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SLEEP AND BIOLOGICAL RHYTHMS

Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep

¹Research Service (151A3), Department of Veterans Affairs of Greater Los Angeles Healthcare System, North Hills; and ²Department of Psychology and ³School of Medicine, University of California, Los Angeles, California; and ⁴Department of Zoology, Patna University, Bihar, India

Submitted 11 September 2008 ; accepted in final form 23 October 2008

Previous work showed that sleep is associated with increased brain protein synthesis and that arrest of protein synthesis facilitates sleep. Arrest of protein synthesis is induced during the endoplasmic reticulum (ER) stress response, through phosphorylation of eukaryotic initiation factor 2 (p-eIF2). We tested a hypothesis that elevation of p-eIF2 would facilitate sleep. We studied the effects of intracerebroventricular infusion of salubrinal (Salub), which increases p-eIF2 by inhibiting its dephosphorylation. Salub increased deep slow wave sleep by 255%, while reducing active waking by 49%. Delta power within non-rapid eye movement (NREM) sleep was increased, while power in the sigma, beta, and gamma bands during NREM was reduced. We found that Salub increased expression of p-eIF2 in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2-immunolabeled neurons in the BF area; Salub administration increased the number of p-eIF2-expressing noncholinergic neurons in the caudal BF. In addition, Salub also increased the intensity of p-eIF2 expression in both cholinergic and noncholinergic neurons, but this was more widespread among the noncholinergic neurons. Our findings support a hypothesis that sleep is facilitated by signals associated with the ER stress response.

protein synthesis inhibition; endoplasmic reticulum stress; phosphorylated eukaryotic initiation factor 2; basal forebrain