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TABLE OF CONTENTS
Abstract
Introduction
Brain Circuitry and

Adenosine Receptor
Interactions
Adenosine
Receptors Overview
Psychostimulants
and Adenosine
Receptors
Mechanisms of
Adenosine
Receptor-Mediated
Pathways in Drug
Addiction
Misuse of Legal
Psychostimulants
Concluding
Remarks and Future
Prospects
Author
Contributions
Funding
Con ict of Interest

Statement
Acknowledgments
Supplementary
Material
Footnotes
References
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Front. Pharmacol., 10 January 2018 | https://doi.org/10.3389/fphar.2017.00985 (https://doi.org/10.3389/fphar.2017.00985)
Abstract
Introduction
Brain Circuitry and
The Role of Adenosine Receptors in

Adenosine Receptor
Interactions
Psychostimulant Addiction
Adenosine
Receptors Overview
Psychostimulants
Inmaculada Ballesteros-Yáñez (http://www.frontiersin.org/people/u/260336)1,
and Adenosine Carlos A. Castillo
(http://www.frontiersin.org/people/u/437663)2*,
Receptors Stefania Merighi
(http://www.frontiersin.org/people/u/487141)
Mechanisms of and
3* Stefania Gessi 3
Adenosine
1
Department of Inorganic and Organic Chemistry and Biochemistry, School of Medicine, University of Castilla-La Mancha, Ciudad Real,
Receptor-Mediated
Spain
Pathways in Drug
2
Department of Nursing, Physiotherapy and Occupational Therapy, School of Nursing and Physiotherapy, University of Castilla-La
Addiction
Mancha, Toledo, Spain
Misuse
3 of Legal
Department of Medical Sciences, Pharmacology Section, University of Ferrara, Ferrara, Italy
Psychostimulants
Concluding
Adenosine
Remarks receptors (AR)
and Future are a family of G-protein coupled receptors, comprised of four
members, named A1, A2A,
Prospects A2B, and A3 receptors, found widely distributed in almost all human
body tissues
Author and organs. To date, they are known to participate in a large variety of
Contributions
physiopathological responses, which include vasodilation, pain, and inflammation. In particular,
Funding
in the central nervous system (CNS), adenosine acts as a neuromodulator, exerting different
functions
Con depending on the type of AR and consequent cellular signaling involved. In terms of
ict of Interest
Statement
molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl
Acknowledgments
cyclase (AC), through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In
Supplementary
the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A
Material
receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are
Footnotes
found at low levels of expression. In addition, AR are able to form heteromers, both among
References
themselves (e.g., A1/A2A), as well as with other subtypes (e.g., A2A/D2), opening a whole range of
possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting
on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic
neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric
complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the
present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-
mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss
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experience. Learn more Studies presented in this review
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reinforce the
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induced effects.
(https://www.frontiersin.org) Furthermore, different experimental data support the hypothesis that A2A/D2
heterodimers are partly responsible for the psychomotor and reinforcing effects of
psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A2A receptor is
proposed as a potential therapeutic target for the treatment of drug addiction. The overall analysis
of presented data provide evidence that excitatory modulation of A1 and A2A receptors constitute
promising tools to counteract psychostimulants addiction.
Introduction
Drug addiction is a complex chronic cognitive disorder characterized by drug seeking and compulsive use,
which is difficult to control despite its harmful consequences. According to DSM-5 (American Psychiatric
Association, 2013), which is used to define mental disorders in epidemiologic studies, it is now accepted that
the criteria
TABLE used
OF CONTENTS to clinically define the terms abuse and dependence should be combined to form a new
category known as Substance use disorders, including craving as a new criterion to increase diagnostic
Abstract
accuracy (Hasin et al., 2013). In terms of epidemiology, drug addiction is currently a global health problem, as
Introduction
can be deduced from comparison of data obtained from the Global Burden of Diseases Study between 1990
andCircuitry
Brain 2015. For
and the period 1990–2015, global exposure to drug use increased by 30.2% for both sexes. In
Adenosine Receptor
addition, by 2015 drug use was a major risk factor for early death and disability in developed countries like
Interactions
the United States, Canada, Australia, and the United Kingdom, being the 5th leading global risk factor for men
Adenosine
and the 12th for women (GBD 2015 Risk Factors Collaborators, 2016).
Receptors Overview
Psychostimulants are a broad class of drugs whose effects include increases in arousal, wakefulness,
Psychostimulants
cardiovascular
and Adenosine stimulation, vigilance, and attention, and which constitute one of the most abused classes of
Receptors
prohibited drugs in the world, including as representative examples cocaine and amphetamine-like
Mechanisms
moleculesof(Chesworth et al., 2016). According to the 2017 report of the European Monitoring Centre for Drugs
Adenosine
and Drug Addiction (European Monitoring Centre for Drugs and Drug Addiction, 2017), it was estimated that
Receptor-Mediated
in the year
Pathways 2016, the global annual prevalence among Europeans aged 15 or over was 3.5 million users of
in Drug
Addiction
cocaine, 2.7 million users of MDMA and 1.8 million users of amphetamines which corresponds to 1.0, 0.8, and
0.5% of
Misuse ofLegal
the European adults, respectively, which occasional consumed mentioned psychostimulants during
Psychostimulants
2016.
Concluding
To date, the therapies developed to manage drug addiction are inadequate and unsatisfactory, and many
Remarks and Future
scientists around the world are focusing on new strategies to improve them. Even though numerous aspects
Prospects
of this phenomenon are not well understood, the neurochemical mechanism common to all drugs causing
Author
abuse in humans
Contributions is the increase of the neurotransmitter dopamine (DA) released from the ventral tegmental
area (VTA), to a region in the mesocorticolimbic part of the brain, like the nucleus accumbens (NAc) and the
Funding
prefrontal cortex (Filip et al., 2012; Morales and Margolis, 2017). This, in turn, increases the physiological
Con ict of Interest
reward and reinforcement
Statement mechanisms (Nestler and Landsman, 2001). This point is particularly important
because DA not only mediates the effects of acute rewarding, but is also thought to be involved in the
Acknowledgments
increased motivation to consume psychostimulants in psychostimulant abusers (Volkow et al., 2012).
Supplementary
Furthermore,
Material
abuse of psychostimulants may induce changes in brain regions not only with relevance for
addictive behavior, but may also promote long-term adverse consequences in areas related to memory and
Footnotes
cognition (Nyberg, 2014). In addition, relapse into drug use after abstinence has been attributed to exposure
References
to cues, stress or re-exposure to the drug itself that induce drug craving; the incubation of craving being a
common phenomenon reported for most drugs of abuse, including psychostimulants, that may last from the
beginning of abstinence for extended periods of time. Although little is known about the molecular
mechanisms that lead to the incubation of craving during drug abstinence, vulnerability to relapse correlates
with changes in the activity and structure of neurons from the limbic and frontal cortical circuitry, induced
by the drug use (Pickens et al., 2011; Wolf, 2016).
The repeated ingestion of psychostimulants, as for most substances with marked abuse potential,
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of the following two common features consistently reported in the literature: on the one hand,
psychostimulants, by blocking molecular reuptake, enhance the extracellular neurotransmitter
concentration in the synapses of monoaminergic neurons (Cooper et al., 1996; Rothman and Baumann, 2003;
Wood et al., 2014); on the other hand, psychostimulants increase DA release in the NAc, a critical area for the
reward circuit (Preedy, 2016). There is a growing body of scientific evidence demonstrating that
psychostimulants affect dopaminergic neurons in the limbic reward system, and that this effect underlies
addiction to stimulants (Siciliano et al., 2015).
Adenosine, an ubiquitous endogenous nucleoside, has been implicated in the reward-related behavior, and
represents a novel and interesting target to interfere with it, as a consequence of its modulatory function on
neurotransmission exerted by DA, glutamate and acetylcholine (Linden, 2001; Cunha, 2005; Gomes et al.,
2011; Lopes et al., 2011; Borea et al., 2016; Burnstock, 2017; Jacobson et al., 2017). Interestingly, adenosine
levels are modified following acute or chronic consumption of drugs of abuse and psychostimulants (Hack
and Christie, 2003; Brown and Short, 2008; Filip et al., 2012), suggesting that a better comprehension of
TABLE OF CONTENTS
adenosine signaling in the brain during addiction may open new pharmacological frontiers to explore
potential
Abstract treatments in preclinical studies and clinical trials over the next years (Stone, 1981; Clark and Dar,
1989; Krauss et al., 1993; Bonci and Williams, 1996; Salem and Hope, 1999). The question of whether
Introduction
adenosine signaling can be used as a potential therapy in abuse disorders remains to be answered.
Brain Circuitry and
Therefore,
Adenosine the goal of this review is to discuss current scientific evidence based on animal models of
Receptor
Interactions
psychostimulant addiction, and to suggest promising candidates in the search for pharmacological
interventions. We will include, when available, the effects of adenosine receptor (AR) ligands on the complex
Adenosine
Receptors
processOverview
of behavior related to psychostimulant consumption, seeking, withdrawal, craving and relapse, and
we will restrict our discussion
Psychostimulants to what we can consider psychostimulant drugs, namely cocaine and
and Adenosine
amphetamine-like molecules.
Receptors
Mechanisms of
Adenosine
Brain Circuitry and Adenosine Receptor Interactions
Receptor-Mediated
Pathways in Drug
The main brain circuitry associated with addiction is distributed across multiple areas. This circuitry is
Addiction
associated with the three stages of the addiction cycle (Koob and Volkow, 2010). The reinforcing effects in an
Misuse of Legal
initial binge/intoxication
Psychostimulants
stage are mediated by DA and opioid neurotransmission, and depend on
modifications in the VTA and striatum (particularly NAc). The negative emotional stage of withdrawal may be
Concluding
due toand
Remarks activation
Future of the amygdala with norepinephrine, dynorphin and corticotropin-releasing factor. The
third stage, craving, depends on the prefrontal cortex, amygdala and hippocampus, and glutamate is the
Prospects
major neurotransmitter involved (reviewed in Kelley and Berridge, 2002; Koob and Volkow, 2010; Kim et al.,
Author
2017; Figure 1). The NAc acts as a hub of convergence from the different regions, and it has been considered
Contributions
a key element
Funding in the neuronal circuitry of drug addiction. This nucleus is composed of two distinct
populations of medium spiny neurons (MSN) with different levels of dopamine D1 and D2 receptors and
Con ict of Interest
projections
Statement (direct and indirect basal ganglia pathways), which are positively and negatively coupled to cyclic
adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, respectively. Striatonigral MSN (direct
Acknowledgments
pathway) send substantia P and dynorphin projections to substantia nigra/VTA and globus pallidus interna,
Supplementary
and are enriched
Material with dopamine D1 receptors. Striatopallidal MSN (indirect pathway) send enkephalin
projections to globus pallidus externa and are enriched with dopamine D2 receptors (Lobo, 2009). Taking
Footnotes
together several studies using different approaches such as analysis of psychiatric disorders, transgenic mice,
References
neuropharmacology and optogenetic techniques, it has been possible to postulate an integrative
representation of the synaptic connections in NAc and the neurotransmitter systems (Silberberg and Bolam,
2015; Figure 2).
FIGURE 1
(https://www.frontiersin.org/files/Articles/320873/fphar-08-00985-HTML/image_m/fphar-08-00985-g001.jpg)
FIGURE 1. Schematic representation of pathways involved in intoxication, withdrawal and craving stages
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in the nucleus accumbens is a common feature ofABOUT(HTTPS://WWW.FRONTIERSIN.ORG/ABOUT/
psychostimulants
(https://www.frontiersin.org) reinforcement at initial stages of psychostimulants intake (dots in black are regions directly involved in
binge and intoxication). The negative emotional stage of withdrawal appears to be related to the activation
of amygdala (dots in white are regions directly involved in negative emotional stage) and, finally, the latter
stage of psychostimulant addiction, craving, depends on prefrontal cortex, amygdala and hippocampal
activities (dots in gray). In blue, glutamatergic pathways; in green, dopaminergic pathways; in red, GABAergic connections. NAc,
Nucleus Accumbens; Amy, Amygdala; dStr, dorsal Striatum; Hipp, Hippocampus; PFC, Prefrontal Cortex; SN/VTA, Substantia Nigra and
Ventral Tegmental Area; Thal, Thalamus.
FIGURE 2
(https://www.frontiersin.org/files/Articles/320873/fphar-08-00985-HTML/image_m/fphar-08-00985-g002.jpg)
FIGURE 2. Integrative scheme of reward circuit in striatum with focus on adenosine and dopamine
receptors and their interactions. A1 and A2A receptors are located pre- and post-synaptically forming
homo-, heterodimers and oligomers in the dendritic spines of medium spiny neurons in striatum (MSN).
TABLE OF CONTENTS
Glutamatergic input from cortex and dopaminergic input from ventral tegmental area project to both MSNs
expressing D1-like and MSNs expressing D2-like dopamine receptors. A2A, adenosine 2A receptors; CB1,
Abstract
endocannabinoid CB1 receptors; DAT, dopamine active transporters; D1, dopamine D1 receptors; D2, dopamine D2 receptors; mGlu5,
metabotropic glutamate subtype 5 receptors; 5HTRs, serotonin receptors.
Introduction
Brain Circuitry and

Adenosine Receptor
Interactions
Adenosine acts in the central nervous system (CNS) as a neuromodulator, with DA neurotransmission being
Adenosine
one of its
Receptors targets.
Overview The modulation of dopaminergic activity is mediated by two main subtypes of AR, being the
antagonist of DA receptors. Specifically, A1 receptors colocalize with D1 receptors, and A2A receptors with D2
Psychostimulants
receptors
and Adenosinein heteromeric complexes (Fuxe et al., 2010). Building on this rationale, the case of A2A receptors is
Receptors
particularly important when we are studying the effects of drugs of abuse, for reasons that have been
extensively
Mechanisms of reviewed previously (Hack and Christie, 2003; Brown and Short, 2008; Filip et al., 2012), and that
Adenosine
we only briefly enumerate here. First, A2A receptors are highly expressed in the striatum, a key brain nucleus
Receptor-Mediated
for the in
Pathways reward
Drug circuitry, and A2A are crucial receptors, modulating behavioral responses induced by drugs of
abuse (Ferré et al., 2007); indeed, their genetic deletion in mice results in a selective decrease of locomotor
Addiction
responses
Misuse of Legalto cocaine and amphetamine (Chen et al., 2000). Furthermore, A2A receptors are able to form
Psychostimulants
heteromers with other adenosine subtypes, resulting in, e.g., the A1/A2A heteromer (Ferré et al., 2008a), and
also with families of receptors relevant for the treatment of some neuropsychiatric disorders and drug
Concluding
Remarks and Future
addiction, producing, e.g., A2A/mGlu5 (Ferré et al., 2002), A2A/D2 (Ferré et al., 2008b; Bonaventura et al., 2015),
Prospects
and A2A/CB1 receptor heteromers (Tebano et al., 2012). This spectrum of interaction opens a wide range of
Author
possibilities in the field of AR pharmacology (Casadó et al., 2009). Interestingly, the oligomer formed by
Contributions
A2A/mGlu5/D2 receptors confers to the A2A subtype the ability to modulate the effects of psychostimulants in
Funding
striatal neurons, through the balance of GABAergic, dopaminergic and glutamatergic signaling (Cabello et al.,
Con ict of
2009; Interest
Kniazeff et al., 2011). The modulation of dopaminergic and glutamatergic signaling by A2A receptors
Statement
has been particularly important in the field of psychiatric disorders, as DA and glutamate are two key players
Acknowledgments
in the processing of moods, which could also be very relevant in drug addiction-related disorders (Cunha et
al., 2008).
Supplementary
Material
Footnotes
Adenosine Receptors Overview
References
Adenosine Metabolism and Adenosine Receptors Structure

In the CNS, extracellular adenosine exists in basal conditions, and its concentration may increase under
pathological situations, including hypoxia, ischemia or cell injury. Adenosine is produced by different
mechanisms, including metabolism of ATP released from neurons or glial cells. Specifically, ATP undergoes
dephosphorylation to ADP and AMP by the activity of particular enzymes named ectonucleoside triphosphate
diphosphohydrolase (CD39), and to adenosine through a specific ecto-5′-nucleotidase (CD73) enzyme (Drury
and Szent-Györgyi, 1929). Alternatively, adenosine may derive from hydrolysis of intracellular
AMP through
a cytoplasmic 5′-nucleotidase, or S-adenosyl-homocysteine (SAH) by SAH hydrolase, and may be released
through facilitated diffusion, using bi-directional equilibrative nucleoside transporters (ENT) (Dunwiddie,
1985; Ledent et al., 1997; Ribeiro, 1999; Hack and Christie, 2003). Under resting conditions, extra- and intra-
cellular levels of adenosine are very similar, but in pathophysiological states (inflammation, ischemia, and
hypoxia), characterized by high levels of this nucleoside, transport through ENTs is the main mechanism
responsible for extracellular adenosine removal. Inside the cell, adenosine is deaminated to inosine through
adenosine deaminase (ADA), or phosphorylated to AMP by adenosine kinase (AK). These enzymes display
different affinities for adenosine, with AK more affine than ADA; thus in physiologic conditions adenosine is
preferentially transformed to AMP, whilst in pathological states predominantly to inosine, a process which
occurs also in the extracellular milieu (Godinho et al., 2015; Borea et al., 2016).
Adenosine affects several functions in the body, exerting its physiological effects through regulation of four
G-protein coupled receptors (GPCRs) named A1, A2A, A2B, and A3, characterized by different affinities for
adenosine, tissue distribution, and coupling with effector systems. They have been cloned and
TABLE OF CONTENTS
pharmacologically characterized in different species, presenting a sequence homology of around 80–95%,
except
Abstract for A3 receptors which vary depending on species and show a variance of 30% in amino-acid
composition between human and rat. The A3 receptor, in contrast to other AR, was the first to be isolated and
Introduction
then pharmacologically characterized (Meyerhof et al., 1991). All AR show a common structure,
Brain Circuitry and
characterized
Adenosine Receptorby seven transmembrane domains connected by three intracellular and extracellular domains
Interactions
(Fredholm et al., 2000). At the extracellular level, the N-terminus presents specific glycosylation sites, while at
the intracellular side, the C-terminus contains phosphorylation and palmitoylation sites, important for
Adenosine
Receptors
receptorOverview
desensitization. The A receptor has a longer C-terminus tail constituted by 122 amino acids,
2A
whereas A1, A2B, and A3 receptors’ C-terminal domains comprise 30–40 amino acids (Fredholm et al., 2001).
Psychostimulants
and Adenosine
Recently, important crystallization results have determined the structures of human A1 and A2A receptors,
Receptors
thus allowing better drug design for A1 and A2A receptor-selective ligands (Jaakola et al., 2008; Lebon et al.,
Mechanisms of
2011; Xu et al., 2011; Carpenter et al., 2016; Glukhova et al., 2017; Sun et al., 2017). In the case of A3 receptors,
Adenosine
structure-based molecular modeling techniques have led to the rational design of potent A3 receptor-
Receptor-Mediated
Pathways
selectivein Drug
ligands (Ciancetta and Jacobson, 2017). Furthermore, AR may be present in the cell membrane in
Addiction
homomer isolated forms or in heteromers and oligomers, providing another possibility of intervention for
Misuse
drug of Legal
development (Cabello et al., 2009). Specifically, the ability of AR to interact with many other receptors,
Psychostimulants
such as A2A/D2 receptor heterodimers located in the striatum (represented in Figure 2), means they play a
Concluding
pivotal role in the modulation and integration of neurotransmission, and may be targeted by drugs for the
Remarks and Future
treatment of neurological diseases, including drug addiction (Chen et al., 2013).
Prospects
Author
Adenosine Receptors: Distribution, Signal Transduction, and Function

Contributions
Funding
AR are widely distributed in almost all organ and tissues, spanning brain, heart, lung, liver, kidney, bone, eye,
Con ict of Interest
skin, joints, and blood cells, suggesting that these proteins are potentially able to affect almost every
Statement
physiological function (Peleli et al., 2017).
Acknowledgments
Specifically, as for the presence of each AR subtype in CNS, the A1 receptor is mainly present in the cortex,
Supplementary
hippocampus,
Material cerebellum, nerve terminals, spinal cord, and glia (Chen et al., 2013). This wide range of
locations reflects the multitude of physiological effects orchestrated by it, including inhibition of
Footnotes
neurotransmitter release, reduction of neuronal excitability, sedation, anticonvulsant and anxiolytic effects,
References
analgesia and regulation of sleep (Stenberg et al., 2003; Gessi et al., 2011; Sawynok, 2016; Vincenzi et al.,
2016a,b; Varani et al., 2017). These effects are mediated through A1 receptors coupling to Gi/Go proteins,
inhibition of AC, activation of phospholipase-C (PLC)β and, particularly in neurons, activation of potassium
channels and deactivation of Q-, P-, and N-type Ca2+ channels. They also modulate mitogen-activated protein
kinases (MAPK) with important functional effects (Schulte and Fredholm, 2003).
The A2A receptor is highly expressed in the striatum, mainly present in GABAergic striatopallidal neurons,
corticostriatal glutamatergic terminals, and cholinergic interneurons, but it is also detectable in the olfactory
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release of glutamate, activation of glia and infiltration of immune cells from the periphery,
through blood
brain barrier passage (Fuxe et al., 2003, 2007b; de Lera Ruiz et al., 2014). The A2A receptor generally couples
to Gs proteins to increase cAMP levels, but in the brain it stimulates Golf, a specific Gs protein in neurons also
associated with AC (Kull et al., 2000), which is supposed to have a prominent role as a mediator of the
locomotor effects of some psychostimulant drugs (Hervé et al., 2001). The signaling cascade starting from
cAMP and PKA regulates different proteins such as cAMP responsive element binding protein (CREB) and DA-
and cAMP-regulated phosphoprotein (DARPP-32) (Preti et al., 2015), which is also involved in the responses to
psychostimulant drugs (Engmann et al., 2015). CREB phosphorylation then increases transcription of
immediate early genes such as c-fos and other genes like preproenkephalin (Ferré, 2008). In addition, the A2A
receptor, with its long C-terminus, could also bind to different accessory proteins like D2 receptors, ADP-
ribosylation factor nucleotide site opener (ARNO), α-actinin, translin-associated protein X (TRAX) and
ubiquitin-specific protease (USP4). A2A receptor activation may also trigger the Ras/Raf-1/MEK/ERK pathway
through PKA-dependent or independent mechanisms (Schulte and Fredholm, 2003).
A2B receptors are present in astrocytes, neurons, and microglia, but their role in the CNS is less well
TABLE OF CONTENTS
characterized in comparison to the other AR subtypes. As for the effector systems, it activates Gs
proteins/cAMP/PKA
Abstract phosphorylation. Furthermore, the A2B receptor stimulates an increase in Gq
protein/PLC/Ca2+, while modulating ion channels through βγ subunits. Coupling to MAPK has been also
Introduction
reported (Merighi et al., 2017).
Brain Circuitry and
Adenosine Receptor
Finally, for A3 receptors, a low level of expression has been detected in the brain, in which it was detected in
Interactions
the cortex, thalamus and hypothalamus, hippocampus, motor nerve terminals, retinal ganglion cells, pial and
Adenosine
intracerebral arteries and glia (Borea et al., 2015; Jacobson et al., 2017). The A3 receptor couples to Gi proteins
Receptors Overview
and decreases cAMP levels, whilst through Gq proteins or Gβγ subunits, it stimulates PLC and increase Ca2+
Psychostimulants
concentration. In addition, a pathway presenting RhoA, a monomeric G-protein and PLD, is relevant for the
and Adenosine
neuroprotection effects of A3 receptors. Inhibition of the transcription hypoxia-inducible factor (HIF-1) has
Receptors
been reported
Mechanisms of in astrocytes with neuromodulatory effects through MAPK and Akt modulation (Gessi et al.,
2013). Interestingly, the reduction of neuroinflammation has been related to analgesia (Janes et al., 2014).
Adenosine
Receptor-Mediated
Pathways in Drug
Addiction
Psychostimulants and Adenosine Receptors
Misuse of Legal
In this section,
Psychostimulants we will describe the current state of knowledge about how adenosine signaling can interfere
with common addictive psychostimulant consumption, focusing on data obtained from animal, particularly
Concluding
Remarks
murine,andmodels
Future and from human studies. Animal models not only give us useful information on the
Prospects
pathophysiological mechanisms of psychostimulant drugs intake that are not accessible to study in human
Author
subjects but also provide an useful tool to assay pharmacological approaches to explore potential treatments
Contributions
before develop clinical trials. Certainly, although animal models may produce similar responses to those
Funding
observed in humans, all the paradigms used in them for drug addiction research imply a lower degree of
complexity
Con than
ict of Interest that observed in human drug addiction. Nowadays, more complex animal models have been
Statement
developed to include some behavioral responses observed in human addictions, such as social peer
Acknowledgments
influences in drug intake (Moser et al., 2011; Ross et al., 2015; Strickland and Smith, 2015). Nevertheless, in
the last part of this section, information obtained
Supplementary from human studies is also provided and the actual
Material
information regarding this issue is discussed.
Footnotes
Psychostimulants can be classified into two broad categories depending on the mechanism by which DA
References
levels are increased; namely, amphetamines (AMPH) behave as DA releasers, while cocaine acts to inhibit DA
reuptake trough the inhibition of the DA active transporter (DAT) (Siciliano et al., 2015). In addition to the
increase in levels of DA in the striatum, AMPH and cocaine are able to induce an increase in norepinephrine
(NE), by blocking NE transporter (NET), while only cocaine also increases serotonin, by inhibiting serotonin
transporter (SERT) (Phillips et al., 2014; Zwartsen et al., 2017).
Cocaine is extracted from coca leaves, mainly in South America where the coca plant is commonly grown.
Despite being the most widely used illicit narcotic drug, cocaine has been used for centuries (if not millennia)
for medical and cultural purposes (Johanson and Fischman, 1989). Although cocaine may be illegally
distributed in several forms, mainly cocaine hydrochloride but also cocaine sulfate or crystalized
as “crack,”
the physiological and psychoactive effects of cocaine in different forms are similar (Hatsukami and
Fischman, 1996).
The family of “amphetamines” or amphetamine-like psychostimulants includes a wide range of compounds

which can be synthetized based on chemical substitutions of the original structure of alpha-
methylphenethylamine. AMPH and methamphetamine (S(+)-methylamphetamine, METH) are the most
studied compounds of the family, but other well-known psychostimulants in this family include
methylphenidate, MDMA (3,4-methylenedioxymethamphetamine, “ecstasy”), ephedrine and cathinone
(synthetic derivatives of which are known as “bath salts”) (Sulzer et al., 2005). Specifically, although
cathinones have a synthetic profile similar to AMPH, their mechanism of action is rather similar to that of
cocaine, being potent DAT inhibitors (López-Arnau et al., 2017). On the other hand, MDMA, in addition to
inhibiting NET and DAT, is both a substrate for SERTs and an inhibitor of them, with an IC50 in the
micromolar range, thus differentiating its behavior from that of AMPH, which is unable to affect SERTs (Rud-
nick and Wall, 1992; Baumann et al., 2005; Zwartsen et al., 2017). Although AMPH and METH have similar
TABLE OF CONTENTS
pharmacokinetics, they differ in their pharmacodynamic properties, with METH inducing DA release in the
NAc more
Abstract efficiently than AMPH (Goodwin et al., 2009). AMPH and METH have been studied for a long time,
but their neurobiology remains largely unknown with discrepancies in the literature between
Introduction
pharmacological and genetic-based experiments.
Brain Circuitry and
Adenosine Receptor
As for psychostimulants-induced changes in AR expression in brain areas only few scientific reports have
Interactions
been reported. Specifically, during a study of cocaine withdrawal and its relationship with sleep architecture,
Adenosine
Yang et al. (2011) reported that A1 receptor expression in the hippocampus of rats was reduced after 14 days
Receptors Overview
of withdrawal, A2A receptor density was increased on withdrawal-day 8 and 14, while the A2B receptors
Psychostimulants
remained unchanged. Other findings provide neurochemical evidence that after 10 days of cocaine self-
and Adenosine
administration, an up-regulation of functional A2A receptors in the NAc of rats was induced that returned
Receptors to
baseline expression
Mechanisms of levels after 7 days of drug withdrawal (Marcellino et al., 2007). In a study of the
motivational mechanisms after cocaine self-administration and extinction, it was reported that, in the dorsal
Adenosine
Receptor-Mediated
striatum of Wistar rats, there was an increase in the affinity of A2A receptors during maintenance and an
Pathways in Drug
increase in A2A receptor density after extinction from cocaine self-administration (Frankowska et al., 2013).
Addiction
Nevertheless, using a paradigm of escalating administration of cocaine dose (“binge”) and subsequent
Misuse of Legal
withdrawal, the
Psychostimulants density of adenosine A1 and A2A receptors in various brain nuclei of Fischer rats was not
different nor in chronic cocaine-treated rats or in the long-term withdrawn rats group (Bailey et al., 2005).
Concluding
Finally,and
Remarks rats trained to self-administer METH for 14 days showed
Future selective altered expression of AR, with A1
Prospects
receptor levels increased in the NAc shell, caudate-putamen and prefrontal cortex, and A2A receptors
decreased in the NAc shell and raised in the amygdala (Kavanagh et al., 2015). Interestingly, it is well known
Author
Contributions
that GPCR act as an oligomer, and indeed homodimers of A and 5-HT1A receptors occur constitutively, and
2A
are further
Funding increased by agonists such as CGS 21680 and 8-OH-DPAT, or reduced by antagonists including SCH
58216
Con and
ict of methysergide,
Interest which could also contribute to psychostimulant addiction (Łukasiewicz, 2007).
Statement
Even though there are no consistent and complete studies about amphetamines- and cocaine-induced
Acknowledgments
changes in AR expression in brain areas, a prominent role in the modulation of psychostimulant addiction
Supplementary
attributed to adenosine is mediated through the activation of AR by complex mechanisms, affecting various
Material
aspects of this phenomenon including locomotor activity, discrimination, seeking behavior and reward.
Footnotes
References
Studies in Animal Models
Although the interactions between adenosine and DA in the striatum were previously known, the role of AR
in AMPH-induced locomotor responses was first characterized only at the end of the last century. Turgeon et
al. (1996) demonstrated that, in Sprague-Dawley rats, AMPH-induced behavior could be pharmacologically
modulated by pretreatment with CHA, an A1 receptor agonist, or APEC, an A2A receptor agonist, which
reduced locomotor responses induced by acute AMPH exposure. However, only the A2A receptor agonist
inhibited c-Fos immunoreactivity, induced by AMPH, in striatum and NAc. In the case of METH, the
We use experimental paradigm
cookies on this website usedyour
to improve to determine the Learn
user experience. role of AR(//www.frontiersin.org/legal/list-of-cookies)
more in METH-mediated effects was METH-induced CLOSE
toxicity. In these studies, administration of the A1 agonist
CPA attenuated the METH-provoked
(HTTPS://WWW.FRONTIERSIN.ORG/REGISTER)
neurochemical
tyrosine hydroxylase changes in Swiss-Webster mice (Delle Donne and Sonsalla, 1994) while, in other
experimental models, represented by Wistar rats, both CPA and CGS 21680, an A2A receptor agonist, were
able to attenuate METH-mediated DA release in the striatum (Gołembiowska and Zylewska, 1998a). In terms
of METH-induced locomotor responses, it was also reported that administration of CHA and CGS 21680
before acute METH exposure in Wistar rats was able to inhibit METH-induced hyperlocomotion (Shimazoe et
al., 2000) but, interestingly, when those same agonists were tested to study METH-induced sensitization
(which occurs after repeated intermittent drug administration), only CGS 21680 was able to inhibit METH-
induced increase of locomotion while CHA had no effect (Shimazoe et al., 2000). In addition, the activation of
A2A receptors could also be the mechanism by which some herbal compounds, PAP9704 and ginsenoside
herbal compounds, attenuate METH-induced hyperlocomotion and conditioned place preference in BALB/C
AnNcrj mice as well as in C57BL/6 mice, respectively (Kwon et al., 2004; Shin et al., 2005). Furthermore,
AMPH-induced stereotyped head movements in Wistar rats were attenuated in a dose-dependent manner
with CGS 21680, poorly reduced when CPA was used and even potentiated when DMPX, an A2 receptor
antagonist,
TABLE was used
OF CONTENTS (Poleszak and Malec, 2000). Finally, it seemed that the inhibition of AMPH-induced
stereotyped head movements, through activation of A1 receptor, could depend on agonist properties, as
Abstract
Ribavirin, an A1 receptor agonist, reduced AMPH-induced total locomotor activity but had no effects on
Introduction
stereotypic activity in Wistar rats (Janać et al., 2005). Relevant literature concerning the functional effects of
Brain Circuitry and
AR ligands in psychostimulant-induced phenomena, with a focus on rodent models, are presented in
Adenosine Receptor
Supplementary Table S1.
Interactions
A complete study of AR and their relationship with cocaine-induced locomotion was carried out by Poleszak
Adenosine
Receptors
and MalecOverview
(2002b) at the beginning of this century. They reported that CPA and CGS 21680, decreased both
cocaine- and AMPH-induced locomotor activity. The agonist doses required to inhibit the effect of AMPH
Psychostimulants
and Adenosine
were higher than those which were active in cocaine-induced hyperactivity, while the A2 antagonist DMPX
Receptors
enhanced the effects of AMPH in Swiss mice (Poleszak and Malec, 2002b). Accordingly, the selective
Mechanisms of
stimulation of A2A receptors in Wistar rats using CGS 2160 reduced the cocaine-induced locomotor response,
Adenosine
the locomotor response during the development of sensitization, and the expression of sensitization in a
Receptor-Mediated
Pathways
cocaineinchallenge
Drug dose, while blocking A2A receptors with the antagonist MSX-3 induced the opposite effects
Addiction
in the three studied paradigms (Filip et al., 2006).
Misuse of Legal
Genetic deletion
Psychostimulants of A2A receptors (A2A KO) in animal models of drug addiction provides a tool to understand
the role of these receptors under certain circumstances by comparison to wild-type animals. Nevertheless,
Concluding
the results
Remarks obtained using A2A KO animals on cocaine-, AMPH-, and METH-induced behavioral responses
and Future
Prospects
seem contradictory. In this sense, it was reported that in 129-Steel and hybrid C57BL/6 × 129-Steel mice, A2A
KO attenuated cocaine-induced locomotor stimulation (Chen et al., 2000). Similar experiments, performed
Author to
Contributions
demonstrate the effects of A genetic deletion with independence of the genetic background, were
2A
reproduced
Funding later in pure 129-Steel mice resulting in missed AMPH-induced locomotor sensitization (Chen et
al., ict
Con 2003). Accordingly, similar results were obtained when hybrid C57BL/6 × 129-Steel animals were used to
of Interest
Statement
generate tissue-specific A2A KO animals, where deletion of forebrain A2A receptors was carried out, which
showed a loss of
Acknowledgments AMPH-mediated locomotor response (Bastia et al., 2005). In contrast, in CD1 background
mice, it was reported that there were no differences in the cocaine-induced locomotor activity, sensitization
Supplementary
and conditioned
Material place preference between A2A KO animals and their littermates (Soria et al., 2006). Authors
only found a lower rate of cocaine self-administration and motivation as well as lower efficacy of cocaine
Footnotes
reinforcing effects in A2A KO mice (Soria et al., 2006). Interestingly, Soria et al. (2006) concluded with the
References
hypothesis that separate neuronal substrates could mediate cocaine-induced locomotor effects and self-
administration in an operant behavior paradigm. In order to corroborate this hypothesis, Shen et al. (2008)
designed two different KO animals to distinguish between striatal versus non-striatal cocaine-mediated
effects. In these experiments, cocaine-induced locomotor activity was enhanced in striatum-specific A2A KO
mice (A2A receptors were deleted in striatal neurons) but attenuated in forebrain-specific A2A KO mice (A2A
receptors were deleted in the neurons of striatum, cerebral cortex, and hippocampus). In addition,
pharmacological inactivation (using KW6002, an A2A receptor antagonist with preferential affinity for post-
synaptic A 2A binding sites) of extra-striatal A 2A receptors in striatum-specific A 2A KO mice attenuated cocaine-
induced LOGIN
hyperlocomotion, while the same antagonist enhanced cocaine-induced hyperlocomotion
(HTTPS://WWW.FRONTIERSIN.ORG/PEOPLE/LOGIN) / REGISTER (HTTPS://WWW.FRONTIERSIN.ORG/REGISTER)
in the
wild-type mice, reflecting the antagonism between striatal A2A receptors and extra-striatal A2A receptors
(Shen et al., 2008). Finally, in CD1 A2A KO mice, a lesser increase in DA levels after acute cocaine exposure
was reported while locomotor activity was further increased in A2A KO mice in comparison to wild-type
littermates (Wells et al., 2012). The genetic models derived from the manipulation of AR, and their effect on
the interaction of AR with psychostimulants, are presented in Supplementary Table S2.
Interestingly, there is some research available about the role of A3 receptors in modulation of AMPH- and
METH-mediated actions. METH-induced DA release was measured in the rat striatum using APNEA, a
putative A3 receptor agonist, which has a biphasic effect when perfused locally to the striatum via
microdialysis. At the lower concentration studied, APNEA induced a decrease in DA outflow, but at the higher
concentration studied, a clear increase in DA outflow was reported, which led researchers to conclude that
the activation of A3 receptors exerts a rather toxic effect on DA neurons (Gołembiowska and Zylewska,
1998b). Nevertheless, when the A3 receptor was genetically deleted, it was reported that the resultant mice
were much more sensitive to the toxic actions of METH, including Iba-1, caspase 3, TNF-α, and vesicular
TABLE OF CONTENTS
monoamine transport 2 (VMAT) increased expression (Shen et al., 2011), and also presented reduced AMPH-
induced
Abstract locomotor response (Björklund et al., 2008).
Introduction
Adenosine receptors modulate psychostimulant-induced discriminative-stimulus effects, as A1 and A2A
receptors
Brain Circuitryantagonists
and (CPT and MSX-3 or DMPX, respectively) partially mimicked the discriminative-stimulus
Adenosine Receptor
effects of METH, by increasing the levels of drug-lever selection, and potentiating the discriminative-stimulus
Interactions
actions of METH, as shown by significant leftward shifts of the METH dose-response curve, behaving like
Adenosine
psychostimulant drugs (Munzar et al., 2002; Justinova et al., 2003). Surprisingly, CPA and CGS 21680 also
Receptors Overview
shifted the dose-response curve to the left for cocaine, but not for METH, suggesting that A1 and A2A receptors
Psychostimulants
have different influences
and Adenosine
on the discriminative-stimulus effects of METH and cocaine in Sprague-Dawley rats
(Justinova et al., 2003).
Receptors
Mechanisms of
Another relevant aspect in drug addiction which is strongly influenced by AR is the seeking behavior. In
Adenosine
terms of the effect of A1 agonists, CPA microinfusions in the NAc of Sprague-Dawley rats inhibited cocaine
Receptor-Mediated
seekinginbehavior
Pathways Drug (Hobson et al., 2013). On the other hand, treatment with A2A agonists such as NECA or CGS
Addiction
21680 reduced the number of cocaine infusions self-administrated by rats, mainly due to an increase in the
latency
Misuse for the first cocaine infusion (Knapp et al., 2001). Accordingly, the activation of A2A receptors, using
of Legal
Psychostimulants
CGS 21680, antagonized the reinstatement of cocaine seeking in Sprague-Dawley rats (Bachtell and Self,
2009). In addition, it was reported that A2A receptor blockade, using CGS15943, increased cocaine-seeking in
Concluding a
Remarks and Future manner and also reinstated cocaine-seeking, functioning as an intravenous reinforcer, in
dose-dependent
Prospects
baboons (Weerts and Griffiths, 2003). The effects of activation and blockade of A2A receptors, using CGS 21680
Author
and MSX-3, respectively, were also tested in Sprague-Dawley rats trained to press a lever for cocaine.
Contributions
Pretreatment with intra-NAc core microinjections of CGS 21680 reduced cocaine-induced reinstatement,
Funding
while MSX-3 exacerbated it (O’Neill et al., 2012). Similar results were obtained in Sprague-Dawley rats, where
Con ict of Interest
intra-NAc microinjections of CPA and CGS 21680 inhibited the expression of cocaine sensitization, and
Statement
microinjections of ABT-702 and DCF (AK and ADA inhibitors, respectively) blocked cocaine sensitization
Acknowledgments
(Hobson et al., 2012). Interestingly, A2A receptor activation (with CGS 21680) in Wistar rats was able to affect
Supplementary
food seeking with a similar potency to that observed for cocaine seeking, whilst A2A receptor antagonists
Material
increased cocaine-, but not food-, seeking behavior, suggesting that possibly a differential expression of A2A
Footnotes
receptors occurs in striatopallidal GABAergic neurons involved in cocaine and food seeking (Wydra et al.,
2015). In
References contrast, it was reported that although the activation of A1 (using CPA) and A2A (using CGS 21680)
receptors impaired initial extinction responding, the blockade of presynaptic A2A receptors using SCH 442416
produced persistent impairment of cocaine-induced seeking in Sprague-Dawley rats (O’Neill et al., 2014).
As reported in Supplementary Table S1, the vast majority of studies have focused exclusively on males.
Nevertheless, there is a large amount of literature concerning the differences in drug-mediated effects
between males and females (for a recent review see Lynch, 2017). Although the focus of the present review is
on the relationship between AR and psychostimulants, sex differences will be briefly commented upon to
provide a fuller picture of the problem of addiction. In this regard, it has been reported that female rats self-
administer higher levels of cocaine or METH, and escalate intake faster than males during extended daily
psychostimulant access (Roth and Carroll, 2004; Reichel et al., 2012). Females also requireABOUT(HTTPS://WWW.FRONTIERSIN.ORG/ABOUT/
shorter periods of
time to show increased motivation to obtain cocaine (Lynch and Taylor, 2004). In addition, following short
access self-administration, females show markedly higher levels of METH seeking (Ruda-Kucerova et al.,
2015), and females present increased cocaine-seeking behavior during cocaine withdrawal (up to 6 months)
compared to males (Kerstetter et al., 2008). Sex-dependent responses to AR’s ligands have also been reported
in Sprague-Dawley rats using ATL444, a novel A2A/A1 receptor antagonist, in studies of motivation for
cocaine. In these experiments, it was reported that ATL444 treatment acutely increased motivation for
cocaine in females but, in males, induced a long-term decrease in motivation for cocaine (Doyle et al., 2012).
Finally, one interesting more recent study, evaluating the effects of A2A receptor deletion on schizophrenia,
found that AMPH induced a lower hyperlocomotion response in male CD1 A2A KO mice at 120–170 min, in
comparison to wild type AMPH-treated mice; this effect was observed to a major extent in female CD1 A2A KO
mice at 70–180 min, in comparison to wild type AMPH-treated mice (Moscoso-Castro et al., 2016).
Rewarding effects induced by AMPH and METH have mainly been evaluated using conditioned place
preference procedures. In this way, Poleszak and Malec (2003) proved that CPA and, under certain
TABLE OF CONTENTS
conditions, CGS 21680, reduced the development of AMPH-induced conditioned place preference in Wistar
rats; however,
Abstract only CGS 21680 was able to decrease the expression of METH-induced conditioned place
preference. In addition, ginseng saponins reduced the METH-induced circling behavior and conditioned
Introduction
place preference in C57BL/6 mice, via activation of the A
Brain Circuitry and 2A receptor, as this reduction was reversed in a dose-
dependent manner
Adenosine Receptor using the A2A receptor antagonist CSC. Interestingly, reduction of AP-1 DNA binding
Interactions
activity and proenkephalin gene expression induced by METH exposure were reduced by CSC (Shin et al.,
2005). Furthermore, C57BL/6J mice with D2 receptors knocked down in the NAc core have been reported
Adenosine to
Receptors
exhibit Overview
a reduction in METH-induced locomotion, as in other paradigms (locomotor sensitization and
conditioned place preference) after repeated METH-treatment, suggesting that D2 receptors are necessary
Psychostimulants
and Adenosine
mediators for the development of METH-induced rewarding effects (Miyamoto et al., 2014). Thus, the
Receptors
antagonism between A2A and D2 receptors further supports the conclusion that the activation of A2A
Mechanisms of
receptors could be a promising way to counteract AMPH- and METH-induced rewarding effects.
Adenosine
Receptor-Mediated
A series of experiments to increase our understanding of the role of A1 and A2A receptors in METH-induced
Pathways in Drug
behavior were designed by Kavanagh et al. (2015), reporting that the initial METH-mediated rewarding
Addiction
effects may be tempered by A1 or A2A receptor activation in a model of rat self-administration. Therefore,
Misuse of Legal
they found that
Psychostimulants in Sprague-Dawley rats, the stimulation of A1 receptors using CPA reduced METH self-
administration, and that the stimulation of both A and A
1 2A receptors (using CPA and CGS 21680,
Concluding
respectively)
Remarks reduced METH-induced place preference (Kavanagh et al., 2015). These results suggest that,
and Future
Prospects
taking into account the antagonism of A1/D1 and A2A/D2 heteromers, both A1 and A2A agonists will be useful
to reduce METH-induced behaviors during the initial exposures to METH but, when METH exposures are
Author
Contributions
more prolonged, the modulation of AR renders only the A agonist powerful enough to counteract the
1
rewarding
Funding properties of METH. Accordingly, A2A KO animals (CD1 background) were less sensitive to METH
rewarding
Con properties, as METH exposure did not induce conditioned place preference in those animals and,
ict of Interest
Statement
although METH-self administration was not altered, the motivation to self-administer METH was reduced
when compared
Acknowledgments with wild-type (Chesworth et al., 2016).
Supplementary
Finally, the important role of AR as possible pharmacological tools to treat psychostimulant addiction has
Material
also been tested in animal models using other members of the amphetamine family, albeit to a lesser extent.
Footnotes
Specifically, it was demonstrated that SCH 58261, but not DPCPX, increased MDMA-induced hyperthermia
(Vanattou-Saïfoudine
References et al., 2010) but, conversely, DPCPX, but not SCH 58261, enhanced MDMA-induced DA
release from striatal slices (Vanattou-Saïfoudine et al., 2011). Accordingly, the blockade of A1 or A2A receptors
using DPCPX or KW 6002, respectively, in mouse striatum increased the MDMA-mediated release of DA and 5-
HT (Górska and Gołembiowska, 2015). In contrast to these pharmacological experiments, when A2A receptors
were knocked down in a CD1 background model, MDMA-mediated reinforcement was dramatically
decreased (although locomotor response was not altered) compared to wild-type littermates (Ruiz-Medina et
al., 2011), suggesting that the lack of A2A receptors will increase resistance to psychostimulant rewarding
properties.
Human Studies
The genomic era has provided the opportunity to study human polymorphisms and so to provide a tool to
design personalized treatments according to observed mutations. Recent meta-analysis of case-control
studies of psychostimulant users (cocaine, AMPH, and METH) have revealed that there is a general down-
regulation of the dopaminergic system, as in psychostimulant users there is a decrease in DA release, in DA
transporter availability, and also in the levels of D2 and D3 receptors, concluding that DA function is down-
regulated both pre- and post-synaptically. This suggests that restoring DA function must be an important goal
in the treatment of psychostimulant abusers (Ashok et al., 2017). Due to the antagonistic relationship
between dopaminergic function and AR, some authors have studied the relationship between A1 and A2A
gene polymorphisms and susceptibility to psychostimulant consumption/addiction. Most relevant human
studies are presented in Supplementary Table S3.
The first study designed to discern the influence of A1 and A2A gene (ADORA1 and ADORA2A, respectively)
polymorphisms
TABLE OF CONTENTS on inter-individual variability in AMPH response was carried out by Hohoff et al. (2005).
Using a sample of 99 healthy volunteers (50 men and 49 women), who received AMPH or a placebo, the
Abstract
authors reported that two ADORA2A polymorphisms (1976C/T and 2592C/Tins) were associated with increases
Introduction
in reported anxiety by participants after AMPH consumption (Hohoff et al., 2005). Nevertheless, these results
Brain Circuitry
should and
be regarded with caution, as the same research group could not reproduce them using the same
Adenosine Receptor
methodology for a larger sample of individuals (Hart et al., 2013). In addition, a study by Kobayashi et al.
Interactions
(2010) searching for the relationship between ADORA2A variations and susceptibility to METH
Adenosine
dependence/psychosis
Receptors Overview
reported that, in a population of 171 Japanese METH dependent/psychotic patients
(compared to 229 control subjects), six ADORA2A polymorphisms were found. The authors reported that only
Psychostimulants
one
and single nucleotide polymorphism (SNP) of the A2A receptor gene was significantly associated with
Adenosine a
subgroup of female patients (METH dependent/psychotic) that consumed only METH and no other
Receptors
psychostimulants
Mechanisms of or drugs (Kobayashi et al., 2010). Interestingly, that SNP was 1976C/T (rs5751876), the same
that Hohoff et al. (2005) associated with anxiety after AMPH consumption, and this SNP is a synonymous
Adenosine
Receptor-Mediated
variant, meaning that it cannot include amino acid substitutions. Finally, in the same Japanese population as
Pathways in Drug
the previous study, seven ADORA1 SNPs were identified but none was specific to any subgroup of METH
Addiction
dependent/psychotic patients, which would suggest that ADORA1 polymorphisms would make little or no
Misuse of Legal
contribution to
Psychostimulants METH vulnerability (Kobayashi et al., 2011); however, further research is needed to confirm
this supposition. In addition, caffeine-induced anxiety has also been associated with ADORA2A 1976C/T
Concluding
polymorphism
Remarks and Future in a sample of 102 individuals (Childs et al., 2008), although other ADORA2A polymorphisms
Prospects
(such as 1976TT) also seem to be related to caffeine-induced anxiety, and could also influence predominantly
women vulnerable
Author to anxiety (Domschke et al., 2012; Gajewska et al., 2013).
Contributions
Despite the huge amount of evidence that connects AR with psychostimulant-mediated actions, the
Funding
translation of this knowledge to the clinic has been quite slow in comparison with other areas. A few reasons
Con ict of Interest
related to particular characteristics of AR could be that AR receptors are widely distributed, not only in the
Statement
CNS but throughout the human body, with adenosine signaling responsible for the regulation of a broad
Acknowledgments
spectrum of physiologic and pathologic actions (for a more detailed discussion see Müller and Jacobson,
Supplementary
2011; Chen et al., 2013). For this reason, it is experimentally difficult to demonstrate the clinical effectiveness
Material
and safety of an AR ligand. Therefore, only two clinical studies (registered in website1) have studied
Footnotes
psychostimulant dependence and its link with AR (Supplementary Table S3). One of these compared the
responses
References of volunteers to acute caffeine (150 and 300 mg), AMPH (20 mg) and placebo between 13 cocaine
users and 10 healthy control subjects (NCT00733993). The main target of the trial was to study caffeine-
mediated effects in cocaine users. Nevertheless, although caffeine and AMPH produced a series of
differential results across the cocaine and control groups, these outcomes were not systematic, perhaps due
to limitations of the study itself (Lane et al., 2014). On the other hand, the effect of an acute dose (100 mg) of
the A2A antagonist SYN115 was studied to elucidate the effects of this antagonist on brain function and
behavior in a group of cocaine-dependent volunteers (NCT00783276). Some subjective effects (consistent with
stimulation) were induced by SYN115 administration in cocaine users (Lane et al., 2012). Furthermore, the
We use administration of SYN115
cookies on this website to cocaine-dependent
to improve volunteers
your user experience. Learn increased brain activation in the orbitofrontal
more (//www.frontiersin.org/legal/list-of-cookies) CLOSE
cortex, insula, and superior and middle temporal pole, as measured by fMRI while the participants
were
performing working memory tasks; this suggests that the blockade of A2A receptors could mitigate cocaine-
associated neurobehavioral deficits (Moeller et al., 2012). In addition, no clinically significant adverse
cardiovascular events were reported by the volunteers in either study (Lane et al., 2012; Moeller et al., 2012).
Finally, epidemiological and preclinical data demonstrate that gender differences exist for the three phases
of drug abuse (represented in Figure 1). The pattern of gender differences establishes that women have
lower prevalence of drug use disorders involving both licit and illicit drugs (including alcohol, sedatives,
cannabis, tranquilizers, opioids, hallucinogens, and cocaine use disorders). Nevertheless, women that begin
to self-administer drugs, even at lower doses than men do, escalate faster to addiction and present higher
rates of relapse compared to men. These gender differences can be interpreted in terms of sociocultural
factors as well as biological/physiological factors (reviewed in Lynch, 2006; Lev-Ran et al., 2013; Bobzean et
al., 2014; Becker and Koob, 2016). Men and women also differ markedly in terms of psychostimulant
use/abuse. For example for METH consumption, women tend to begin METH use at earlier ages and seem
more dependent on METH consumption than men, although women do suffer a decreased degree of toxicity
TABLE OF CONTENTS
and respond better to treatment (Dluzen and Liu, 2008). In addition, women present more severe problems
related
Abstract to cocaine intake, beginning to use cocaine at earlier ages, and some pharmacological treatments for
drug addiction have poor outcomes among women compared to men (Kennedy et al., 2013; DeVito et al.,
Introduction
2014). Several pathophysiological studies have demonstrated that the reinforcing effect of cocaine is strongly
Brain Circuitry and
influenced
Adenosine by the female hormonal cycle; in fact, some authors suggest that gender differences in addiction
Receptor
Interactions
are due to differences in the reinforcement pathways of neural systems induced by ovarian hormones
(Anker and Carroll, 2011; Bobzean et al., 2014). These findings highlight the importance of taking gender
Adenosine into
Receptors
accountOverview
when analyzing psychostimulant use, and designing prevention programs and personalized
treatment programs.
Psychostimulants
and Adenosine
Receptors
Mechanisms of Adenosine Receptor-Mediated Pathways in Drug Addiction

Mechanisms of
Adenosine
Receptor-Mediated
As noted in previous sections, it has been reported that AR interact in an antagonistic way with DA receptors,
Pathways in Drug
A1 receptors being colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2
Addiction
receptors, counteracting DA-induced behavioral effects (Ferré et al., 1997; Ginés et al., 2000; Hillion et al.,
Misuse of Legal
2002; Fuxe et
Psychostimulants
al., 2007a). Specifically, the stimulation of striatal D2 receptors is responsible for the locomotor,
sensitizing and rewarding effects of drugs of abuse such as cocaine and amphetamines, and A2A receptor
Concluding
stimulation
Remarks counteracts them (Heffner et al., 1989; Popoli et al., 1994; Rimondini et al., 1997; Poleszak and
and Future
Malec, 2000, 2002a; Shimazoe et al., 2000; Knapp et al., 2001; Bachtell and Self, 2009; Jastrzêbska et al., 2014;
Prospects
Johnson and Lovinger, 2016). In general, the process of addiction depends on an increase in DA
Author
neurotransmission in the striatum and an activation of its receptors. Specifically, cocaine induces
Contributions its effects
by indirectly
Funding increasing DA levels and directly activating D2 receptors (Fuxe et al., 2007a; Ferraro et al., 2012),
thus enhancing dopaminergic signaling. The DA receptors most involved are of the D2 subtype, as
Con ict of Interest
demonstrated
Statement by their persistent striatal decrease following drug detoxification, and their induction of
relapse as a consequence of chronic drug administration.
Acknowledgments
Interestingly, A2A and D2 receptors are co-expressed in the striatum, forming heteroceptors, especially in the
Supplementary
Material
GABAergic striatopallidal neurons, where A receptor activation increases GABA release and counteracts
2A
the effects
Footnotes induced by D2 receptors. These receptors may be linked to each other in two opposite ways. On the
one hand,
References these receptor subtypes may form heteromers, causing antagonistic interactions between A2A
receptors and D2 receptors at the AC level, related to Gs/olf and Gi type V AC signaling. On the other hand, at
the membrane level, A2A receptor activation exerts a counterbalancing effect to D2 receptor stimulation, by
reducing its affinity for DA and decreasing functional effects induced by D2 receptor stimulation (Ferré et al.,
1991, 1994). In support of this relationship, transgenic animal models overexpressing A2A receptors in the
brain showed reduced D2 receptors in the striatum. Accordingly, A2A receptor activation decreases
behavioral responses to psychostimulants, indicating that the A2A receptor may represent a novel drug target
for the treatment of drug addiction. In particular, A2A receptor stimulation decreases cocaine reward and
We use seeking behavior,
cookies on this websiteby
toreducing D2user
improve your agonist affinity
experience. (Pintsuk
Learn et al., 2016). In the context of the antagonistic
interaction between A2A/D2 receptors, it has also/ REGISTER
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been reported that the D2 receptor, through
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coupling to Gi,
inhibits A 2A receptor-mediated cAMP/PKA signaling, and thus CREB phosphorylation and c-fos expression
(Pinna et al., 1997; Kull et al., 2000; Hillion et al., 2002). However, synergistic A2A and D2 receptor interaction
has been revealed, again at the AC level in the striatum, linked to the overexpression of activator of G protein
(AGS3) and Gs/olf and Gi type II/IV AC pathway. This relationship becomes important when AGS3 is
upregulated, such as during ethanol consumption, and withdrawal from cocaine, ethanol or morphine,
because its activity stabilizes and inhibits the GDP-bound form of Gi, at the same time increasing the βγ-
dependent effect of Gs/olf protein, producing a strong increase in cAMP-PKA signaling. Even though in the
striatum the first A2A/D2 antagonistic relationship is predominant, due to the higher distribution of AC V,
when AGS3 is upregulated, such as during chronic exposure to addictive drugs, the synergistic interaction
between A2A and D2 receptors becomes relevant, suggesting that A2A receptor antagonists may represent a
class of drug to combat addiction and relapse (Ferré et al., 2008b). In addition, neuroprotection exerted by
A2A receptor agonists seemed to be mediated by an increase in nuclear factor-κB (Kermanian et al., 2012,
2013; Soleimani et al., 2012).
TABLE OF CONTENTS
Furthermore, neuromodulation of neuronal networks by systemic A2A receptor activation inhibits the
reward
Abstract and motivational properties of cocaine targeting A2A/D2 heteroreceptors in the striatopallidal GABA
pathway. Microdialysis studies have related this effect to their increase and reduction of GABAergic and
Introduction
dopaminergic transmissions, respectively, in the NAc, as a consequence of an antagonistic A /D interaction,
Brain Circuitry and 2A 2
both at the membrane
Adenosine Receptor cell surface and at the intra-cellular level (Fuxe et al., 2007a; Trifilieff et al., 2011;
Interactions
Franco et al., 2013; Wydra et al., 2015; Borroto-Escuela et al., 2017). A /D heteromers involved in reward
2A 2
mechanisms reside in GABAergic neurons of the ventral striatopallidal area that are responsible for
Adenosine
Receptors Overview
rewarding, motivational and seeking effects induced by cocaine, as well as by food (Wydra et al., 2013).
However, both systemic treatment with an A2A receptor antagonist and its direct injection into the
Psychostimulants NAc
and Adenosine
reduced relapse in heroin-addicted rats and prevented DA increases in the NAc shell induced by
Receptors
tetrahydrocannabinol (THC), but not those mediated by cocaine (Yao et al., 2006; Justinova et al., 2011).
Mechanisms of
Furthermore, A2A receptor antagonists alone may behave like psychostimulants by triggering cocaine-
Adenosine
seeking behavior, thus decreasing their utility in the treatment of drug-dependence. Indeed, some findings
Receptor-Mediated
Pathways in Drug
on the addictive properties of A2A receptor antagonists have reported that they substituted for cocaine in
Addiction
baboons (Weerts and Griffiths, 2003), also inducing conditioned place preference (Harper et al., 2006) and
Misuse of Legal
restored cocaine-seeking behaviors in rats (O’Neill et al., 2014). In addition, the blockade of A2A receptors
Psychostimulants
increased DA in the striatal network in cocaine-dependent subjects, which resulted in major prefrontal
Concluding
cortex stimulation (Moeller et al., 2012). However, in rats trained to self-administer heroin, the
Remarks and Future
administration of A2A antagonists eliminated reinstatement (Yao et al., 2006), opening the possibility
Prospects of using
A2A antagonists as therapeutic ligands in the management of abstinence in the addiction of some drugs. The
Author
effect of cocaine
Contributions exposure in fetal brains and the modulation of DA and adenosine effects have also been
addressed; specifically, from E8 to E14 embryonic days, cocaine treatment induced changes in DA and
Funding
adenosine signaling which increased basal cAMP levels in the striatum and cerebral cortex. This effect could
Con ict of Interest
be reverted by
Statement blocking A2A receptors (using SCH58261), suggesting that A2A receptors could be considered
good candidates as targets to treat prenatal cocaine exposure-related syndromes. Indeed, D2 and A2A
Acknowledgments
receptors counterbalance each other’s effects in the embryonic brain in a similar manner to what happens in
Supplementary
the mature brain (Kubrusly and Bhide, 2010).
Material
A2A receptors,
Footnotes independent of their interaction with D2 receptors in A2A/D2 heteromers, are also present in
other complexes with mGlu5 and CB1 in striatal GABAergic neurons, as well as with A1, mGlu5, and CB1 in
References
striatal glutamatergic terminals (Figure 2), that may be involved in the modulation of reward, exerting an
important role in the regulation of dopaminergic and glutamatergic effects in addiction (Kalivas and Volkow,
2011; Cahill et al., 2014; Zhang et al., 2014; Johnson and Lovinger, 2016). In this sense, the blockade of A2A
receptors increased cocaine-mediated locomotor effects through the activation of CB1 receptors in rat
striatum (Tozzi et al., 2012). It has also been demonstrated that an interaction between A2A receptors and
metabotropic glutamate 5 receptors (mGlu5) in the striatum avoided METH-, but not cocaine-, induced
hyperactivity and rewarding behavior, making a combined antagonism of A2A and mGlu5 receptors in the
therapy of METH addiction possible (Wright et al., 2016). Accordingly, the influence of adenosine on
glutamatergic transmission in the striatal region has been reported (Fuxe et al., 2008). Finally,
it was reported
that the functions and pharmacology of extra-striatal A2A receptors must also be taken into account (Shen et
al., 2008), although their function could not be totally extrapolated from the available data for striatal A2A
receptors. In this sense, the apparent controversial data obtained from pharmacological studies and genetic
approaches using KO animals (presented in Supplementary Tables S1, S2) must be carefully exposed as the
genetic background effects in A2A KO animals may invalidate them as a model to study A2A receptors (Filip et
al., 2012). To conclude, the exploitation of the full potential of AR as drug targets will not only necessitate a
full comprehension of AR-mediated mechanisms, but will also require the availability of ligands which let us
distinguish among the different receptor populations discussed in this paper (Popoli and Pepponi, 2012).
Misuse of Legal Psychostimulants

The consumption of legal psychostimulants has increased over recent years. For example, the misuse of
prescribed psychostimulants, which are approved for the treatment of attention deficit hyperactivity
TABLE OF CONTENTS
disorder, for weight control or for the treatment of narcolepsy (Phillips et al., 2014), both by the patients
themselves,
Abstract and by non-affected individuals, based on misconceptions or simple lack of knowledge of the
associated risks, is becoming more and more common nowadays (Lakhan and Kirchgessner, 2012; McHugh
Introduction
et al., 2015). This has been the case for methylphenidate consumption among college students as a study aid
Brain Circuitry and
to enhance
Adenosine their academic performance (Maier et al., 2013; Webb et al., 2013; Vrecko, 2015). Although their
Receptor
use as a study aid is not the only reason why these substances are consumed (Drazdowski, 2016), this is one
Interactions
historically significant
Adenosine example, with reports of the use of amphetamines as study aids dating back to 1937
Receptors
(Strohl, Overview
2011).
Psychostimulants
In addition, caffeine, which is the most consumed psychoactive drug in the world, could also be of particular
and Adenosine
importance when addressing psychostimulant or drug addiction-related problems. Indeed, caffeine is
Receptors
commonly found as an adulterant in the preparation of illicit drugs (Prieto et al., 2016) and in energy drinks
Mechanisms of
consumed in combination with alcohol or other psychostimulants (Reissig et al., 2009; Vanattou-Saïfoudine
Adenosine et
Receptor-Mediated
al., 2012; Ferré, 2016). Interestingly, both acute and chronic adverse effects rise following concurrent
Pathways in Drug
consumption of caffeine and psychostimulant drugs. Specifically, caffeine worsens the psychostimulant’s
Addiction
toxicity by increasing hyperthermia, cardiotoxicity, and seizures, as well as influencing the stimulatory,
Misuse of Legal
discriminative,
Psychostimulants
and reinforcing effects of psychostimulant drugs. These effects have been investigated for the
cases of MDMA and cocaine ingested with caffeine (Comer and Carroll, 1996; Kuzmin et al., 1999; Vanattou-
Concluding
Saïfoudine
Remarks et al., 2012; Górska et al., 2017). The molecular mechanism underlying the action of caffeine is
and Future the
antagonism of AR, with A1 and A2A subtypes the most involved. Indeed, it has been reported that caffeine
Prospects
induces increased DA release through A1 receptor blockade (Okada et al., 1997). More recently, findings
Author by
Ferré (2016) attribute caffeine potentiation of the psychomotor activating and reinforcing effects of
Contributions
psychostimulants
Funding to the existence of A2A/D2 heteromers, where the antagonism of A2A receptors by caffeine
reverts the inhibitory brake exerted by adenosine on D2 receptor signaling. Therefore, as ingestion of
Con ict of Interest
caffeine
Statement with cocaine and MDMA can significantly alter the drug-induced effects, understanding the
molecular mechanisms underpinning this interaction will help to define correct approaches for the
Acknowledgments
management of these side effects and toxicity.
Supplementary
Material
Footnotes
Concluding Remarks and Future Prospects
References
Although the A2A receptor has been far more extensively studied (refer to Supplementary Table S1 for
summary), some papers considered in this review do highlight the role of A1 receptor activation to modulate
psychostimulant-mediated effects. The properties of A1 agonists, mainly CPA, as anxiolytics have been
previously reported in mice lacking A1 receptors (Giménez-Llort et al., 2002), in animal models of cocaine or
alcohol consumption (Prediger et al., 2006; Hobson et al., 2013; O’Neill et al., 2014), and in classical behavioral
studies (Jain et al., 1995). In this sense, electrophysiological studies in basolateral amygdala reported that
application of CPA inhibits excitatory postsynaptic currents and glutamate release (Rau et al., 2014). This
evidence, and the experiments reported in this review, will make A receptor signaling an important target
1
for the development of novel pharmacological treatments for the common anxiety-like disorders
reported
during the process of drug-seeking and withdrawal, and as such will produce lasting changes in relapse
susceptibility.
Evidence for the role of A2A receptors in psychostimulant-mediated effects seems to be somewhat
contradictory between different pharmacological studies, experimental models tested (particularly self-
administration vs. experimenter-administration) and genetic approaches using A2A KO animals (refer to
Supplementary Table S2 for more detail). However, the overall analysis of the presented data indicates that
excitatory modulation of GPCR heteroreceptor complexes, in this case A2A/D2 heteroreceptors using A2A
agonists, is a promising tool to counteract psychostimulant-induced effects. Indeed, a prominent role in the
modulation of psychostimulant addiction attributed to adenosine is mediated through A2A activation by
complex mechanisms, affecting various aspects of this phenomenon including locomotor activity,
discrimination, seeking behavior and reward.
In this review, we have discussed current scientific evidence mainly based on animal models of
psychostimulant
TABLE OF CONTENTS addiction, and suggested promising candidates in the search for pharmacological
interventions. This is particularly important because, nowadays, the main treatments against
Abstract
psychostimulant addiction are focused on behavioral interventions (Phillips et al., 2014), while AR
Introduction
pharmacology could be a powerful weapon to modify the neurochemical alterations that occur during
psychostimulant
Brain Circuitry and addiction. AR are widely distributed in the CNS where they mediate a myriad of functions
Adenosine Receptor
and interact with other neurotransmitter systems, which provides an opportunity to modulate specific
Interactions
complex brain functions. In addition, selective ligands are available for the different AR subtypes, which
Adenosine
increase the chances to achieve nuclei-specific modulation, representing a pharmacological opportunity to
Receptors Overview
control addictive psychostimulant consumption and health-related problems. Certainly, identifying strategies
Psychostimulants
to fully understand AR signaling in drug addiction may provide insight into the factors contributing to
and Adenosine
consumption/craving/relapse of abused psychostimulants, thus revealing novel therapeutic approaches.
Receptors We
suggest that
Mechanisms of efforts could be made in three main aspects of adenosine pharmacology affecting
psychostimulant addiction. Firstly, we have stated in this review that there is broad experimental evidence
Adenosine
Receptor-Mediated
that pharmacological stimulation of A1 and A2A receptors may counteract the effects induced by
Pathways in Drug
psychostimulants of abuse, but it is also important to highlight that approaches including a combination of
Addiction
AR drugs, like A1/A2A ligands, may help form a more robust strategy when AR are the basis of
Misuse of Legal
pharmacological
Psychostimulants interventions. Secondly, as stated in Section “Mechanisms of Adenosine Receptor-Mediated
Pathways in Drug Addiction,” due to the ability of AR to form homomers, heteromers and oligomers, it is
Concluding
mandatory
Remarks to obtain specific ligands capable of discriminating among those different receptor populations.
and Future
Prospects
Thirdly, due to the lack of information concerning the effects consequent to alcohol and psychostimulant co-
abuse, which is very common in drug addiction (Althobaiti and Sari, 2016; Barrett et al., 2016; Sánchez-López
Author
Contributions
et al., 2017), it would be of particular interest to investigate the role of AR in those interactions.
Funding
Con ict of Interest

Author Contributions
Statement
Acknowledgments
CC developed the original idea. SG and CC designed the review. IB-Y and SG prepared the images. SG and CC
prepared the tables. CC and SM edited
Supplementary and reviewed the final version of the article. All listed authors
Material
contributed to writing the article.
Footnotes
References
Funding
This work was supported by Universidad de Castilla-La Mancha (GI20174050).
Con ict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
Acknowledgments
IB-Y and CC would like to thank Prof. Mario Durán (UCLM) and Prof. Emilio Ambrosio (UNED) for their
generosity and kind advice.
Supplementary Material
The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fphar.2017.00985/full#supplementary-material
(https://www.frontiersin.org/articles/10.3389/fphar.2017.00985/full#supplementary-material)
TABLE S1 | The role of adenosine receptor (AR)’s ligands in psychostimulant-induced effects upon behavior
and function. The most relevant animal studies on the interaction between adenosine and psychostimulants
are shown. Arrows represent decrease (↓) and increase (↑). When adenosine ligands induced no effect, the
TABLE OF CONTENTS
symbol “≈” is used. Although PAP9704 and ginsenosides are not ligands of AR, the effects of those ligands are
Abstract
reported in this table as authors suggests that their biological effects are mediated by AR.
Introduction
TABLE S2 | Genetic manipulation of AR in murine models and psychostimulant-induced effects. Genetic
Brain Circuitry
models and from the manipulation of AR used to explore the interaction between adenosine and
derived
Adenosine Receptor
psychostimulants are shown. Arrows represent decrease (↓) and increase (↑). The symbol “≈” is used to
Interactions
indicate no difference between the genetic model and the wild-type animal (∗Unless other comparison is
Adenosine
stated).
Receptors Overview
TABLE S3 | Most relevant human clinical studies targeting AR. Ordered by publication date, most relevant
Psychostimulants
and Adenosine
clinical studies carried out in humans targeting the relationship between AR and psychostimulant addiction
Receptors
are shown. For each reference it is described the type of study, the number of subjects enrolled and its main
Mechanisms
objective ofand results. The number of the clinical trial is provided for the studies registered at
Adenosine
ClinicalTrials.gov (http://ClinicalTrials.gov).
Receptor-Mediated
Pathways in Drug
Addiction
Footnotes
Misuse of Legal
Psychostimulants
1. ^ ClinicalTrials.gov (http://ClinicalTrials.gov)
Concluding
Remarks and Future
References
Prospects
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Introduction
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Fredholm, B. B., Arslan, G., Halldner, L., Kull, B., Schulte, G., and Wasserman, W. (2000). Structure and function of adenosine receptors and
their genes. Naunyn Schmiedebergs Arch. Pharmacol. 362, 364–374.
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Statement
Gessi, S., Merighi, S., Stefanelli, A., Fazzi, D., Varani, K., and Borea, P. A. (2013). A(1) and A(3) adenosine receptors inhibit LPS-induced
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HT release in the mouse striatum. Neurotox. Res. 27, 229–245. doi: 10.1007/s12640-014-9501-0
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Acknowledgments
&title=The+role+of+adenosine+A1+and+A2A+receptors+in+the+caffeine+effect+on+MDMA-induced+DA+and+5-
Supplementary
HT+release+in+the+mouse+striatum%2E&journal=Neurotox%2E++Res%2E&author=Górska+A.++M.&author=and+Gołembiowska+K.&public
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Prospects
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Kermanian, F., Soleimani, M., Ebrahimzadeh, A., Haghir, H., and Mehdizadeh, M. (2013). Effects of adenosine A2a receptor agonist and
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antagonist on hippocampal nuclear factor-kB expression preceded by MDMA toxicity. Metab. Brain Dis. 28, 45–52. doi: 10.1007/s11011-012-
Funding
9366-y
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Misuse of Legal
Psychostimulants
Keywords: Adenosine A receptors, Adenosine A
1 2A receptors, amphetamines, cocaine, dopamine, psychostimulants, behavioral e ects, striatum
Concluding
Remarks
Citation:and Future
Ballesteros-Yáñez I, Castillo CA, Merighi S and Gessi S (2018) The Role of Adenosine Receptors in Psychostimulant Addiction. Front. Pharmacol.
8:985. doi: 10.3389/fphar.2017.00985
Prospects
Received: 17 October 2017; Accepted: 22 December 2017;
Author
Published: 10 January 2018.
Contributions
Edited by:
Funding
Francisco Ciruela (https://loop.frontiersin.org/people/1757/overview), University of Barcelona, Spain
Con ict of Interest

Reviewed by:
Statement
Olga Valverde (https://loop.frontiersin.org/people/52631/overview), Pompeu Fabra University, Spain
Ester Aso (https://loop.frontiersin.org/people/139418/overview), Bellvitge University Hospital, Spain
Acknowledgments
Copyright © 2018 Ballesteros-Yáñez, Castillo, Merighi and Gessi. This is an open-access article distributed under the terms of the Creative Commons Attri-
Supplementary
bution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the
Material
original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use,
Footnotes
distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Carlos A. Castillo, carlosa.castillo@uclm.es (mailto:carlosa.castillo@uclm.es) Stefania Merighi, stefania.merighi@unife.it

References
(mailto:stefania.merighi@unife.it)
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Abstract
Introduction
Brain Circuitry and

Adenosine Receptor
Interactions
Adenosine
Receptors Overview
Psychostimulants
and Adenosine
Receptors
Mechanisms of
Adenosine
Receptor-Mediated
Pathways in Drug
Addiction
Misuse of Legal
Psychostimulants
Concluding
Remarks and Future
Prospects
Author
Contributions
Funding
Con ict of Interest

Statement
Acknowledgments
Supplementary
Material
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References
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TABLE OF CONTENTS
© 2007 - 2020 Frontiers Media S.A. All Rights Reserved
Abstract
Introduction
Brain Circuitry and

Adenosine Receptor
Interactions
Adenosine
Receptors Overview
Psychostimulants
and Adenosine
Receptors
Mechanisms of
Adenosine
Receptor-Mediated
Pathways in Drug
Addiction
Misuse of Legal
Psychostimulants
Concluding
Remarks and Future
Prospects
Author
Contributions
Funding
Con ict of Interest

Statement
Acknowledgments
Supplementary
Material
Footnotes
References

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The Role of Adenosine Receptors in

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Adenosine Receptors: Distribution, Signal Transduction, and Function

The family of “amphetamines” or amphetamine-like psychostimulants includes a wide range of compounds

Mechanisms of Adenosine Receptor-Mediated Pathways in Drug Addiction

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