The Sandman in a Bottle

Abstract

The Types and Functions of Sleep Aids For millions of Americans who lay awake at night unable to fall asleep, sleeping pills offer a quick and easy way to prevent drowsiness and fatigue the next day. As of 2006, according to an article in Forbes, prescription sleeping pills garnered around $2 billion annually in the United States (Wells 2006). In 2005, 43 million prescriptions were written for prescription sleep aids, and sales of these drugs are pro- jected to rise to $5 billion annually by 2010 (Lazarus 2006). A poll conducted by the National Sleep Foundation found that 10% of working Americans use either a prescription or over-the-counter medication to help them fall asleep (NSF 2008). Yet even as the use of sleep aids rises, scientists are still in the process of figuring out the details of how these drugs work. Today, sleep aids, also known as sedative-hypnotics, fall into three main categories. The first category consists of drugs that act at the GABAA receptor. These include the ben- zodiazepines and the barbiturates. The newest additions to this group are the z-drugs such as Ambien® and Lunesta®, so called because their chemical names all begin with z. The second category of drugs is the antihistamine family of drugs. These drugs are the primary sedative ingredients in medicines like Benadryl®, NyQuil® and other over-the- counter sleep aids. Finally, newest category of sleep aids consists of drugs that act as melatonin receptor agonists. Currently, the only such drug approved for use by the FDA is Rozerem®, although others are undergoing clinical trials. The Neural Circuitry of the Sleep-Wake Cycle Like many animals, humans cope with the daily ris- ing and setting of the sun by sleeping at night and being awake during the day. This cycle involves two competing brain pathways-one involving arousal and the other involv- ing sleep promotion. The arousal and sleep promotion path- ways inhibit one another so that when one becomes strongly activated, the other is rapidly inactivated. This circuit has been called a flip-flop switch, named after the similarly func- tioning circuit known to electrical engineers. This mecha- nism accounts for the suddenness of falling asleep and wak- ing up (Saper et al. 2005). The arousal pathway actually consists of two sepa- rate pathways. The first pathway activates the thalamus, the area of the brain responsible for transmitting information to the cortex. The second pathway activates the cortex and involves a number of different brain regions. One area that is The Sandman in a Bottle THE MIND FALL THE MIND by Matthew Koh particularly relevant to the action of sleep aids is the tubero- mammillary nucleus (TM). The TM contains neurons that respond to the neurotransmitter histamine. From the TM, these neurons project to multiple regions of the brain, includ- ing the basal forebrain, hypothalamus, and amygdala. H1 receptors are located on the postsynaptic cells of these pro- In 2005, 43 million prescriptions were writ- ten for prescription sleep aids, and sales of these drugs are projected to rise to $5 bil- lion annually by 2010. jections and promote wakefulness by stimulating these cells (Barbier and Bradbury 2007). The ventrolateral preoptic nucleus (VLPO) is the main area involved in sleep promotion. The cells in this region contain gamma-amino butyric acid (GABA) and galanin, two inhibitory neurotransmitters. The VLPO proj- ects to all of the major wakefulness-promoting areas of the brain and inhibits these regions (Saper et al. 2005). Central control of all circadian rhythms is provided by the suprachiasmatic nucleus (SCN), a brain region locat- ed directly above the optic chiasm. The SCN receives infor- mation from the retina that it uses to coordinate the body's internal clock with the outside world. Cells in the SCN con- tain receptors for melatonin, which is secreted by the pineal gland in response to signals from the SCN itself (Moore 2007). When activated, melatonin receptors inhibit the SCN. Next, the dorsomedial nucleus of the hypothalamus (DMH) receives input from the SCN and sends output to the VLPO and LHA. The connections to the VLPO are inhibitory whereas those to the LHA are excitatory (Chou et al. 2003). So, when the SCN is inhibited by melatonin, the VLPO becomes less inhibited while the LHA becomes more inhib- ited and sleep is induced. These details of the anatomy involved in sleep regu- lation are necessary for an overall picture of the mechanisms of sleep aids. All of the sleep aids that are mentioned below interact with some step in the sleep-wake neural circuitry. GABAA Receptor Drugs