8.5: Neurochemical signals

Many of the neurotransmitters that the brain uses for signaling are capable of modifying some aspects of sleep. For example:

• Glutamatergic signaling is heightened during the awake state, and many glutamatergic neurons increase their activity during REM sleep.
• Drugs that increase the action of GABA by acting as positive allosteric modulators are used as sedatives and sleep aids.
• Norepinephrine, acting through increasing activity of the sympathetic nervous system, enhances alertness.

Be aware that many neurotransmitters can affect sleep behavior. However, we are only going to describe the function and actions of three sleep-related neurochemicals.

Adenosine

Adenosine is a molecule that has a variety of functions in the body. In addition to being one of the four main building blocks of DNA (the “A” of the A:T G:C base pairing combinations), it acts as a signaling molecule in the body that is involved in inflammation, the immune response, and modulation of heart rate.

It is also used as part of the molecule that stores cellular energy: ATP, or adenosine triphosphate. Each molecule ofATP has phosphate bonds that release tremendous energy when the bonds get hydrolyzed (broken apart). Vesicles, in addition to containing neurotransmitters, have many molecules of ATP. Throughout the day, as the body uses up cellular energy, there is anincrease of adenosine as a result. Therefore, as our energy consumption increases, so do adenosine levels, thus signaling to the brain that we are sleepy.

If you are able to chemically block the action of adenosine, you can stave off sleepiness, increasing alertness and ability to focus. Odds are good that you have used a psychostimulant to block adenosine signaling this morning, or are drinking some right now. Caffeine, for example, is an adenosine receptor antagonist, and is the world’s most popular unregulated psychostimulant drug. Other common adenosine receptor antagonists include theobromine and theophylline, both of which can be found in tea and chocolate. They are chemically very similar to caffeine and adenine, part of the chemical structure of adenosine.

Melatonin

Melatonin is an endogenous hormone that helps the brain regulate the sleep-wake cycle. Melatonin is produced by a single gland in the brain called the pineal gland, so named for its pinecone-like shape. Specialized cells in the pineal gland convert the amino acid tryptophan into melatonin, which is then secreted into the bloodstream. Increased melatonin levels helps to signal the body to prepare for sleep.

The production of melatonin is heavily dependent on exposure to sunlight. While some of the cells in the retina are responsible for passing specific visual information into the brain, other cells (such as the photosensitive retinal ganglion cells) communicate whether or not it is daytime. These cells send their axonal projections separately from the optic nerve that sends most visual information. Rather, they project through a pathway called the retinohypothalamic tract (RHT), synapsing on a clump of cells in the hypothalamus called the suprachiasmatic nucleus (SCN). In turn, these cells of the SCN send inhibitory projections to the pineal gland. In the day time, the SCN tonically inhibits activity of the pineal gland, resulting in low production of melatonin. But when daylight starts to decrease, the RHT sends a weaker excitatory signal onto the SCN, which allows increased pineal gland activity.

Half-life
Exogenous substances that enter the body usually get degraded over time through natural enzymatic processes. The half-life, also written as t1/2, is the time that it takes for the concentration of the substance to be degraded to one half of what it originally was.

The half-life of caffeine is about 5 hours. This implies that if you drink a full cup of coffee at 2 PM and plan on going to bed at midnight, the caffeine in your bloodstream is similar as if you just chugged a quarter of a cup of coffee before trying to sleep.

Light exposure is the main environmental influence that decreases melatonin levels. But, not all wavelengths of light are equally potent at dampening melatonin production. The shorter wavelengths of light, down in the violet-blue range, are much more efficient at activating the RHT compared to longer, yellow-red wavelengths. Increased RHT activation leads to decreased melatonin production, which can delay the onset of sleep. Fluorescent or LED lighting and digital devices, such as computer screens and cell phone screens, use blue wavelengths of light. Therefore, the best advice to optimize your sleep habits is to eliminate exposure to all digital devices about one hour before your intended bed time.

Histamine

Histamine is a small signaling molecule that has a variety of functions. In the body, histamine mediates the sensation of itch, participates in the inflammatory response, and activates the immune system. In the brain, histamine is a neurotransmitter that acts as a pro- wakefulness signal (the opposite of adenosine and melatonin, which both increase drowsiness.) Most people understand the role of histamine in the context of allergies. Seasonal allergy sufferers often take a histamine antagonist (antihistamine) to decrease the severity of allergen exposure. Many antihistamines warn against operating heavy machinery while taking these drugs, since drowsiness is one of the major side effects. Newer generations of antihistamines are more effective at minimizing drowsiness, so they often advertise “non-drowsy” on the packaging.