Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep.
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 2alpha (p-eIF2alpha). We tested a hypothesis that elevation of p-eIF2alpha would facilitate sleep. We studied the effects of intracerebroventricular infusion of salubrinal (Salub), which increases p-eIF2alpha 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-eIF2alpha in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2alpha-immunolabeled neurons in the BF area; Salub administration increased the number of p-eIF2alpha-expressing noncholinergic neurons in the caudal BF. In addition, Salub also increased the intensity of p-eIF2alpha 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.
Methippara
Melvi M
MM
Research Service (151A3), Department of Veterans Affairs of Greater Los Angeles Healthcare System, North Hills, CA 91343, USA
Bashir
Tariq
T
Kumar
Sunil
S
Alam
Noor
N
Szymusiak
Ronald
R
McGinty
Dennis
D
D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004569:Electroencephalography; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012894:Sleep Stages / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D014851:Wakefulness / Q000187:drug effects
D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D006993:Hypnotics and Sedatives; D011500:Protein Synthesis Inhibitors; C496827:salubrinal; D013890:Thiourea