Although approximately 20 million prescriptions for hypnotic medications are written each year, the molecular mechanisms by which they act, and the neuroanatomic site(s) at which they act. remain unclear. This problem is complicated by the wide range of pharmacologic classes of compounds which induce sleep, and it is uncertain whether these various agents differ in their mechanisms or site of action. The investigator has begun to build a case that a common molecular mechanism for several types of sleep-inducing compounds may involve interaction with the benzodiazepine (BZ)-GABAa receptor complex. The current proposal, based on the investigator's observations that microinjection of pentobarbital or the BZ hypnotic triazolam into the medial preoptic area (MPA) of the anterior hypothalamus induces sleep. addresses the anatomical site(s) of action of sleep-inducing drugs. The goal is to bring together these observations from the investigator's laboratory and those from other laboratories indicating similar effects from microinjections of ethanol and adenosine. The investigator shall explore these observations further, addressing the following questions: 1. Do these findings hold when all these compounds are examined in the same laboratory, under similar conditions, and do these various agents show clear dose-responsiveness? 2. Are these effects specific to the BZ-GABAa recognition site? 3. Are these effects specific to the MPA, or do they occur with injection into other structures? 4. Do they result as a consequence of altering hypothalamic temperature, or by a more direct mechanism? 5. Is an intact MPA necessary for sleep induction by these agents when given parenterally? In a broader sense, the goal of this proposal it to move beyond the conventional approach of simply identifying a hypnogenic compound, and instead to develop a series of critical questions which should be asked about any substance which alters sleep, including: 1) where does it act?; 2) on which receptors does it act?; 3) with which physiological processes does it interact?; and 4) which brain sites are critical for its hypnogenic effect? The investigator's goal, then, is both to characterize the properties of four classes of hypnogenic substances, and to begin to build a framework to make the currently diverse and complex literature on putative sleep substances more structured and comprehensible.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010682-04
Application #
6362823
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Aigner, Thomas G
Project Start
1998-04-01
Project End
2004-02-29
Budget Start
2001-03-15
Budget End
2004-02-29
Support Year
4
Fiscal Year
2001
Total Cost
$234,971
Indirect Cost
Name
University of Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Mendelson, Wallace B; Bergmann, Bernard M; Tung, Avery (2003) Baseline and post-deprivation recovery sleep in SCN-lesioned rats. Brain Res 980:185-90
Tung, Avery; Szafran, Martin J; Bluhm, Bryan et al. (2002) Sleep deprivation potentiates the onset and duration of loss of righting reflex induced by propofol and isoflurane. Anesthesiology 97:906-11
Mendelson, Wallace B (2002) Melatonin microinjection into the medial preoptic area increases sleep in the rat. Life Sci 71:2067-70
Mendelson, W B (2001) Neurotransmitters and sleep. J Clin Psychiatry 62 Suppl 10:5-8
Tung, A; Bluhm, B; Mendelson, W B (2001) Sleep inducing effects of propofol microinjection into the medial preoptic area are blocked by flumazenil. Brain Res 908:155-60
Laposky, A D; Homanics, G E; Basile, A et al. (2001) Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice. Neuroreport 12:4143-7
Tung, A; Bluhm, B; Mendelson, W B (2001) The hypnotic effect of propofol in the medial preoptic area of the rat. Life Sci 69:855-62
Mendelson, W B (2001) The sleep-inducing effect of ethanol microinjection into the medial preoptic area is blocked by flumazenil. Brain Res 892:118-21
Tung, A; Lynch, J P; Mendelson, W B (2001) Prolonged sedation with propofol in the rat does not result in sleep deprivation. Anesth Analg 92:1232-6
Mendelson, W B (2000) Sleep-inducing effects of adenosine microinjections into the medial preoptic area are blocked by flumazenil. Brain Res 852:479-81

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