Abstract
Adenosine is a neuroprotective agent that inhibits neuronal activity and modulates neurotransmission. Previous research has shown adenosine gradually accumulates during pathologies such as stroke and regulates neurotransmission on the minute-to-hour time scale. Our lab developed a method using carbon-fiber microelectrodes to directly measure adenosine changes on a sub-second time scale with fast-scan cyclic voltammetry (FSCV). Recently, adenosine release lasting a couple of seconds has been found in murine spinal cord slices. In this study, we characterized spontaneous, transient adenosine release in vivo, in the caudate-putamen and prefrontal cortex of anesthetized rats. The average concentration of adenosine release was 0.17±0.01 µM in the caudate and 0.19±0.01 µM in the prefrontal cortex, although the range was large, from 0.04 to 3.2 µM. The average duration of spontaneous adenosine release was 2.9±0.1 seconds and 2.8±0.1 seconds in the caudate and prefrontal cortex, respectively. The concentration and number of transients detected do not change over a four hour period, suggesting spontaneous events are not caused by electrode implantation. The frequency of adenosine transients was higher in the prefrontal cortex than the caudate-putamen and was modulated by A1 receptors. The A1 antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine, 6 mg/kg i.p.) increased the frequency of spontaneous adenosine release, while the A1 agonist CPA (N6-cyclopentyladenosine, 1 mg/kg i.p.) decreased the frequency. These findings are a paradigm shift for understanding the time course of adenosine signaling, demonstrating that there is a rapid mode of adenosine signaling that could cause transient, local neuromodulation.
Highlights
Adenosine is an important neuroprotective modulator in the brain that regulates neurotransmission and blood flow
Adenosine increases in the brain during pathological events, such as ischemia [1] and seizures [2], where it can act as a retaliatory metabolite
No information about basal levels is obtained with fast-scan cyclic voltammetry (FSCV) because all data are background subtracted
Summary
Adenosine is an important neuroprotective modulator in the brain that regulates neurotransmission and blood flow. Adenosine increases in the brain during pathological events, such as ischemia [1] and seizures [2], where it can act as a retaliatory metabolite. The increases in adenosine during these pathologies typically last for minutes to hours [3]. Adenosine activates inhibitory A1 adenosine receptors a couple of minutes after onset, which decreases cAMP concentrations, hyperpolarizes neurons, and prevents excitatory firing [5,6]. While these studies demonstrate adenosine signaling on a longer time scale, there is growing evidence that adenosine signals on a much shorter time scale
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