# Neurochemical mechanisms of sedative effects on sleep homeostasis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $298,807

## Abstract

PROJECT SUMMARY/ABSTRACT
Sedative-hypnotics are administered to about two-third of the patients admitted to the intensive care unit (ICU).
Although patients might appear to be “sleeping,” there are varying effects of sedatives on sleep architecture.
The dissociation between the behavioral phenotype of sleep (quiescence, eyes closed) and the restorative
effects of sleep can mislead care providers and cause adverse consequences for patients. For example, it is
known that certain sedative strategies are associated with a higher incidence of delirium, which is associated
with increased mortality. The lack of rational sedation strategies is rooted in a profound gap in our knowledge
at the neurobiological level. Two main questions persist and have not been explored: (1) do sedative-hypnotics
accomplish the beneficial effects of sleep? and if so, (2) what is the mechanism? The long-term goal of the
proposed studies is to identify sedative regimens that can be used more effectively in ICU and perioperative
care to achieve homeostatic sleep recovery, and the neurochemical mechanisms through which sedative-
hypnotics could provide a sleep-like state with positive functional outcomes. The overall objective of the
proposed studies is to examine the effect of sedatives on sleep homeostatic neural circuitry, and to identify the
mechanisms of differential effects on slow-wave sleep and rapid eye movement sleep. The central hypothesis,
supported by our preliminary data, is that sedatives modulate levels of nitric oxide (NO) and adenosine, the
signaling molecules that serve as the “currency” of sleep debt, in basal forebrain to provide recovery from
sleep loss. The rationale for the proposed research is that it will provide the fundamental mechanistic
understanding of the interaction between sedatives and sleep homeostasis, which is currently unknown. The
study will use four clinically relevant sedative-hypnotics (propofol, dexmedetomidine, midazolam, sevoflurane)
and test the hypothesis by pursuing three specific aims that investigate 1) the relationship between sedative-
induced changes in sleep homeostasis and the changes in NO and adenosine levels in basal forebrain, 2) the
causal influence of NO and adenosine in basal forebrain on sedative-mediated recovery sleep, and 3) the role
of NO synthase isoforms in sedative-mediated recovery of distinct sleep phases, i.e., slow-wave sleep vs. rapid
eye movement sleep. The approach is innovative because this will be the first study to develop a mechanistic
understanding of the processes mediating homeostatic sleep recovery during sedation. In addition, two
technical innovations from our laboratory – high density EEG recordings and mass spectrometric analysis of
simultaneous changes in >55 brain analytes in rats – will be used for mapping changes in rat brain cortical
networks as an index of sedative-mediated sleep recovery, and comparison of basal forebrain neurochemistry
between sedation and non-sedation states. The ...

## Key facts

- **NIH application ID:** 9830657
- **Project number:** 5R01GM121919-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Dinesh Pal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $298,807
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830657

## Citation

> US National Institutes of Health, RePORTER application 9830657, Neurochemical mechanisms of sedative effects on sleep homeostasis (5R01GM121919-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830657. Licensed CC0.

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