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The Journal of Neuroscience, August 2, 2006, 26(31):8092-8100; doi:10.1523/JNEUROSCI.2181-06.2006

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Behavioral/Systems/Cognitive
Adenosine and Sleep Homeostasis in the Basal Forebrain

Carlos Blanco-Centurion,¹ Man Xu,¹ Eric Murillo-Rodriguez,¹ Dmitry Gerashchenko,¹ Anjelica M. Shiromani,¹ Rafael J. Salin-Pascual,¹ Patrick R. Hof,² and Priyattam J. Shiromani¹

¹West Roxbury Veterans Affairs Medical Center and Harvard Medical School, West Roxbury, Massachusetts 02132, and ²Mount Sinai School of Medicine, New York, New York 10029

Correspondence should be addressed to Dr. Priyattam J. Shiromani, Department of Neurology, Harvard Medical School and Veterans Affairs Medical Center, Building 3, Room 2C109, 1400 VFW Parkway, West Roxbury, MA 02132. Email: pshiromani{at}hms.harvard.edu

It is currently hypothesized that the drive to sleep is determined by the activity of the basal forebrain (BF) cholinergic neurons, which release adenosine (AD), perhaps because of increased metabolic activity associated with the neuronal discharge during waking, and the accumulating AD begins to inhibit these neurons so that sleep-active neurons can become active. This hypothesis grew from the observation that AD induces sleep and AD levels increase with wake in the basal forebrain, but surprisingly it still remains untested. Here we directly test whether the basal forebrain cholinergic neurons are central to the AD regulation of sleep drive by administering 192–IgG–saporin to lesion the BF cholinergic neurons and then measuring AD levels in the BF. In rats with 95% lesion of the BF cholinergic neurons, AD levels in the BF did not increase with 6 h of prolonged waking. However, the lesioned rats had intact sleep drive after 6 and 12 h of prolonged waking, indicating that the AD accumulation in the BF is not necessary for sleep drive. Next we determined that, in the absence of the BF cholinergic neurons, the selective adenosine A₁ receptor agonist N6-cyclohexyladenosine, administered to the BF, continued to be effective in inducing sleep, indicating that the BF cholinergic neurons are not essential to sleep induction. Thus, neither the activity of the BF cholinergic neurons nor the accumulation of AD in the BF during wake is necessary for sleep drive.

Key words: adenosine; purines; basal forebrain; sleep; REM sleep; homeostasis; microdialysis

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Received Feb. 10, 2006; revised June 20, 2006; accepted June 20, 2006.

Correspondence should be addressed to Dr. Priyattam J. Shiromani, Department of Neurology, Harvard Medical School and Veterans Affairs Medical Center, Building 3, Room 2C109, 1400 VFW Parkway, West Roxbury, MA 02132. Email: pshiromani{at}hms.harvard.edu

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