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The adenosine A_2A receptor of the basal ganglia

P. J. Richardson

It is widely recognised that Parkinson's disease (PD) is caused by the deterioration of the dopaminergic neurones of the nigrostriatal pathway, resulting in abnormal neural processing in the basal ganglia and consequent motor abnormalities. The current mainstay of therapy for this disease is dopamine replacement using the precursor L-DOPA. However, the duration of L-DOPA therapy is severely limited, and it is associated with the development of incapacitating side-effects such as dyskinesias, on/off episodes and hallucinations. It was therefore of considerable interest when two groups in the late 1980s and early 1990s suggested that the adenosine A_2A receptor could be a suitable target for novel anti-PD drugs. It was hoped that such agents would exhibit fewer side-effects than the current dopamine-based therapies. Indeed it appears that in primate and rodent models of PD, A_2A receptor antagonists do not cause dyskinesias, unlike L-DOPA (Kanda et al. 2000).

The original evidence for this receptor being a suitable target in PD came from an analysis of its ability to control the release of acetylcholine and GABA in the striatum, and its ability to modulate the affinity of the dopamine D₂ receptor for dopamine (Richardson et al. 1997). The GABAergic striatopallidal output neurones (of the so-called indirect pathway) are of particular interest in PD because they express increased levels of enkephalin and GAD67 mRNAs in experimental models, consistent with these neurones being overactive in this disease state. Indeed the neural basis of PD is thought to be, at least in part, a consequence of an imbalance in the two major output systems of the striatum with the striatonigral neurones (of the direct pathway) being relatively underactive in PD. A_2A receptors, which are highly expressed in striatopallidal neurones, reduce inhibitory GABAergic influences onto these same cells (Mori et al. 1996). Since this was due to the regulation of GABA release, it was inferred that it occurs on the nerve terminals of recurrent collaterals, and that adenosine therefore reduces the auto-feedback control of striatopallidal neurones. Thus adenosine A_2A receptor antagonists, by increasing this feedback, may reduce the overactivity of the striatopallidal neurones and thereby ameliorate Parkinson's disease. However, it was important to determine the effect of A_2A receptor stimulation in the target area of these neurones, i.e. the external segment of the pallidum, where neurochemical experiments had given contradictory results.

In this situation the paper in this issue of The Journal of Physiology from Shindou et al. (2001) is particularly welcome. Shindou et al. analysed the effect of A_2A receptor stimulation in the external segment of the globus pallidus (GPe) on GABA-mediated IPSCs. In contrast to the situation in the striatum, A_2A receptor agonists increased GABA-mediated inhibitory transmission in this region. The authors argue that, in the absence of evidence for A_2A receptor mRNA being expressed in this area, this effect probably occurs on the nerve terminals of the striatopallidal neurones which, as mentioned above, express high levels of A_2A receptor mRNA. A_2A receptor antagonists would therefore cause a reduction in pallidal GABA release, thus reducing the influence of the overactive striatopallidal neurones. Indeed as predicted by this model, microdialysis experiments showed that A_2A receptor antagonists reduced pallidal GABA concentrations in vivo (Ochi et al. 2000). The influence of adenosine acting on the A_2A receptor in the striatum and GP would therefore be to increase GABA release from striatopallidal neurones, and thus presumably inhibit pallidal output neurones including those to the subthalamic nucleus. The resulting overactivity of this nucleus would have profound effects on the activity of the rest of the basal ganglia, including the major output stations, i.e. the internal segment of the GP (GPi), and the substantia nigra pars reticulata. Indeed it has been suggested (Plenz & Kitai, 1999) that the GPe and subthalamic nucleus (STN) form a basal ganglia pacemaker, controlling the output from the direct and indirect pathways. This pacemaker is likely to malfunction under conditions of dopamine depletion, with excessive inhibition of the GPe arising from overactivity of the striatopallidal pathway. From the above it can be inferred that A_2A receptor antagonists, by reducing the influence of the overactive striatopallidal neurones, could restore this pacemaker's more normal (perhaps less synchronised) activity.

One particularly intriguing aspect of this paper centres on the possibility that the A_2A receptor reduces GABA release from striatopallidal terminals in the striatum while increasing it from striatopallidal terminals in the GPe. This assumes that both the striatal and pallidal effects of this receptor are mediated on these neurones. Given the high levels of A_2A expression in these neurones this appears likely, but the possibility remains that the striatal effects are mediated by GABAergic interneurones and there may also be low but significant levels of A_2A receptor in GP neurones. These points remain to be clarified.

In conclusion Shindou et al. (2001) have shown a second action of the A_2A receptor in the basal ganglia complementary to that operating in the striatum leading to increased activity of striatopallidal neurones. There is obviously some way to go before we fully understand the mechanism of action of A_2A antagonists. For instance, it is not known whether other central sites of A_2A receptor expression are relevant to their anti-PD action, nor are the mechanisms underlying the apparent balance between dopamine and adenosine fully understood.

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Figure 1. Proposed actions of the adenosine A2A receptor on the indirect pathway of the basal ganglia In the absence of dopamine (PD), increased activity of the striatopallidal pathway causes a reduction in the pallido-STN activity and a consequent increase in the STN output to other nuclei including the GPi. Blockade of the A2A receptor reduces striatopallidal activity, increasing GABAergic feedback in the striatum, while reducing GABA release in the GP by reducing receptor mediated facilitation of GABA release. The resulting increase in pallido-STN activity may then reduce STN output to more normal levels.

	REFERENCES

KANDA T., JACKSON, M. J., SMITH, L. A., PEARCE, R. K. B., NAKAMURA, J., KASE, H., KUWANA, Y. & JENNER, P. (2000). Experimental Neurology 162, 321-327	[Medline]
MORI A., SHINDOU, T., ICHIMURA, M., NONAKA, K. & KASE, H. (1996). Journal of Neuroscience 16, 605-611	[Abstract]
OCHI M., KOGA, K., KUROKAWA, M., KASE, H., NAKAMURA, J. & KUWANA, Y. (2000). Neuroscience 100, 53-62	[Medline]
PLENZ D. & KITAI, S. T. (1999). Nature 400, 677-682	[Medline]
RICHARDSON P. J., KASE, H. & JENNER, P. G. (1997). Trends in Pharmacological Sciences 18, 338-344	[Medline]
SHINDOU T., MORI, A.,KASE, H. & ICHIMURA, M. (2001). Journal of Physiology 532, 423-434	[Abstract/Full Text]

This Article Abstract Full Text (PDF) Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Richardson, P. J. Search for Related Content PubMed PubMed Citation Articles by Richardson, P. J. Related Collections Perspectives