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

Abstract

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.

Keywords: REM sleep; endocrinology; melatonin; neuropharmacology; pharmacology—sedative-hypnotics; pharmacology—wake promoting agents; psychiatry; sleep deprivation.

Figure 1.

Effects of methysergide (gray bars) and placebo (white bars) on sleep-related GH secretion (left), and on GH secretion during a daytime insulin tolerance test (right). Adapted from reference [8].

Figure 2.

Effects of pentobarbital (PB) 1 µg and 100 µg and vehicle microinjected into the medial preoptic area of rats on sleep latency and total sleep time. The study consisted of 2-h recordings performed after microinjection at 10:00 A.M., under 12:12 h L:D conditions such that lights come on at 8:00 A.M. Adapted from reference [31].

Figure 3.

Effects of oleamide 10 mg/kg and vehicle administered intraperitoneally to mice on sleep latency and total sleep time. The study consisted of 2-h recordings performed after injection at 10:00 A.M., under 12:12 h L:D conditions such that lights come on at 8:00 A.M. Adapted from reference [49].