Fig. 1. Brain expression patterns for subtypes of receptors for three neurotransmitters known to modulate dopaminergic neurotransmission. Composite distributions of specific radioligand binding to subtypes of muscarinic cholingeric (M₁ and M₂), adenosinergic (A_2A) and ionotropic glutamate (AMPA and kainate) receptor subtypes are shown in coronal sections from the rostral, mid, and caudal rat brain (containing striatum, hippocampus, and pons, respectively), as adapted from Tohyama and Takatsuji (1998) with permission from Oxford University Press and Igaku-Shoin Ltd. Increasing density of radioligand binding is color-coded over a spectrum from white to blue to yellow to red. Most striatal receptors that modulate dopaminergic neurotransmission are also widely distributed throughout the brain, whereas the A_2A subtype of adenosine receptor is largely restricted in its expression to the striatum and the underlying olfactory tubercle.

Fig. 2. Schematic of the proposed mechanism of antiparkinsonian activity of A_2A receptor antagonists. As depicted in a simplified basal ganglia diagram of the normal state (left panel), the inhibitory influence of the striatonigral “direct” pathway on basal ganglia output (from the SNr/GPi complex) is counterbalanced by the disinhibitory influence of the striatopallidal “indirect” pathway to this complex. At the striatal level, dopamine, acting on D₁ receptors, facilitates transmission along the direct pathway and inhibits transmission along the indirect pathway throughout D₂ receptors. Adenosine excites neurons in the indirect pathway via adenosine A_2A receptors in the striatum and globus pallidus pars externa (GPe). The loss of striatal dopamine in Parkinson's disease (PD) (center panel) disinhibits striatal spiny projection neurons of the indirect pathway, which leads to a marked suppressed activity of the GPe and therefore disinhibition of subthalamic nucleus (STN). Depletion of dopamine leads also to a decreased activation of striatal spiny neurons in the direct pathway. The resulting imbalance between the activity in the direct and the indirect pathways leads to increased inhibitory output from the internal GP (GPi) and substantia nigra pars reticulata (SNr) with excess inhibition of thalamocortical neurons, resulting in the characteristic reduced movement of PD. A_2A receptor blockade in PD (right panel) should result in recovery of GPe activity. This in turn would relieve excessive excitatory drive from the STN to the GPi-SNr complex, thereby restoring some balance between the direct and the indirect pathways. Note, however, that the reduced activity in the direct pathway would not be normalized by blocking adenosine A_2A receptors. Consequently, overactivity of GPi-SNr output neurons (and the resultant motor deficits) in PD may be only partially reversed by A_2A antagonists alone. The schematic is adapted from Albin et al., 1989. See also Kase et al., 2003. See text for further citations.

Fig. 3. Changes in striatal peptide expression in animal models of dyskinesia: summary of published data. The graphed and tabular data represent the percentage of control-side mRNA levels of enkephalin and dynorphin in the striatum of a parkinsonian animal with or without l-dopa treatment and in a few studies with l-dopa treatment plus A_2A receptor inactivation. In the parkinsonian state, enkephalin levels are increased while dynorphin levels are reduced. As a consequence of l-dopa treatment, enkephalin levels generally do not change significantly compared to the parkinsonian state without treatment although dynorphin levels are increased. The result is an imbalance between the two major striatal output pathways. A_2A receptor inactivation theoretically may help reestablish the balance between the two major pathways; in some experimental studies, it does significantly decrease either enkephalin or dynorphin levels. ①, ②, and ③ in the graphs correspond to the reference numbers near the bottom part of the tabular figure. They are color-coded to help the reader in following them through the three different states that are summarized in the figure (parkinsonian state, plus l-dopa, and plus l-dopa with A_2A inactivation). *For further discussion on the data of this paper, see Section 4.1 (Herrero et al., 1995, Jolkkonen et al., 1995, Zeng et al., 1995, Morissette et al., 1997, Henry et al., 1999, Perier et al., 2002, Quik et al., 2002, Tel et al., 2002, Winkler et al., 2002, Gross et al., 2003 and Perier et al., 2003).

Fig. 4. Sites of adenosine A_2A receptors whose blockade could protect dopaminergic nigrostriatal neurons. As detailed in the text and portrayed in this schematic, A_2A receptors on the nerve terminals of excitatory glutamatergic (Glu) neurons ① represent a widely distributed mechanism for enhanced excitotoxicity (lightening symbol, ) that may converge on dopaminergic (DA) nigrostriatal neurons. Blockade of A_2A receptor-facilitated glutamate release may account for reduced excitotoxic injury to nigrostriatal neurons as well as cortical and striatal neurons (not shown). A_2A receptors are densely expressed on GABAergic striatopallidal neurons ②, where their facilitative effect on GABA release in the external globus pallidus (GPe) could indirectly contribute to excitotoxic stimulation of dopaminergic nigral neurons via disinhibition of the glutamatergic projection from subthalamic nucleus (STN) to the substantia nigra pars compacta (SNc). Glial cells (e.g., astrocytes) can also express A_2A receptors ③ and actively regulate the neuronal environment throughout the CNS. Blockade of these receptors by caffeine may protect nearby dopaminergic neurons, possibly by activating (disinhibiting) the glial glutamate transporter leading to lower extracellular levels of excitatory amino acids. Question marks (?) reflect uncertainty over the presence of A_2A receptors on certain neuronal or glial cells in vivo. Ctx and Str refer to cortex and striatum, respectively.

Fig. 5. A_2A antagonists in PD: an overview of the pathophysiological pros and cons. Potentially beneficial (green) and detrimental/unfavorable (red) biological aspects of developing adenosine A_2A antagonist for PD. A check mark () indicates clinically demonstrated significance, whereas a question mark (?) indicates unproven or untested in humans. Caveats to proposed clinical effects are shown in brackets. See text for details and references; the list is not exhaustive. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Biological properties of human adenosine receptor subtypes

For more information on adenosine receptors, see reviews in Fredholm et al., 2000 and Fredholm et al., 2001.