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.

R01DA010682

1998-04-01

2004-02-29