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Modulation of GABAergic transmission in the striatopallidal system by adenosine A_2A receptors

A potential mechanism for the antiparkinsonian effects of A_2A antagonists

From the Pharmaceutical R & D Division (Dr. Mori), Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan; and Pharmaceutical Research Institute (T. Shindou), Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.

Address correspondence and reprint requests to Dr. Akihisa Mori, Pharmaceutical R & D Division, Kyowa Hakko Kogyo Co., Ltd., 1-6-1 Ohtemachi, Chiyodaku, Tokyo 100, Japan; e-mail: moria{at}kyowa.co.jp

The selective localization of adenosine A_2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson’s disease (PD). The results of behavioral studies using A_2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A_2A antagonists as a novel treatment for PD. However, little is known about the role of A_2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A_2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A_2A receptor-mediated dual modulation of the striatopallidal system. Striatal A_2A 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 A_2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.

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