Looking back at a life in sleep research-and some thoughts for the future

In reviewing my studies, some of which are nearing the half century mark, I've described work on sleep-related growth hormone, the effects of hypnotics on the perception of sleep, REM sleep induction in humans by cholinergic drugs, the benzodiazepine receptor, the anatomic sites of action of hypnotics, the endocannabinoid system and sleep, and the relation of anesthesia to sleep. Special mention along the way goes to cases in which drugs produced totally unexpected effects, including methysergide producing opposite effects on growth hormone secretion in sleep and a waking provocative test, the converse actions on sleep of the B-10 benzodiazepine enantiomers, and the promotion of wakefulness by microinjection of the hypnotic triazolam into the dorsal raphe nuclei. This work is placed in the context of what was known at the time, as well as what has been observed in subsequent years. Many of these studies indicate that the medial preoptic area may be a common site for the sleep-promoting action of a wide range of agents including traditional hypnotics, ethanol, propofol and melatonin. In the future it may be worthwhile looking at the beta-carbolines, and also the endocannabinoid system, when exploring drugs with new mechanisms of action for treating sleep/wake disorders. An Addendum to this paper describes memories of working with Frederick Snyder, J. Christian Gillin, Richard Jed Wyatt, and Floyd E. Bloom.