Adenosinergic Modulation of Sleep-like Brain States Under Urethane Anesthesia
Creators: Singh, Aakanksha 
Publisher: name: University of Alberta Library
Year: 2022

<p>The reason and functional relevance of why we sleep continues to perplex researchers. One fundamental reason behind why sleep remains a mystery is because it is challenging to study given how easily it is disrupted. Anesthesia has been suggested to be a model for studying sleep given the behavioural and neurobiological similarities between the two states of unconsciousness. Sleep is often thought of as a unitary process, but it is highly dynamic. There are two distinct stages of sleep – NREM and REM. Cycling between these two states occurs in a periodic and rhythmic fashion over the course of our sleep episode. Unlike other anesthetics which promote a coma-like or at best a NREM-like unitary state, the acute laboratory anesthetic urethane closely imitates the forebrain activity dynamics of natural sleep. Under urethane, spontaneous cycling between a deactivated (NREM-like) and activated (REM-like) EEG pattern occurs, and these two states have peripheral physiological correlates that also mimic natural sleep. This makes urethane anesthesia a powerful model to study sleep-state dynamics which allows for the facilitated examination of brain mechanisms involved in sleep. </p>

<p>A variety of molecules have been suggested to act as “sleep factors” and contribute to both the onset and maintenance of sleep. Among these factors is adenosine, a highly potent sleep-promoting molecule that may be imperative for expression of sleep need. Adenosine exerts its influence on sleep via two receptors – the A1 and the A2A receptor. In this thesis, I tested the influence of adenosine, its antagonist caffeine, and two receptor specific agonists for A1 and A2A receptors to evaluate if parallel effects to sleep occur in sleep and the urethane model. It is crucial that we continue to validate existing models of natural sleep to strengthen them as avenues to study sleep. </p>

<p>Male Sprague Dawley rats were anesthetized with urethane to surgical plane after which bipolar electrodes were used to record LFPs from the cortex and hippocampus. After establishing a baseline consisting of stable, cyclic alternations between the deactivated and activated state for at least one hour, either adenosine or caffeine was administered peripherally (IV) or centrally (ICV). Any changes in brain state alternations were compared to our baseline recording. My results indicated that adenosine promoted the deactivated state whereas caffeine decreased the deactivated state. These drugs were also co-administered in an attempt to challenge the effect of adenosine with its antagonist caffeine. This led to an interesting biphasic response in which an increase in the deactivated state was observed initially followed by a decrease in this state. I then tested the effect of central administration of adenosine A1 agonist CPA and A2A agonist CGS 21680. CGS 21680 lead to an increase in the deactivated state similar to what was observed with adenosine. CPA also increased the deactivated state, but this effect was extremely robust, and the activated state was eliminated for an extended period of time with some return of cycling observed towards the end of my experiments.</p>

<p>Cumulatively, my results indicate that adenosine and its agonists promote the deactivated state but that activation of A1 vs. A2A receptors mediate very different responses. A1 activation promotes the deactivated state much more powerfully than A2A activation. Caffeine on the other hand, decreases the deactivated state. Importantly, these results are consistent with effects on sleep state in natural sleep, which further validates the urethane model.</p>