial modifications
[6,7]. Accordingly, there is no clear definition of particular brain circuits affected in these
conditions, nor there is any agreement on whether these conditions are due to metabolic [8–
10] or neuroinflammatory deregulations [11,12]. Finally the currently holly grail of
therapeutics (neurogenesis) actually seems to be a part in all physiological and pathological
processes in the brain [13,14], making it difficult to anticipate how this can be manipulated as
a therapeutic strategy.
Without a clear rationale to discuss the validity of considering any particular molecular target
as a promising candidate to develop novel drugs to manage psychiatric conditions, one is left
with the evaluation of the efficacy of novel drugs in alleviating the behavioural symptoms that
are characteristic of these diseases. The development of drugs is normally carried out in a safer
and faster manner using animal models of disease. And this constitutes the second major hurl
to test the interest of potentially novel drugs to manage psychiatric disorders. In fact, there is
currently no single animal model that satisfactory mimics the most common behavioural
changes found in psychiatric disorders [15–17]. There are obviously animal models that
replicate particular behavioural changes (but only a limited set) and some animal behavioural
tests providing a reasonable predictability of the efficiency of some (but not all) of the drugs
currently used to alleviate the symptoms of psychiatric disorders [18,19].
The recognition of our current limitations in exploring novel targets to develop new drug-based
therapeutic strategies to manage psychiatric disorders should be kept in mind when evaluating
the subsequently presented evidence suggesting the possible interest of adenosine A
2A
receptors.
PHYSIOLOGICAL ROLE(S) OF ADENOSINE A
2A
RECEPTORS IN THE BRAIN
There are several reviews dealing with the localization and role of A
2A
receptors in the brain
[20–23]. This short overview is just supposed to recapitulate some features of central A
2A
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receptors that might be relevant to the putative interest of this receptor in the realm of
psychiatric disorders.
Until the beginning of this century, there was a general consensus that central A
2A
receptors
were confined to the basal ganglia, where they played a role in the control of signal processing
in medium spiny neurons [24–27]. In fact, this particular pool of A
2A
receptors is by far the
most abundant in the mammalian brain, but this should not underscore the fact that A
2A
receptors have a much broader distribution in different brain areas and in different cell types,
albeit with a considerably lower density. These A
2A
receptors in medium spiny neurons have
been established to be determinant for the control of motor function, since their selective
genetic elimination abrogates the ability of A
2A
receptor to control motor function [28],
probably the most evident behavioural effect caused by A
2A
receptor ligands [23,29–31].
How these A
2A
receptors located in medium spiny neurons act to control motor function is still
an open issue (reviewed in [31]). There is a predominant trend arguing that the main action of
these striatal A
2A
receptors is the control of dopaminergic signalling, that plays a key role in
striatal signal processing and thus in motor control [32]. In particular the pioneering work at
the Karolinska Institute (reviewed in Ferré et al., present issue) clearly substantiated a tight
interaction between A
2A
and dopamine D
2
receptor signalling. However, it is also clear that
A
2A
receptors can control motor function in the absence of dopaminergic signalling [33,34].
This indicates that even striatal A
2A
receptors work through dopamine-independent
mechanisms to impact on brain function. In fact, A
2A
receptors have been localized
presynaptically in a majority of glutamatergic nerve terminals, where they form heteromers
with A
1
receptors and where they play an important facilitatory role of cortico-striatal
glutamatergic neurotransmission [35].
The concept of dopamine-independent effects of A
2A
receptor function is particularly relevant
in the case of extra-striatal A
2A
receptors, where dopaminergic signalling is far less intense.
The most compelling evidence come from the recent study using the brain-region specific
A
2A
receptor knockout models in which A
2A
receptor was selectively deleted either in striatal
neurons (striatum A
2A
KO) or entire forebrain neurons (including striatum, cerebral cortex and
hippocampus, forebrain A
2A
KO) [36–38]. Using these novel knockout models, we recently
showed that cocaine-induced psychomotor activity is enhanced in striatum A
2A
KO mice, but
attenuated in forebrain A
2A
KO mice; urthermore, selective inactivation of A
2A
receptor in
extra-striatal cells by administering the A
2A
receptor antagonist KW6002 to striatum A
2A
KO
mice attenuated cocaine effects, rather than enhanced cocaine effects by administering
KW6002 into wild-type mice [39]. These results identify a critical role of A
2A
receptors in
extra-striatal neurons in providing a prominent excitatory effect on psychomotor activity
[39]. Theprecise localization of these extra-striatal A
2A
receptors involved in psychomotor is
not clear yet, but several studies have found that these extra-striatal A
2A
receptors are mostly
synaptically-located in contrast to the most abundant striatal A
2A
receptors [40]. In particular,
extra-striatal A
2A
receptors are located in glutamatergic synapses [41]. It is important to point
out that those extra-striatal A
2A
receptors also include the A
2A
receptors localized in striatal
glutamatergic terminals [35] (thus, the term extra-striatal can be a bit misleading). These
A
2A
receptors control both the release of glutamate [35,42,43] as well as NMDA receptors
[44]. Interestingly, these receptors do not seem to be activated by ambient levels of adenosine
[44–46]. Instead, they are selectively recruited upon high frequency trains of afferent
stimulation that are normally used to trigger synaptic plasticity phenomena [44]. This is due
to the fact that A
2A
receptors seem to be selectively activated by a pool of adenosine formed
upon the extracellular catabolism of ATP [44,47], which is mainly released upon higher
frequencies of nerve stimulation [48]. This engagement of A
2A
receptors selectively upon high
frequency trains of stimulation designed to trigger plastic changes in excitatory synapses has
lead to the proposal that the adenosine system would help defining salience of information in
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excitatory circuits through a combined action of A
2A
receptors, as an ancillary system of
NMDA receptors, in synapses engaged in plastic changes, together with the action of inhibitory
A
1
receptors (activated through astrocytic-mediated heterosynaptic depression) in non-
stimulated synapses [21]. Hence A
2A
receptors would play a selective role in controlling plastic
changes in brain circuits, defining the threshold for induction of plastic changes in excitatory
synapses.
Other possible physiological functions potentially controlled by A
2A
receptors are also worth
considering, although the weight of evidence in their support is currently weaker. One aspect
that merits further investigation is the possible ability of A
2A
receptors to control inhibitory
transmission in brain circuits. Neurochemical findings showed that A
2A
receptors controlled
the evoked release of GABA from different preparations [49,50], but this has only received a
direct electrophysiological support in the adult brain in the case of collateral projection between
medium spiny neurons [51] and in their projection to the pallidus [52]. This topic is of particular
relevance given the importance of long-distance interneurons and local interneurons in the
definition of cortical excitability [53]. The interest on this subject is strengthened by the recent
observation that adenosine receptor blockade following caffeine administration seems to
mainly affect inhibitory rather than excitatory transmission in the Human cortex [54]. Another
potential role of A
2A
receptors in physiological conditions is as coordinator of metabolic
activity in brain tissue. Thus, adenosine has long been recognised as a key paracrine modulator
in different mammalian tissue, being responsible for function such as cardiac dromotropism,
tuberulo-glomerular filtration control, post-prandial vasodilatation and control of excessive
immune/inflammatory reactivity [55]. In fact, ATP (one of the most abundant intracellular
molecules) and adenosine are released from stressed cells (either suffering insults or upon work
overload) and this extracellular adenosine acts on both A
1
and A
2A
receptors to prompt
adaptation and/or restore homeostasis [56,57]. In brain tissues, A
2A
receptors control capillary
vasodilatation [58], the uptake of excitatory amino acids by astrocytes and the pattern of
metabolism in astrocytes [59]. This is expected to have a dramatic impact both on the
availability and use of metabolic resources that are fundamental to the optimal performance of
brain circuits, but the true contribution of A
2A
receptors for brain metabolism still needs to be
thoughtfully tested.
ROLE OF ADENOSINE A
2A
RECEPTORS IN THE CONTROL OF
NEURODEGENERATION
The impact of A
2A
receptors in the control of neuronal damage was first proposed by John
Phillis in a model of cerebral ischemic injury [60]. It was later confirmed that either the
pharmacological blockade or the genetic elimination of A
2A
receptors conferred a robust
neuroprotection in animal models of brain ischemia [61,62]. This was later extended to a variety
of situations that had in common the deleterious impact of chronic noxious insults to adult
brain tissue (reviewed in [20,57]), such as glutamate excitotoxicity [63–65], free radical
toxicity [66], epilepsy [67–69], MPTP toxicity [70–72], 6-hydroxydopamine toxicity [70,71],
3-nitropropionic acid toxicity [37,73,74] or β-amyloid toxicity [75,76]. Interestingly, the
neuroprotection afforded by A
2A
receptor blockade is most evident in cortical areas (reviewed
in [57]), where the density of A
2A
receptors is nearly 20 times lower than in the striatum
[77]. It is important to note that the neuroprotective effect of A
2A
receptor antagonists in general
correlates with their ability to improve cognitive behaviour in animal models of neurological
disorders [20,57,78]. Consequently, A
2A
receptor activity in brain may achieve the modulation
of cognitive function, particularly those associated with degenerative disorders (such as
Parkinson’s disease, Huntington’s disease and Alzheimer’s disease), through its control of
neuronal cell death.
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The mechanism underlying this ability of A
2A
receptors to impact on brain tissue damage is
still a matter of hot debate. The use of tissue-specific transgenic mice fostered by our group in
Boston University School of Medicine, indicated that non-neuronal A
2A
receptors were
responsible for the control of brain tissue damage; in ischemic models or models of 3-
nitropropionic acid-induced toxicity, it was concluded that the key role was played by A
2A
receptors from bone marrow-derived cells [37,79], whereas in MPTP-induced neurotoxicity
A
2A
receptors in glial cells were the ones that played the key role in controlling brain tissue
damage [28]. This is in agreement with the localization of A
2A
receptors in microglia cells and
their ability to control microglia activation and burst of neuroinflammation [80]. However,
there is also robust evidence showing that neuronal A
2A
receptors can also control the demise
of neuronal damage. This was shown in the case of cultured neurons (virtually devoid of
microglia or inflammatory cells), where A
2A
receptor blockade abrogated either β-amyloid-
[81] or staurosporine-induced neurotoxicity [82] through a control of mitochondria membrane
potential and release of pro-apoptotic factors. These stimuli caused an initial synaptic damage
that later evolved into overt loss of neuronal viability, in light of the particular synaptic
localization of cortical A
2A
receptors and with the wide spreading idea that chronic
neurodegenerative diseases begin with synaptic dysfunctions that later evolve into different
demises of neurodegeneration [83–85]. In agreement with this role of synaptic A
2A
receptors
in the control of brain tissue damage is the observation that A
2A
receptor antagonists prevented
restraint stress-induced synaptic damage in the CA3 area of the rat hippocampus without any
apparent involvement of changes in inflammatory-related cells [86]. Clearly, this existence of
multiple and apparently conflicting hypothesis illustrate how little we actually know about the
different possible demises of brain tissue damage as well as of how little we know on the
biology of A
2A
receptors.
A consensual idea would be to propose that there might be a successive participation of A
2A
receptors located in different cells types according to the duration and/or intensity of noxious
brain insult: with mild noxious insults, there might be a main role of synaptic A
2A
receptors;
with more prolonged noxious stimuli, microglia A
2A
receptors would play a predominant role,
in view of the importance of microglia in the amplification of early brain damage [87–89];
finally, with more severe damage, causing loss of preservation of the blood-brain barrier, it
might be that A
2A
receptors in inflammatory cells invading the brain parenchyma play the
more pronounced role. Clearly, this is a hypothetic scenario that still needs experimental
confirmation.
A final topic that deserves consideration is the transducing mechanisms operated by A
2A
receptors to fulfil their physiological role(s) and to impact on brain tissue damage. There is
general agreement in the field that the transducing system operated by adenosine A
2A
receptors
is through the adenylate cyclase/cAMP/protein kinase A pathway [90]. This has received direct
experimental confirmation in heterologous expression system (where this was the only pathway
that was investigated) and in striatal medium spiny neurons [91–92]. However, it is now clear
that A
2A
receptors can couple to different transducing pathways (reviewed in [23,57]), being
a prototypical example of a pleiotropic receptor. At least for its impact on neuroprotection, it
is clear and evident that A
2A
receptors do not act through the cAMP pathway: in fact, it is well
known that bursting the cAMP pathway affords neuroprotection [93,94]; in contrast, it is the
blockade of A
2A
receptors (which would trigger but rather prevent accumulations of cAMP)
that actually confers neuroprotection. The clarification of the transducing pathways operated
by A
2A
receptors is an issue of particular relevance since “normalisation of signaling” through
manipulating A
2A
receptors is a potential important issue in the realm of psychiatric disorders.
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ADENOSINE AND MOOD DISORDERS
Mood disorders are one of the greatest burdens of disease in Europe and the development of
effective strategies to manage these conditions should represent a major socio-economic
priority [95–97]. The interest in the role of adenosine in mood disorders stems from three
concurrent lines of research: first, there is evidence that the consumption of coffee, and
particularly of caffeine (an adenosine receptor antagonists, as discussed below) might modify
the mood profile both of volunteers as well as of psychiatric patients; secondly, there is
evidence that different therapeutic strategies used to control mood disorders cause effects
related to the adenosine modulation system; thirdly, there is evidence from animal models that
the manipulation of adenosine receptors modifies behavioural responses considered relevant
for mood function in Humans. These first two lines of evidence will be discussed in parallel,
whereas the last one will be separately discussed since it is the only one that allows directly
relating A
2A
receptors with mood disorders (until data from the use of A
2A
receptor ligands in
Humans becomes publicly available).
Several studies in Humans have explored the relation between coffee intake and the mood
changes. These studies are likely to be relevant to the understanding of the putative role of the
adenosine modulation system in the control of mood for two reasons: first because it is
becoming evident that most of the effects of caffeine on brain related functions are mostly due
to the effects of caffeine, since they are not mimicked by decaffeinated coffee or other drinks
such as fruit juice (reviewed in [98]); secondly, the only known molecular target of caffeine
at physiological (i.e. nontoxic) doses are the A
1
and A
2A
adenosine receptors, where caffeine
acts as a competitive antagonist [99,100]. The consumption of coffee is well documented to
increase alertness (reviewed in [98,101]) and there is a trend to consider that caffeine improves
performance and cognition, especially in situations decreasing performance of cognition
(reviewed in [20,57,78]). There is also a general perception that caffeine consumption may
render individuals more anxious. Actually, large consumption of coffee (or caffeine) has been
argued to trigger a constellation of behavioural modifications that has led to coining the term
‘caffeinism’ [102–104]. In this situation, there are both anxiety disorders as well as greater
incidence of depressive-like conditions [103,105]. Another situation where there is a strong
link between caffeine intake and modifications of mood is upon withdrawal of caffeine [106,
107]. Apart from headache, fatigue and decreased alertness [108–109], withdrawal from
regular consumption of caffeine triggers a variety of anxiety-like symptoms, such as irritability,
sleepiness, dysphoria, nervousness or restlessness [106,107,110–112]. It is interesting to note
that some of these same withdrawal symptoms are similar to those described to occur upon
‘caffeinism’. This leads to two inter-twinned ideas that should be kept in mind when evaluating
the putative role(s) of adenosine and its receptors in the control of mood. The first idea is that
adenosine (and in an inverse manner caffeine) act on two receptors with globally opposite
function, namely inhibitory A
1
and facilitatory A
2A
receptors. Hence, it is possible that
different concentrations (or doses) of caffeine and adenosine may cause opposite effects
operated by different receptors. The second idea is a re-phrasal of the previous idea, i.e. that
the adenosine neuromodulation system should be viewed as a paracrine system designed to
maintain homeostasis or promote adaptation of neuronal systems. This means that the
fundamental role of this adenosine modulation system is to narrow the window of functioning
of biological systems, curtailing its edges of extremes of functioning. Adhering to these ideas
will make it obvious that two much or too little adenosine in a system will cause its failure to
properly adapt to its environment. This might be a possible underlying cause to explain the
similarity between withdrawn of caffeine and ‘caffeinism’
A second line of evidence that is suggestive of a role of adenosine receptors in the control of
mood is the observations that different therapeutic strategies used to control mood disorders
have effects related to the adenosine modulation system [113]. In fact, both electroconvulsive
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therapy and sleep deprivation are two types of treatments of mood disorders, both of which
causing short term and long term adaptations of the adenosine neuromodulation system. Thus,
there are short term adaptive neuronal responses that are operated through inhibitory A
1
receptors, namely in terms of the slow wave sleep [114] and cerebral metabolic activity [115,
116]. There are also more long term adaptive changes, such as up-regulation of A
1
receptors
[117,119] and possibly of A
2A
receptors (reviewed in [57]) the former being a strong candidate
to mediate the reduction of cerebral blood flow [116,120–122], which is observed after these
treatments. It should be made clear that at this stage there is a tentative parallel between the
effects operated by these mood disorder treatments and the adenosine modulation system in
the brain, but it still remain to be directly shown that the mood beneficial effects of these
treatments is hampered by manipulation of adenosine receptors.
ADENOSINE A
2A
RECEPTORS AND ANXIETY
The role of adenosine A
2A
receptors in anxiety is still to be defined. In fact, whereas higher
doses of caffeine tend to increase [103,123–127] and lower doses of caffeine tend to reduce
anxiety levels in Humans [128,129], it is currently difficult to ascribe these opposite effects to
the a putative differential manipulation of A
1
and A
2A
receptors. In animal models aimed at
measuring spontaneous anxiety-like responses (such as the light/dark box or the elevated plus
maze), there is an anxiogenic-like behaviour in both A
1
receptor knockout mice [130,131] as
well as in A
2A
receptor knockout mice [132–134]. In contrast, careful studies by our group in
CNRS showed that the anxiogenic-like effect of caffeine in rodents is not shared by selective
A
2A
receptor antagonists [135].
Another line of evidence that indicates a possible role of A
2A
receptors in anxiety-related
conditions derives from polymorphism analysis of the A
2A
receptor gene. Thus, it was observed
that there is a significant association between self-reported anxiety after caffeine administration
and two linked polymorphisms on the A
2A
receptor gene, the 1976C>T and 2592C>T
polymorphisms [137]. Likewise this same polymorphism in the A
2A
receptor gene was also
observed to be associated with the incidence of panic disorder [137,138], which can be envisage
as a situation of anticipatory anxiety. Finally, another polymorphism of the A
2A
receptor gene
(1083TT genotype) is inversely correlated with caffeine consumption [139] and is related with
the inter-individual sensitivity to caffeine [140]. This is reminiscent of the idea that there is
little evidence for a correlation between the consumption of caffeine and anxiety in volunteers
[141,142], but there seems to be an anxiogenic effect of caffeine in a sub-group of patients
with different psychiatric disorders [143–147]. It remains to be studied if this differential effect
of caffeine on anxiety in psychiatric patients may be related to the presence of polymorphisms
in the A
2A
receptor gene [148].
ADENOSINE A
2A
RECEPTORS AND DEPRESSION
Whether caffeine affects the evolution of depression-like conditions is currently not clear from
the epidemiological point of view. In fact, in non-hospitalised cohorts, there is no difference
in the consumption of caffeine between control and depressed subjects, albeit there is a trend
for greater caffeine-induced anxiety effects in depressed patients [145–147]. Likewise, an
analysis of life-long caffeine consumption in twin pairs failed to note any evident relation
between caffeine intake and the risk for common psychiatric disorders [142].
The association of the adenosine modulation system with depression has been initially
developed based on observations showing that adenosine and its analogues caused depressant-
like behavioural effects in two widely used animal models of depression. Thus, elevating the
adenosine levels increased the time of immobilization in rats submitted to inescapable shocks
as well as in the forced swimming test [149–151]. Further arguing for an ability of the adenosine
system to control depression is the observation that classical antidepressants reverse the
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adenosine-induced immobility in these tests [152]. Interestingly, classical tricyclic
antidepressants such as nortriptiline, chlorimipramine or desipramine can bind to adenosine
receptors [153] and dose-dependently reduce the activity of ectonucleotidases in cortical nerve
terminals [154], a key controller of the extracellular formation of adenosine from released
adenine nucleotides [56]. Accordingly, these tricyclic antidepressants modify the outflow of
adenosine from cortical cups [155–156] and the glucose and ATP levels in healthy volunteers
[157–160].
The most direct evidence to implicate adenosine receptors in the control of depression was
obtained by our group in CNRS. In a series of careful studies, we found that A
2A
receptor
antagonists prolong escape directed behaviour in two screening tests for antidepressants, the
tail suspension and forced swim tests [161]. Further support for a potential role of A
2A
receptor
antagonists as novel anti-depressants was provided by the observation that A
2A
receptor
antagonists also displayed an attenuated ‘behavioural despair’ in these two screening tests
[162]. The observation that a dopamine D
2
receptor-like antagonist (haloperidol) prevented
the antidepressant effects resulting from A
2A
receptor blockade or inactivation led to the
hypothesis these effects of A
2A
receptors might involve adenosine-dopamine interactions
[161,162], in view of the effectiveness of drugs acting on dopaminergic signalling to manage
mood disorders. However, additional mechanisms such as the A
2A
receptor interaction with
other neurotransmitter systems in forebrain regions (but outside the striatum) or the ability to
control glial metabolism and neuroinflammation should also be explored by future studies.
This putative deleterious role of A
2A
receptors in depression [162] is in notable agreement with
other observations showing that the blockade of A
2A
receptors relieves the early stress-induced
hippocampal modifications [86]. One of the consequences of chronic stress is favouring the
implementation of a state of depression in susceptible individuals [163]. Interestingly,
adenosine controls the release of corticotrophin and cortisol/corticosterone release [164–167]
and the ability of adenosine receptor activation to modulate hippocampal excitability [23], a
key region in the control of HPA [168], and control memory and cognition, mostly through
A
2A
receptors [20,57,78,169,170]. Finally, adenosine receptors can also control the release of
serotonin through A
1
and A
2A
receptors [171] and it has been shown that the ability of caffeine
to reduce restraint-induced stress correlates with a striking ability of caffeine to reduce the
levels of serotonin in the hippocampus, an effect attributed to A
2A
receptors [172]. This is
particularly relevant since depression as well as the early stress-induced re-modelling of
hippocampal circuits are under the control of serotonin (e.g. [173–174]) and several novel
antidepressant drugs target the serotoninergic system [175].
Another avenue of research that can link A
2A
receptors with the aetiology of depression resides
in the tight interaction between A
2A
receptors and Trk-B receptors [176], which signal the
presence of neurotrophins such as brain-derived neurotrophic factor (BDNF). Thus, there is a
continuous build-up and strengthening of the ‘neurotrophin hypothesis of
depression’ (reviewed in [177,178]) and evidence is accumulating to suggest that A
2A
receptors
are tight controllers of the actions of BDNF, either through transactivation in an acute manner
[179–181] or normalization of its signalling in more chronic situations [182]
Furthermore, it is important to keep in mind that the effect of the adenosine modulation system
on depressive-like conditions might be more complex. In fact, the group of Ana Lúcia
Rodrigues has consistently shown that the administration of adenosine, either peripherally or
intracerebroventricularly has an antidepressant effect. This involves the recruitment of A
1
and
A
2A
receptors [183] and involves systems such as NO/cGMP [184] or the opioid system
[185].
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ADENOSINE A
2A
RECEPTORS AND SCHIZOPHRENIA
Another psychiatric condition where several studies suggest a role for the adenosine
modulation system is schizophrenia. Comparing the features of schizophrenia with some
physiological roles of adenosine or with the effects of caffeine and theophylline that are used
to probe the role of endogenous adenosine, Diogo Lara has championed the idea that
adenosinergic activity might be deficient in schizophrenia [186,187]. Thus, caffeine might
exacerbate positive symptoms ([188–190]; but see [191]) and conversely dipyridamole and
allopurinol may be beneficial for schizophrenia [192–195]; this provides compelling direct
evidence since caffeine blocks adenosine A
1
and A
2A
receptors and both dipyridamole and
allopurinol prevent purine degradation by inhibiting adenosine transporters and xanthine
oxidase. Furthermore, the expected deficiency of sensorimotor gating, evaluated as a disturbed
prepulse inhibition or P50 evoked potential, which is characteristic of schizophrenic
individuals [196], is mimicked by theophylline in healthy volunteers [197]. Furthermore, there
are co-morbidity relations, namely with insomnia (particularly with delta activity, see [198]),
which is mimicked by caffeine consumption [199] and prevented by activation of adenosine
receptors [117], and after seizures [200], which is also mimicked by xanthenes and prevented
by adenosine A
1
receptor activation [201]. Altogether these observations support a putative
role for deficient levels of adenosine in the brain of schizophrenic patients and are supportive
of the adenosine hypofunction hypothesis of schizophrenia. This hypothesis has been further
refined to better match the two-hit hypothesis of schizophrenia, to account for the neuro-
developmental aspect of this disorder [186,187]. Thus, A
1
receptors have a profound effect of
brain development [202], possibly through the control of the function of oligodendrocytes
[203–206], which would correspond to the first-hit phase. Furthermore, the role of A
1
receptors
in neuroprotection is only fully implemented during adolescence in rodents [207–209], which
is compatible with the second hit phase modelling schizophrenia.
In spite of these tempting scenario mainly implying A
1
receptors as a candidate system in the
aetiology of schizophrenia, there is also compelling observations that suggest a possible role
for A
2A
receptors. Thus, it was observed that the startle (a measure of sensorimotor function)
habituation was reduced by A
2A
receptor antagonists [210] as well as in A
2A
receptor knockout
mice [211]. Furthermore, A
2A
receptors can also act as ‘go-between’ normalizing (or re-
balancing) an impaired glutamatergic-dopaminergic communication that seems to be crucial
importance for proper function of the ventral striatum and prefrontal cortex. A recent study
with a transgenic model selectively altering the activity of adenosine kinase in forebrain region
has provided some direct evidence in supporting the notion that subtle changes in adenosine
level can lead to the emergence of behavioural endophenotypes implicated in schizophrenia
[212]. Thus, transgenic mice with over-expression of adenosine kinase in the forebrain (to
increase adenosine levels) display severe but selective deficits across different learning
paradigms, indicating the cognitive function deficient [212]. In addition, altered adenosine
level in forebrain also produces abnormal response to psychostimulants, such as amphetamine
and MK-801 [212].
Regarding the dopaminergic involvement in schizophrenia, it is noteworthy that activation of
adenosine A
2A
receptors reduces the affinity of dopaminergic D
2
receptors for dopamine, being
the probable mechanism underlying the antipsychotic-like profile of adenosine agonists
[213], the hyperdopaminergic effect of caffeine [100,213] and the exacerbation of psychotic
symptoms by caffeine in schizophrenic patients [195]. The recent finding of increased basal
D
2
receptors occupancy by dopamine in schizophrenic patients [214,215] is compatible with
a decreased adenosinergic tone, which via A
2A
-D
2
receptor interaction would increase the
affinity of D
2
receptors for dopamine [27,213]. Moreover, striatal dopamine release is under
tonic inhibition by adenosine acting on presynaptic A
1
receptors [216,217], which is also in
line with the increased release of dopamine in schizophrenia [218]. Finally, it was observed
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that the ability of clozapine (an atypical anti-psychotic, an and to a lesser extent haloperidol)
to induced c-fos expression is blocked by A
2A
receptor antagonists [219] and this anti-psychotic
also affected key pathways of formation of ATP-derived adenosine acting on A
2A
receptors,
the ecto-nucleotidase pathway [220]. Altogether, these observations are consistent with the
possibility that the manipulation of A
2A
receptor might help restore an adequate dopaminergic
signalling.
Concerning the NMDA hypofunction model of schizophrenia [221], adenosine A
1
and A
2A
receptor agonists have been shown to prevent behavioural and EEG effects of NMDA
antagonists [222,223]. This effect is in agreement with several lines of evidence: i) activation
of NMDA receptors releases adenosine [224–228] and ATP [229,230]; ii) administration of
NMDA antagonists reduces the basal outflow of adenosine [225,226,228]; iii) the effects of
NMDA antagonists may result from increased glutamate release [231–233], and both A
1
and
A
2A
receptors control the evoked release of glutamate namely in the striatum [35,42,43]; iv)
the psychostimulant effects of NMDA receptor antagonists are largely abrogated by genetic
or pharmacological blockade of A
2A
receptors [39,234]; v) NMDA receptor function is
modulated both by A
1
and by A
2A
receptors [44,235–239]. Taken together, these results
suggest that the NMDA hypofunction model may also be corrected by manipulating A
2A
receptors.
Despite indirect data indicating a potential role for adenosine in the aetiopathology of
schizophrenia, direct investigation of the adenosine system in patients is lacking. Acute
administration of high doses of caffeine to schizophrenic patients exacerbates positive
symptoms but, interestingly, fails to produce anxiety [195,240]. Also, the subtype of adenosine
receptor (A
1
or A
2A
) eventually involved in schizophrenia remains undefined. The only post-
mortem study of adenosine receptors in schizophrenia reported an increase in striatal A
2A
receptors [241,242], with no difference between patients on and off medication before death.
Also, the A
2A
receptor gene, located in the 22q12–13 region, is a candidate gene for
susceptibility to schizophrenia [243–245].
ADENOSINE A
2A
RECEPTORS AND ADHD
Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous phenotypically complex
disorder, whose exact aetiology is unknown. Most probably it does not have a unique cause
and represents the final result of different factors that interact with each other, with every factor
having a small contribution and increasing the vulnerability to the disorder through their
cumulative effects [246,247]. Without underscoring the importance of environmental and
psychosocial factors, a substantial genetic component has been detected in the appearance of
ADHD, mostly due to data obtained from family, twin and adoption studies [246,248]. Thus,
the heritability of ADHD has been estimated to be between 0.5 and 0.9, which makes it the
most heritable mental disorder among children. The search for the most probable genetic traits
associated with ADHD has mainly targeted genes involved with catecholaminergic
transmission, with a special focus on dopamine [249]. Evidence supporting dopaminergic
dysfunction in ADHD derives from different research areas: i) first the psychostimulant
medication used to counteract ADHD mostly interferes with dopamine transmission [246,
250]; ii) behavioural studies in animals indicate a prominent role of dopaminergic transmission
in motor control and attention processes [251], which dysfunction are hallmarks of ADHD;
iii) neuroimaging studies in ADHD patients demonstrate abnormalities (smaller volumes,
hypofunction, decrease blood flow) in brain areas with predominant dopaminergic innervation
such as the prefrontal cortex, cingulate gyrus and anterior basal ganglia [252]; iv) case-control
and family-based allele frequency studies clearly identified different genes related to
dopaminergic transmission (e.g. dopamine receptors and transporter) among the genes
associated with higher risk of ADHD [246,248]. In particular, a clear association between
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ADHD patients and the presence of a particular isoform of the dopamine D
4
receptor, the 7R
allele (see below), has been extensively replicated (e.g. [253,254]. The fact that this D
4–7
receptor allele has a two-fold higher incidence in ADHD probands suggests that it is associated
with a significant fraction of the genetic risk for ADHD, which is in accordance with meta-
analysis confirming that D
4–7
receptor is a susceptibility gene for ADHD [255,256].
This evidence clearly indicates that the D
4–7
receptor should be a potential target for the
development of novel effective therapeutic strategies to manage ADHD. The D
4
receptor
belongs to the family of dopamine D
2
receptor and displays a number of polymorphisms in
Humans, mainly consisting of different repeats in its third exon which encodes the third
intracellular loop of D
4
receptors; the most common variants have 2, 4 and 7 repeats, which
represent more than 90% of the observed allelic diversity [257]. This region is involved in the
G protein coupling of D
4
receptors and it is interesting to note that the allelic variant that
represents a risk factor for ADHD displays a reduced efficacy. Therefore, the therapeutic aim
would be to design selective D
4
receptor agonists to bolster this defective signalling associated
with D
4–7
receptor. However, in spite of considerable effort by different research groups, no
single compound has yet proven sufficiently potent and selective to activate D
4
receptors (e.g.
we have found that Ro 10–5824, the most potent and selective D
4
receptor agonist available
has hitherto unrecognised non- D
4
receptor targets in native rodent tissue; unpublished
observations). Since D
4
receptors belong to the same family as D
2
receptors, there is a growing
interest in exploring the possibility that A
2A
receptors may physically interact, not only with
D
2
receptors (see above), but also with D
4
receptors.
The hypothesis that the manipulation of A
2A
receptors may be a novel therapeutic strategy to
manage ADHD is particular compelling in view of the use of caffeine administration to treat
this condition [258,259]. In fact, the evidence supporting a dopaminergic dysfunction in ADHD
justifies the psychostimulant medication used to counteract ADHD [246,250,260]. Caffeine is
the most widely consumed psycho-stimulant drug worldwide and its only known molecular
target at non-pathological doses is the antagonism of adenosine receptors, mainly adenosine
A
1
and A
2A
receptors [99]. However, the use of caffeine in ADHD is not widespread nor a
first choice because it was reported to be less efficient to manage ADHD when compared with
other psychostimulant drugs [261]. This contention merits to be revisited in view of the dosage
of caffeine used in these studies, which is inadequate to sustain a prolonged blockade of A
2A
receptors as expected from the pharmacokinetic profile of caffeine [99]. In fact, given that the
pharmacokinetic profile of caffeine in children and adolescents indicates a considerably faster
elimination of the drug [262–265], this once-a-day schedule of caffeine administration is
clearly inadequate to provide a plasma level of caffeine sufficient to antagonise A
2A
receptors
throughout the day (in fact, it only allows a 4–6 hours effective antagonism of A
2A
receptors).
Certainly, an adequate use of a novel drug (caffeine), which is innocuous for children [266,
267], if effective, would represent a qualitative increment over the traditional repeated use of
psychostimulants, which can have severe side effects if repeatedly used in children.
The putative interest of A2A receptors in ADHD has been emphasised by the group of Reinaldo
Takahashi, based on the beneficial effects of A
2A
receptor antagonists in Spontaneous
Hypertensive Rats (reviewed in [78]). In fact, it has been shown that these animals have
attention deficits that may underlie their poorer memory performance [268–270]. Furthermore,
these cognitive dysfunctions in SHR are prevented by methylphenidate, which is effective in
ADHD [271]. It was observed that caffeine and A
2A
receptor antagonists are also effective to
prevent memory deficits in SHR, while essentially devoid of effects in normal rats [78,272].
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CONCLUDING REMARKS
As stressed in the beginning of the review, the lack of clear end–points and of animal models
of psychiatric diseases has seriously hampers the ability to critically evaluate the potential of
any particular molecule as a relevant target to develop novel drugs to manage psychiatric
disorders. The interest in the adenosine system mostly stems from the recognition that its main
function is to assist maintaining homeostasis in biological systems. Hence, it should be
considered a system of choice to manipulate brain circuits to restore their proper function.
In the particular case of mood disorders, A
2A
receptors emerge as a promising candidate target
since these receptors tightly interact physically and functionally with D
2
receptors, which are
major targets of psychoactive drugs. The interest on A
2A
receptors is further emphasised by
their prominent role in controlling synaptic plasticity in glutamatergic synapses: thus, a major
role of A
2A
receptors is to normalize the functioning of glutamatergic synapses which
dysfunction seems a common feature of many chronic brain diseases. In accordance with this
view, A
2A
receptor blockade affords a robust neuroprotection against different chronic insults
to the brain. This neuroprotection afforded by A
2A
receptor blockade not only depends on the
normalization of glutamatergic synapses but also on the ability of A
2A
receptors to control
mitochondria-induced apoptosis as well as to the effectiveness of A
2A
receptors to control
neuro-inflammation. Thus, A
2A
receptors might not only control the trigger of neuronal
dysfunction of brain circuits (glutamate excitotoxicity) but also its main system of
amplification (neuroinflammation and metabolic imbalance) as well as its main effector system
(apoptotic-induced neuronal damage).
Some caution needs to be introduced in this idyllic scenario. First, there is the need to
understand the time window of opportunity to manipulate A
2A
receptors in brain diseases.
There is also an emerging awareness that there are different populations of A
2A
receptors
located in different cellular (and/or sub-cellular) populations that play different and often
opposite roles in the control of the function (and dysfunction) of neuronal circuits. In this
respect, considerable work still needs to be achieved to allow understanding the molecular
mechanisms by which A
2A
receptors affect brain function. There is growing evidence that
A
2A
receptors are pleiotropic, coupling to different transducing systems, possibly as a function
of their heteromerization with different receptors. This opens a thrilling opportunity to
manipulate A
2A
receptors as a novel strategy of “normalisation of signaling” to manage mood
disorders.
Finally, there is still an obvious need to validate this potential of A
2A
receptors where it is in
fact relevant, i.e. in patients. This is currently largely restricted to the use of caffeine. Caffeine
is known to be a selective adenosine receptor antagonists in rodents (especially in mice), but
it might have other hitherto unknown molecular targets in humans. Furthermore, caffeine is
not selective for A
2A
receptors and also antagonises A
1
receptors, making it difficult to
unambiguously ascribe effects of caffeine as being mediated by A
2A
receptors. This is hoped
to change dramatically in the near future since A
2A
receptor antagonists have already been
approved as novel anti-parkinsonian drugs, which is hoped to bolster our knowledge on the
role of A
2A
receptors in the control of psychiatric disorders.
Acknowledgements
RAC thanks Fundação para a Ciência e Tecnologia and Fundação Oriente for continuous support.Supported also by
NIDA IRP funds.
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