Regulation of Arousal by Adenosine A1 and A2A Receptors in the Prefrontal Cortex of C57BL/6J Mouse.

Abstract

Adenosine levels in the basal forebrain and cortex increase with prolonged wakefulness to promote sleep. Caffeine increases wakefulness by blocking adenosine receptors, yet the neurotransmitter systems and brain regions through which adenosine receptor blockade causes arousal are incompletely understood. The prefrontal cortex (PFC) contributes to the regulation of sleep and wakefulness. This thesis research sought to elucidate the mechanisms by which adenosine A1 and A2A receptors in PFC modulate acetylcholine (ACh) release, behavioral and electroencephalographic (EEG) arousal, and sleep. Aim 1 tested the hypothesis that adenosine A1 and A2A receptors in mouse PFC modulate PFC ACh release, behavioral arousal, and EEG delta power. Microdialysis administration of adenosine A1 and A2A receptor agonists and antagonists significantly altered ACh release, anesthesia recovery time, and EEG delta power. The data support the interpretation that caffeine promotes arousal, in part, by blocking PFC adenosine A1 receptors. Aim 2 tested the hypothesis that endogenous adenosine in the PFC acts through adenosine A1 receptors to modulate sleep and wakefulness. Microinjection of an adenosine A1 receptor antagonist into the PFC increased wakefulness and decreased NREM sleep. These results suggest that one mechanism by which the PFC modulates behavioral arousal is through descending input to caudal arousal control centers. The pontine reticular formation (PRF) regulates sleep/wake states and Aim 3 tested the hypothesis that adenosine A1 and A2A receptors in the PFC modulate ACh release in the PRF. Microdialysis delivery of an adenosine A2A receptor agonist, A1 receptor antagonist, and caffeine to the PFC increased PRF ACh release, whereas administering an A1 receptor agonist decreased PRF ACh release. These findings are the first to demonstrate that pharmacological manipulation of the PFC can alter neurotransmitter release in the PRF, and suggest that one mechanism by which PFC adenosine A1 and A2A receptors modulate behavioral arousal is by altering PRF ACh release. The results support the interpretation that adenosine A1 and A2A receptors in the PFC modulate ACh release and behavioral arousal (Aim 1); modulate sleep and wakefulness (Aim 2); and modulate ACh release in the PRF (Aim 3).