Guanosine contributes to rapid purinergic regulation of dopamine during ischemia.

Purinergic modulation of neurotransmission is a primary strategy employed in rapid neuroprotection during and after ischemic stroke. While the contributions of adenosine and ATP to the purinome are well-documented, guanosine-based regulatory activity has remained under-investigated. In the ischemia-vulnerable CA1 region of the hippocampus, dopamine serves as both a neurotransmitter involved in long-term potentiation during memory acquisition and as a regulator focused on modulating glutamate activity. Dopamine has been suggested as a potential protective force against glutamate-induced excitotoxicity in early ischemia. Here, we investigate changes in dopamine signaling during ischemia and demonstrate that guanosine administration during injury has an immediate protective effect. We observe rapid suppression of dopamine release following ischemic insult that is completely restored with administration of a low micromolar dose of guanosine. Changes in dopamine signaling and short-term mRNA production further suggest that guanosine's rapid regulatory role may be partially achieved through the adenosine A1 and A2a receptors and that it facilitates dopamine reuptake through the dopamine transporter DAT. We present the first evidence that guanosine plays a rapid regulatory role in dopamine neurotransmission and that it may function as a broad facilitator of neurotransmitter reuptake, diversifying our understanding of the purinome in ischemia.