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The Journal of Neuroscience, January 21, 2009, 29(3):871-881; doi:10.1523/JNEUROSCI.4111-08.2009

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Behavioral/Systems/Cognitive
Adenosine A₁ and A_2A Receptors in Mouse Prefrontal Cortex Modulate Acetylcholine Release and Behavioral Arousal

Christa J. Van Dort,^1,2 Helen A. Baghdoyan,¹ and Ralph Lydic^1,2

Departments of ¹Anesthesiology and ²Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109

Correspondence should be addressed to Dr. Ralph Lydic, Department of Anesthesiology, University of Michigan, 7433 Medical Sciences Building I, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5615. Email: rlydic{at}umich.edu

During prolonged intervals of wakefulness, brain adenosine levels rise within the basal forebrain and cortex. The view that adenosine promotes sleep is supported by the corollary that N-methylated xanthines such as caffeine increase brain and behavioral arousal by blocking adenosine receptors. The four subtypes of adenosine receptors are distributed heterogeneously throughout the brain, yet the neurotransmitter systems and brain regions through which adenosine receptor blockade causes arousal are incompletely understood. This study tested the hypothesis that adenosine A₁ and A_2A receptors in the prefrontal cortex contribute to the regulation of behavioral and cortical arousal. Dependent measures included acetylcholine (ACh) release in the prefrontal cortex, cortical electroencephalographic (EEG) power, and time to waking after anesthesia. Sleep and wakefulness were also quantified after microinjecting an adenosine A₁ receptor antagonist into the prefrontal cortex. The results showed that adenosine A₁ and A_2A receptors in the prefrontal cortex modulate cortical ACh release, behavioral arousal, EEG delta power, and sleep. Additional dual microdialysis studies revealed that ACh release in the pontine reticular formation is significantly altered by dialysis delivery of adenosine receptor agonists and antagonists to the prefrontal cortex. These data, and early brain transection studies demonstrating that the forebrain is not needed for sleep cycle generation, suggest that the prefrontal cortex modulates EEG and behavioral arousal via descending input to the pontine brainstem. The results provide novel evidence that adenosine A₁ receptors within the prefrontal cortex comprise part of a descending system that inhibits wakefulness.

Key words: microdialysis; EEG; anesthesia; C57BL/6J mouse; sleep; microinjection

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Received Aug. 28, 2008; revised Dec. 15, 2008; accepted Dec. 20, 2008.

Correspondence should be addressed to Dr. Ralph Lydic, Department of Anesthesiology, University of Michigan, 7433 Medical Sciences Building I, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5615. Email: rlydic{at}umich.edu

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				E. E. Icaza, X. Huang, Y. Fu, R. R. Neubig, H. A. Baghdoyan, and R. Lydic Isoflurane-Induced Changes in Righting Response and Breathing Are Modulated by RGS Proteins Anesth. Analg., November 1, 2009; 109(5): 1500 - 1505. [Abstract] [Full Text] [PDF]

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