Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/53/4/527.full.pdf

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Publisher Summary This chapter describes the role of adenosine in brain function Adenosine is an endogenous neuromodulator that influences many functions in the central nervous system (CNS) The levels of adenosine increase when there is an imbalance between the rates of energy use and the rates of energy delivery Increased neuronal activity, and hypoxia or ischemia results in elevated levels of adenosine Adenosine receptors (ARs) were based on the ability of methylxanthines, such as theophylline and caffeine to act as antagonists The two receptors, A1 and A2, inhibit and stimulate adenylyl cyclase respectively The functions of ARs include: (1) regulation of nerve activity, (2) regulation of transmitter release, (3) interaction with other transmitter systems, and (4) various other functions Increased extracellular adenosine in response to ischemia and hypoxia acts as a neuro-protectant during cerebral ischemia and other neuronal insults ARs (A 1 Rs and A 2A Rs) are expressed at moderate to high levels in the brain areas enriched with dopaminergic innervation, thus providing an anatomical basis for interaction between these neurotransmitter systems Different features of the phenotypes provide clues to the roles of defects in AR genes in human disease The chapter discusses the roles of adenosine A 2A receptors in neurodegenerative disorders and ARs in psychiatric disorders Caffeine is used to improve wakefulness and the main actions of caffeine are mediated by brain ARs Adenosine might be an endogenous regulator of sleep–wake cycles, as adenosine analogs induced a sleep-like state In addition, ARs may play many roles in pathways that contribute to pain Clearly much additional work is needed to pinpoint the sites and mechanisms of action, as well as the roles in chronic pain states

Adenosine and Brain Function

Four adenosine receptors have been cloned from many mammalian and some non-mammalian species In each case the translated part of the receptor is encoded by two separate exons Two separate promoters regulate the A1 receptor expression, and a similar situation may pertain also for the other receptors The receptors are expressed in a cell and tissue specific manner, even though A1 and A2B receptors are found in many different cell types Emerging data indicate that the receptor protein is targeted to specific parts of the cell A1 and A3 receptors activate the Gi family of G proteins, whereas A2A and A2B receptors activate the Gs family However, other G proteins can also be activated even though the physiological significance of this is unknown Following the activation of G proteins several cellular effector pathways can be affected Signaling via adenosine receptors is also known to interact in functionally important ways with signaling initiated via other receptors

Structure and function of adenosine receptors and their genes

In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15-30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D(1)/D(2) receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.

https://www.jneurosci.org/content/jneuro/28/18/4795.full.pdf

Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex.

The striatum receives massive cortical excitatory inputs and is densely innervated by dopamine. Striatal projection neurons form either the direct or indirect pathways. Models of Parkinson's disease propose that dopaminergic degeneration imbalances both pathways, although direct electrophysiological evidence is lacking. Here, striatal neurons were identified by electrophysiological criteria and Neurobiotin labeling combined with either immunohistochemistry or in situ hybridization. Their spontaneous discharge activity and spike response to cortical stimulation were recorded in vivo in anesthetized rats rendered hemi-parkinsonian by 6-hydroxydopamine. We showed that striatonigral neurons (direct pathway) were inhibited whereas striatopallidal neurons (indirect pathway) were activated by dopaminergic lesion. We also identified, with antidromic stimulations, corticostriatal neurons that preferentially innervate striatonigral or striatopallidal neurons and showed that dopaminergic depletion selectively decreased the spontaneous activity of the former. Therefore, dopamine degeneration induces a cascade of imbalances that spread out of the basal ganglia and affect the whole basal ganglia-thalamo-cortical circuits. Fast-spiking GABA interneurons provide potent feedforward inhibition of striatal projection neurons. We showed here that these interneurons narrowed the time window of the responses of projection neurons to cortical stimulation. In the dopamine-depleted striatum, because the intrinsic activity of these interneurons was not altered, their feedforward inhibition worsened the striatal imbalance. Indeed, the time window of the evoked responses was narrower for striatonigral neurons and wider for striatopallidal neurons. Therefore, after dopaminergic depletion, cortical inputs and GABA interneurons might imbalance striatal projection neurons and represent two novel nondopaminergic mechanisms that might secondarily contribute to the pathophysiology of Parkinson's disease.

https://www.jneurosci.org/content/jneuro/26/14/3875.full.pdf

Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats.

Opposite tonic modulation of dopamine and adenosine on c-fos gene expression in striatopallidal neurons.

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Opposite tonic modulation of dopamine and adenosine on c-fos gene expression in striatopallidal neurons.