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The Journal of Neuroscience, May 15, 2003, 23(10):4278-4287

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A₁ Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A₁ Receptor in the Cholinergic Basal Forebrain

Mahesh M. Thakkar, Stuart Winston, and Robert W. McCarley

Department of Psychiatry, Harvard Medical School, Veterans Affairs Boston Healthcare System, Brockton Veterans Affairs Medical Center, Brockton, Massachusetts 02301

We hypothesized that adenosine, acting via the A₁ receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of wakefulness-promoting neurons in the basal forebrain. Adenosine A₁ receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A₁ receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A₁ receptor antisense in the basal forebrain, spontaneous levels of sleep-wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2–5 showing a reduction of 50–60%. There was an even greater postdeprivation reduction in delta power (60–75%) and a concomitant increase in wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A₁ receptor suppressed A₁ receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A₁ receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.

Key words: non-REM sleep; adenosine; substantia innominata; cholinergic; basal forebrain; A₁ receptor; antisense; microdialysis

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Received Sep. 19, 2002; revised Feb. 10, 2003; accepted Feb. 27, 2003.

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