Characterization of Spontaneous, Transient Adenosine Release in the Caudate-Putamen and Prefrontal Cortex

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.

Automated algorithm for measurement of spontaneous adenosine transients in large electrochemical data sets

“…The frequency of spontaneous adenosine events for a single transient was every 2-3 minutes. This study demonstrates that adenosine events are spontaneous and do not follow any regular pattern and therefore are random events 5 .…”

“…Adenosine is a constituent of all cells since it is a byproduct of ATP catabolism 1 and is found in many regions of the brain including the caudate-putamen 3 , hippocampus 4 , nucleus accumbens 3 , and cortex 5 . Endogenous adenosine acts as a neuromodulator and plays an active role in the regulation of cerebral blood flow 6,7 .…”

“…In response to energy depletion induced by ischemia, extracellular concentrations of adenosine can increase 1000 fold. During pathological events like cerebral ischemia and inflammation the increase of adenosine typically lasts minutes to hours 5 . Recently, adenosine was shown to rapidly modulate stimulated dopamine release in the caudate-putamen by A 1 receptors 8 .…”

“…Recently, a new form of adenosine release has been found for the first time 5 . An adenosine transient is a non-stimulated occurrence of adenosine with event duration on the order of seconds.…”

“…The primary product is produced in an irreversible oxidation and further oxidizes to a secondary product at our CFMEs 5 . This can be visualized in a color plot of in vivo spontaneous transient adenosine release (Figure 1.3A).…”