Modulation of GABAergic transmission in the striatopallidal system by adenosine A _2A receptors

Abstract

The selective localization of adenosine A2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson's disease (PD). The results of behavioral studies using A2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A2A antagonists as a novel treatment for PD. However, little is known about the role of A2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A2A receptor-mediated dual modulation of the striatopallidal system. Striatal A2A receptors may increase the excitability of medium spiny neurons (MSNs) by modulating an intrastriatal GABAergic network. In addition, pallidal modulation occurs at striatopallidal MSN terminals located at the GP, enhancing GABA release onto GP projection neurons and directly suppressing their activity. Blockade of these modulatory functions by A2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.

Adenosine A2A Receptor Facilitates Calcium-Dependent Protein Secretion through the Activation of Protein Kinase A and Phosphatidylinositol-3 Kinase in PC12 Cells

“…Although activation of A 2A -R in general facilitates calcium-dependent exocytosis of synaptic vesicles (with a few exceptions) (Sebastiao and Ribeiro, 2000;Cunha and Ribeiro, 2000a;Mori and Shindou, 2003;Okada et al, 2001;Marchi et al, 2002;Kirk and Richardson, 1994;Kurokawa et al, 1994;Cunha and Ribeiro, 2000b), it has not been investigated so far whether A 2A -R activation also facilitates exocytosis of dense-core secretary vesicles. We established a stable cell line of PC12 cells expressing NPY-Venus, a fusion protein between NPY and a yellow fluorescence protein variant relatively resistant to low pH (Venus), which has been shown to be efficiently targeted to dense-core vesicles (Nagai et al, 2002).…”

“…However, it is still largely unknown how A 2A -R modulates cellular functions. Recent studies have shown that activation of A2A-R facilitates calcium-dependent secretion of various neurotransmitters such as GABA, serotonin and glutamate in hippocampal and laterodorsal tegmental cells (Sebastiao and Ribeiro, 2000;Cunha and Ribeiro, 2000a;Mori and Shindou, 2003;Okada et al, 2001;Marchi et al, 2002;Cunha and Ribeiro, 2000b). These results tempted us to dissect the downstream signaling pathways of A 2A -R in regulation of calcium-dependent secretion.…”

Role of the Central Ascending Neurotransmitter Systems in the Psychostimulant Effects of Caffeine

“…Recent studies support the existence of A 2A receptors in the striatal collaterals of the enkephalinergic MSNs, activation of which facilitates GABA release [28]. Less clear is the significance of some studies suggesting that activation of striatal A 2A receptors in striatal GABA terminals inhibits GABA release [29]. Finally, functional A 2A receptors have also been suggested to be localized in nerve terminals from cholinergic interneurons (which should also be included in the striatal spine modules, mostly as asynaptic varicosities that release acetylcoline by volume transmission [16]) where they are co-localized with A 1 receptors [30].…”

Treatment of Parkinson's Disease: What's in the Non-dopaminergic Pipeline?

“…By binding to A 2A receptors, adenosine activates striatopallidal neurons, opposing the inhibitory effects mediated by D2 receptor binding [12,13]. These findings suggest that blockade of A 2A receptors should inhibit the excessive activity of the indirect pathway that results from dopamine depletion.…”