Distribution, biochemistry and function of striatal adenosine A2A receptors
Introduction
Seventy years ago Drury and Szent-György (1929) reported that adenosine can influence circulation, respiration and gastrointestinal motility in intact animals. Some 40 years later data on a role of adenosine were obtained using brain tissue. Electrical stimulation was found to increase accumulation of adenosine 3′,5′-cyclic monophosphate (cAMP) in brain slices (Kakiuchi et al., 1968). This was blocked by methylxanthines, which also blocked the cAMP elevating effects of adenosine (Sattin and Rall, 1970). It was also shown that electrical stimulation could release adenosine from brain tissue (McIlwain, 1972). Soon thereafter the presence of methylxanthine-sensitive adenosine receptors on nerve and glial cells from several species was well established [see Daly (1977)]. Meanwhile, it was found that adenosine depresses neuronal firing rate in vivo (Phillis et al., 1975) and in vitro (Dunwiddie and Hoffer, 1980). The depressant effect of adenosine was blocked by methylxanthines, which also enhanced neuronal activity by blocking endogenous adenosine (Dunwiddie et al., 1981). This adenosine-mediated depression could be partly explained by a direct hyperpolarization of neurons and partly by an indirect decrease of a tonic excitatory input. Indeed, it was found that adenosine was able to block the release of numerous neurotransmitters, such as acetylcholine, dopamine, serotonin and noradrenaline (Hedqvist and Fredholm, 1976, Vizi and Knoll, 1976, Harms et al., 1978Harms et al., 1979, Fredholm and Hedqvist, 1980) and it was postulated that an important role for adenosine is to modulate neuronal responses mediated by synaptically released classical neurotransmitters. Thus, by 1980 the concept of methylxanthine-sensitive adenosine receptors mediating a modulatory role of adenosine in many tissues including the brain was well established [see Fredholm, 1980, Snyder et al., 1981].
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Metabolism and levels of adenosine
Under normal conditions there is generation of adenosine both intracellularly and extracellularly. The intracellular production is mediated either by an intracellular 5′-nucleotidase, that dephosphorylates AMP Schubert et al., 1979, Zimmermann et al., 1998, or by hydrolysis of S-adenosyl-homocysteine (Broch and Ueland, 1980). Intracellularly generated adenosine can be transported into the extracellular space via specific bidirectional transporters that efficiently keep the intra- and
Adenosine receptors
The concept of methylxanthine-sensitive adenosine receptors coupled to the formation of cAMP was well established by the early 1970s De Gubareff and Sleator, 1965, Afonso and O'Brien, 1970. When it was found that adenosine derivatives, with different order of potency, were able to increase or decrease intracellular cAMP, the presence of two distinct adenosine receptors was suggested van Calker et al., 1979, Londos et al., 1980. The receptors that inhibited adenylyl cyclase were classified as A1
Distribution of A2A receptors in the brain
The distribution of A2A receptors has been studied using immunohistochemistry, ligand-binding to membranes and brain slices (i.e. autoradiography), whereas reverse transcriptase-polymerase chain reaction (RT-PCR), northern blotting and in situ hybridization have been employed to detect its messenger RNA (mRNA).
In the presence of an A1 receptor agonist, a high level of [3H]NECA binding was demonstrated in striatum using membranes or autoradiography Yeung and Green, 1984, Bruns et al., 1986,
Striatum as a part of the basal ganglia
The basal ganglia are composed of several subcortical nuclei, including the striatum, the globus pallidus (external part in primates or GPe), the entopeduncular nucleus (internal part or GPi), the subthalamic nucleus (STN), and the substantia nigra (SN), which are involved in the integration of sensorimotor, associative and limbic information to produce motor behaviors. Recently, the central part of amygdala has been suggested to be a specialized autonomic-projecting sub-region of striatum
Stimulation of adenylyl cyclase and cAMP accumulation
As noted above, adenylyl cyclase stimulation was used to define A2A receptors in striatum. Indeed, not only exogenous (Wilkening and Makman, 1975), but also endogenous adenosine can regulate cAMP formation in striatum Fredholm, 1977, Premont et al., 1977. Striatal A2A receptors, as well as D1 receptors, are mainly coupled to Ca2+-inhibitable adenylyl cyclases (type V and VI) (Chern et al., 1996). In striatal extracts from animals with 6-OHDA lesions of the dopaminergic axons the ability of an A
Consequences of activation of striatal A2A receptors
The present article is focused on the function of A2A receptors in striatum. This does not imply that extrastriatal A2A receptors are without function. On the contrary: there is much evidence that these receptors are important. It has for example been shown that i.p. administration of an adenosine deaminase inhibitor, which raises the levels of endogenous adenosine two- to threefold in the superior colliculus of the rat, also increases the amplitude of potentials evoked in this area by optic
IEGs as a functional neuroanatomical tool to determine biochemical activation of neuronal pathways
That the expression of c-Fos can be dramatically up-regulated in the brain following a challenge with a pharmacological agent was first demonstrated with convulsant drugs Morgan et al., 1987, Dragunow and Robertson, 1987b. An induction of c-Fos could also be observed after kindling [e.g. Dragunow and Robertson (1987a)] and it was soon realized that induction of c-Fos was a general response to a variety of stimuli. For example, an up-regulation of c-Fos occurred in a subset of spinal dorsal horn
Caffeine- and A2A receptor-mediated regulation of neuropeptides in striatum
Pharmacological blockade of A2A receptors has also been shown to counteract D2 receptor antagonist-induced increases of preproenkephalin mRNA expression in rats (Richardson et al., 1997). Furthermore, in transgenic mice lacking A2A receptors there is a decreased level of preproenkephalin mRNA in striatum (Ledent et al., 1997).
Acute treatment with stimulatory doses of caffeine has no significant effects on preproenkephalin mRNA, but a higher concentration (100 mg kg−1, i.p.) of caffeine causes an
Caffeine as a psychostimulant and the involvement of A2A receptors
Caffeine, the most widely used of all psychostimulants, is metabolized to theophylline, paraxanthine and theobromine. Coffee beans and tea leaves contain mainly caffeine, whereas cocoa beans contain mainly theobromine. Caffeine and related methylxanthines are phosphodiesterase inhibitors, but only at concentrations >0.2 mm. Similarly, concentrations in the millimolar range are necessary to cause a release of calcium from a storage pool in the sarcoplasmic reticulum. The concentrations of
Conclusions and perspectives
It has been known for over 20 years that adenosine receptors in the striatum are functionally important and that they interact with dopaminergic transmission. We now have a rather clear picture, as described above, of how adenosine acts and how it interacts with dopamine.
One single gene encodes functional A2A receptors. Autoradiography with agonist as well as antagonist radioligands and immunohistochemistry detects very high levels of A2A receptors in striatum (i.e. nucleus caudatus, putamen,
Acknowledgements
The authors want to thank Professor Bertrand Bloch, Professor Paul Greengard, Mrs Mia Lindskog, Dr George G. Nomikos, Dr Håkan Hall and Dr Francois Gonon for collaborative efforts on elucidating the role of striatal A2A receptors. Mrs Janet Holmén for her critical reading of the manuscript. This work was financially supported by the Swedish Medical Research Council (Project No. 2553), the Swedish Society for Medical Research, Lars Hiertas Minnesfond,Åke Wibergs stiftelse, the Institute for
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