Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry: Implications for drug addiction, sleep and pain
Introduction
There is emerging evidence that A2A receptor antagonists might be useful clinically in treating Parkinson's disease. A2A receptor antagonists show promising results as an adjuvant to l-DOPA therapy (see Section 2.3). The dorsal striatum, which contains a high density of A2A receptors (Rosin et al., 1998), appears to be the site of action for the antiparkinsonian effects of A2A antagonists. The dorsal striatum receives its dopaminergic input from the substantia nigra (pars compacta), the predominant area of neurodegeneration in Parkinson's disease (Hirsch et al., 1988, Rinne, 1993). The ventral striatum, which receives its dopaminergic input from the ventral tegmental area (VTA; see Section 2.1), also contains the same density of A2A receptors (see Lillrank et al., 1999). The ventral striatum (nucleus accumbens) is implicated in drug addition. Here we review recent experimental evidence suggesting that A2A receptor antagonists could become new therapeutic agents for drug addiction.
It is commonly stated that A2A receptors are localized primarily in the striatum while A1 receptors are distributed much more widely (see Ferré et al., 1992, Ferré et al., 1997). Although the striatum contains the highest density of A2A receptors in the brain (Rosin et al., 1998), morphological and functional studies have identified lower levels of A2A receptors in other brain areas. A2A receptors appear to be involved in some adenosine-regulated brain functions previously thought to be mediated solely by A1 receptors. Adenosine is an endogenous sleep-promoting substance and it is currently believed that A1 receptors in the cholinergic basal forebrain mediate sleep-inducing mechanisms (recently reviewed in Basheer et al., 2004). Here we review evidence demonstrating a key role of hypothalamic A2A receptors in sleep regulation.
Nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors (recently reviewed in Liu and Salter, 2005). Here, we review recent evidence demonstrating that A2A receptors in peripheral nerve endings also regulate nociception. Taken together, this review emphasizes the possible application of A2A receptor ligands in pathological conditions other than Parkinson's disease.
Section snippets
The ventral striatum in drug addiction
The striatum is functionally subdivided into dorsal and ventral striatum. The dorsal striatum receives glutamatergic input from sensoriomotor and association cortical areas and dopaminergic input from the substantia nigra pars compacta (Parent and Hazrati, 1995, Gerfen, 2004). The ventral striatum, mostly represented by the nucleus accumbens (with its two compartments “shell” and “core”), receives glutamatergic input from limbic and paralimbic cortices and the amygdala and hipoccampus, as well
Adenosine and its role in sleep
The concept of humoral, rather than neural, regulation of sleep dates as far back as almost 100 years ago when Kuniomi Ishimori and Henri Piéron demonstrated the presence of some endogenous sleep-promoting substance(s) that accumulated in the cerebrospinal fluid (CSF) of sleep-deprived dogs (Kubota, 1989). More than 30 so-called endogenous sleep substances in the brain, CSF, urine, and other organs and tissues of animals have been reported since then by numerous investigators. For example,
Adenosine and its role in pain
In considering the role of the A2A receptor in pain it should first be stressed that the evidence comes predominantly from experimental animal studies, and thus strictly speaking we are talking about the role of the A2A receptor in nociception (i.e. a response to a noxious stimulus). The description of pain requires verbalization and is thus exclusively a human phenomenon. Nevertheless, there has been clinical use of adenosine in pain and thus some aspects of adenosine receptor modulation can
Acknowledgements
This work has been supported by the National Institute on Drug Abuse Intramural Research Funds, by EC (LSHM-CT-2004-005166) and GlaxoSmithKline.
References (185)
- et al.
Effects of (−)-N6-(-phenylisopropyl)-adenosine (PIA) and caffeine on nociception and morphine-induced analgesia, tolerance and dependence in mice
Eur. J. Pharmacol.
(1985) - et al.
Quantitative autoradiography of adenosine receptors and NBTI-sensitive adenosine transporters in the brains of mice deficient in the preproenkephalin gene
Brain Res.
(2004) - et al.
Adenosine and sleep–wake regulation
Prog. Neurobiol.
(2004) - et al.
Effects of A1 and A2A adenosine receptor ligands in mouse acute models of pain
Neurosci. Lett.
(2002) - et al.
AGS proteins: receptor-independent activators of G-protein signaling
Trends Pharmacol. Sci.
(2005) - et al.
Formalin-induced pain and mu-opioid receptor density in brain and spinal cord are modulated by A1 and A2a adenosine agonists in mice
Brain Res.
(2002) - et al.
Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications
Eur. J. Pharmacol.
(2005) - et al.
Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking
Neuron
(2004) - et al.
Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A(2A) adenosine receptors
Neuroscience
(2000) Regulation of adenylyl cyclase in the central nervous system
Cell Signal.
(2000)
Peripheral origins and central modulation of subcutaneous formalin-induced activity of rat dorsal horn neurons
Neurosci. Lett.
Complex role of peripheral adenosine in the genesis of the response to subcutaneous formalin in the rat
Eur. J. Pharmacol.
Adenosine–dopamine interactions in the brain
Neuroscience
Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia
Trends Neurosci.
Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease
Parkinsonism Relat. Disord.
Neurotransmitter receptor heteromers and their integrative role in “local modules”. The striatal spine module
Brain Res. Rev.
Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine
Brain Res.
Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells
Biochem. Pharmacol.
The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus
Neuroscience
Endocannabinoid signaling system and brain reward: emphasis on dopamine
Pharmacol. Biochem. Behav.
Potentiation of cocaine's discriminative effects by caffeine: a time-effect analysis
Pharmacol. Biochem. Behav.
Modulation of paracetamol antinoiception by caffeine and by selective adenosine A2 receptor antagonists in mice
Eur. J. Pharmacol.
Dopaminergic mechanism for caffeine-produced cocaine seeking in rats
Neuropsychopharmacology
Dopamine gating of glutamatergic sensorimotor and incentive motivational input signals to the striatum
Behav. Brain Res.
Prostaglandins and adenosine in the regulation of sleep and wakefulness
Curr. Opin. Pharmacol.
Intra-accumbens pertussis toxin sensitizes rats to the locomotor activating effects of a single cocaine challenge
Brain Res
Reduced response to the formalin test and lowered spinal NMDA glutamate receptor binding in adenosine A2A receptor knockout mice
Pain
Distribution and postnatal ontogeny of adenosine A2A receptors in rat brain: comparison with dopamine receptors
Neuroscience
Expression of adenosine A2a receptor gene in rat dorsal root and autonomic ganglia
Neurosci. Lett.
KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity
Eur. J. Pharmacol.
Up-regulation of adenosine transporter-binding sites in striatum and hypothalamus of opiate tolerant mice
Brain Res.
Alterations of adenosine A1 receptors in morphine dependence
Brain Res.
Memory and addiction: shared neural circuitry and molecular mechanisms
Neuron
Characterization of [3H]ZM 241385 binding in wild-type and adenosine A2A receptor knockout mice
Eur. J. Pharmacol.
Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration
Pharmacol. Biochem. Behav.
Kuniomi Ishimori and the first discovery of sleep-inducing substances in the brain
Neurosci. Res.
Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus
Neurochem. Int.
Potentiation of formalin-evoked adenosine release by an adenosine kinase inhibitor and an adenosine deaminase inhibitor in the rat hind paw: a microdialysis study
Eur. J. Pharmacol.
Involvement of primary sensory afferents, postganglionic sympathetic nerves and mast cells in the formalin-evoked peripheral release of adenosine
Eur. J. Pharmacol.
Antinociceptive effects of novel A2B adenosine receptor antagonists
J. Pharmacol. Exp. Ther.
Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons
Pharmacol. Rev.
Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal
J. Neurosci.
Multiple receptors involved in peripheral alpha2, mu and A1 antinociception, tolerance and withdrawal
J. Neurol. Sci.
Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons
J. Neurosci.
A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors
Psychopharmacology
Ethanol operant self-administration in rats is regulated by adenosine A2 receptors
Alcohol Clin. Exp. Res.
Changes in spinal delta and kappa opioid systems in mice deficient in the A2A receptor gene
J. Neurosci.
Enhanced morphine withdrawal and mu-opioid receptor G-protein coupling in A2A adenosine receptor knockout mice
J. Neurochem.
Adenosine A(2A) receptor antagonist treatment of Parkinson's disease
Neurology
Systemic adenosine infusion alleviates spontaneous and stimulus-evoked pain in patients with peripheral neuropathic pain
Anesth. Analg.
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2019, Life SciencesCitation Excerpt :Additionally, sex hormone modulation of P1R expression in the context of pain has been recently proposed by Fried et al. [166]. It is known that activation of A1 and A2A receptor induces antinociception and nociception, respectively [167]. Given that estradiol increases A1 receptor expression in breast cancer cell line [168] and ovariectomy decreases A2A receptors expression [169], the occurrence of menstrual migraine at the start of the menses, during which estrogen and progesterone levels suddenly decrease [166], suggests a plausible crosstalk between sex hormones and adenosine signaling, underlying sexually dimorphic pain.