Nearly everyone understands that coffee can help people wake up in the mornings or stay awake during late nights, but far fewer understand exactly how it does this. One key pharmacological effect of caffeine is its competitive inhibition of the adenosine receptor. Adenosine, a dephosphorylated form of ATP, signals the shortage of energy in the brain and promotes sleeping. Adenosine is created over the course of the day, as a natural byproduct of using up our internal energy stores (it forms the core of adenosine triphosphate (ATP), the energy-storage molecule that powers most of the biochemical reactions inside cells). As a result, its accumulation means that the brain has used much of its available energy, meaning that sleep is necessary to restore energy .
With prolonged wakefulness, increasing levels of adenosine are evident in the brain, initially in the basal forebrain (figure I) and then throughout the cortex. The increased levels of adenosine serve the purpose of slowing down cellular activity and diminishing arousal. Adenosine levels then decrease during sleep. As a result of this regular oscillation, adenosine concentration is linked to the circadian rhythm. Thus, by acting as an adenosine antagonist, caffeine prevents the processing of sleep-inducing signals to promote wakefulness .
Figure I: Localization of basal forebrain in the brain
Almost everything we consume, from the late-night hot chocolate to that apple a day, contains sugar. This might sound daunting, but there is a good reason. Sugar is a general term used to describe carbohydrates, and glucose, a form of carbohydrate, is the primary energy source for our bodies, including the brain. In fact, even though the brain takes up only 2% of our body mass, it uses up more than 20% of our energy intake . The brain depends on glucose to produce ATP, which is responsible for fueling a wide range of processes including the maintenance of sodium and potassium ion gradients by the Na+/K+ ATPase.
While other body tissues can shift to amino acids or fatty acids to produce energy, the brain has a strict dependence on glucose because neurons are not capable of storage and therefore must rely on the constant supply from the bloodstream. The transportation of glucose from the bloodstream is dependent on the blood-brain barrier (BBB) , a layer of endothelial cells separating blood vessels from the brain. Glucose transporters are embedded in both the inner surface of the layer, the luminal side, and the outer surface, the abluminal side. There are also auxiliary transporters floating inside the endothelial cells between the two membranes. The BBB can sense blood glucose levels and induce the creation of more glucose transporters or their migration from one membrane to another in response to low levels, and therefore is responsible for the regulation of glucose entering the brain.
Several neurotransmitters are also linked to glucose consumption . For example, levels of serotonin rise in response to the presence of carbohydrates. This is because the neurotransmitter is derived from the amino acid tryptophan, whose levels vary depending on carbohydrate levels in the diet. Since serotonin secretion is also involved in functions such as mood regulation, blood pressure regulation, and sleep onset, there is a strong link between “sugar” and “mood.” Sugar also activates the reward system, or the mesolimbic pathway, from the ventral tegmental area to the nucleus accumbens (NAc). The NAc receives inputs from the amygdala, the prefrontal cortex, and the hippocampus, and serves as an interface of emotion, motivation, and action. Consumption of substances with high sugar content activates the mesolimbic pathway and dopaminergic transmission in the NAc, creating rewarding effects. Moreover, while the constant consumption of one type of substance will usually level out the activation of dopaminergic systems, sugar is one of the few substances that does not have this effect, which means its “rewarding effect” does not fade away with continued intake. Another popular belief about sugar and the brain is that sugar causes hyperactivity. While no studies have found significant results on this correlation, sucrose (disaccharide) and aspartame (artificial sweetener) have been shown to at least influence behavior. One’s blood sugar levels rise rapidly immediately after consumption, which induces increased production of insulin and reduces the levels of certain amino acids in the bloodstream such as tyrosine and phenylalanine, precursors of epinephrine and dopamine. Low levels of these neurotransmitters are linked to symptoms of attention deficit hyperactivity disorder (ADHD) .
Figure 2: Mesolimbic pathway and its associated brain regions
Sugar is indispensable for the brain’s normal functions, as the disruption of regular glucose metabolism can lead to severe conditions. For instance, only a brief period of glucose deprivation, a condition known as hypoglycemia, starves neurons and may result in dizziness, double vision, tremors, and excessive sweating. If these symptoms are prolonged, they may be followed by delirium, convulsions, and loss of consciousness.
After a thanksgiving dinner, many people may begin to feel drowsy and decide to go to sleep early. This is often attributed to tryptophan; however, the idea that turkey induces sleep is actually no more than a myth. Turkey contains the same amount of tryptophan per unit of mass as chicken, and other sources of protein (even cheese) have more tryptophan per unit of mass. However, eating a large meal (as is customary on Thanksgiving) causes increased blood flow to the digestive system. This increase in blood flow to the digestive tract decreases blood-flow to the brain, causing sleepiness .
Because of its widespread use, the drug Aspirin has become almost synonymous with any painkiller. But how exactly does this work? Aspirin, which has the active ingredient acetylsalicylic acid, is a Non-Steroidal Anti-Inflammatory Drug, which, as its name suggests, means that it is not a steroid (this use of the word steroid should not be confused with anabolic steroids that athletes may illegally use - formally a steroid is a compound that is related to cholesterol, like testosterone). In order to exert its painkilling effects, acetylsalicylic acid binds to a key amino acid of cyclooxygenase, an enzyme that produces prostaglandins. Because prostaglandins play a key role in producing inflammation and pain, inhibiting their production is an effective means to prevent pain .
One interesting property of cyclooxygenase (COX) is that it has two isoforms - in other words, the mRNAs that encodes the enzyme can be processed two different ways to produce two similar (but still distinct) proteins. COX2 is the isoform that plays a key role in the inflammatory response, but acetylsalicylic acid can also interact with COX1 because of its similar properties. However, COX1 does not contribute to the inflammatory response - it actually is a component of platelets. For this reason, Aspirin can also be used to prevent arterial thrombosis, a potentially deadly heart condition in which blood clots block an artery .
No matter how cold a jalapeño pepper might feel, the minute we put one in our mouths and take a bite we are are overcome with an intense burning sensation. This experience can be explained when one considers a natural chemical contained in that jalapeño: capsaicin. Capsaicin is a compound found in many peppers that inflicts this sensation through indirect stimulation of our heat and pain receptors. It acts as an agonist on our TRPV1 channels to lower the threshold that the temperature needs to be to create the sensation of heat. Instead of the normal average threshold of 43 degrees Celsius, capsaicin shifts this to around room temperature. As a result, the capsaicin can often cause a painful and hot sensation in our mouths when we consume peppers or pepper derivatives, stimulating receptors that previously would have required intense heat or acidity to signal and produce the sensation of such burning. In addition to causing this painful sensation, capsaicin consumption can lead to decreased sensitivity and nociceptor function as well as decreased mitochondrial respiration for long periods of time after exposure. This increased exposure results in a temporary desensitizing effect on the receptors that it acts on . Another interesting consequence of capsaicin is a temporarily increased metabolic rate. This comes as a result of an increase in the secretion of adrenaline due to the TRPV1 channels that capsaicin agonizes in the adrenal glands. Despite this temporary increase, Galgani et al. (2010) found there was no noticeable impact on metabolic rate when measured 2 hours after exposure suggesting that its effects are very minimal when it comes to metabolic rate and the secretion of adrenaline from TRPV1 receptors in the adrenal glands .
The amount of heat we feel when consuming chile peppers is directly correlated to the concentration of capsaicin in that pepper. This is measured in Scoville heat units. Scoville heat units, of which a jalapeño pepper has 10,000 and pure capsaicin, 16,000,000, are representative of the dilution in alcohol that would be required to remove the effect capsaicin has on TRPV1 channels. There are other compounds that are hotter than pure capsaicin, like resiniferatoxin, which has 16,000,000,000 heat units and can cause chemical burns if in contact with human skin .
Despite the intense burning and pain it can inflict on some, the irony of capsaicin is that it is known pharmacologically to have analgesic effects and is used to quell sensory peripheral nerve pain. In this context, though, it is topically applied. The benefit of its application is that it is a safer and more effective alternate to the typical treatment which uses opioids to treat neuropathic pain leading often to more side effects and the risk of addiction. But as well as these analgesic properties for peripheral nerve pain, there has been some studies that have implicated capsaicin in aiding and controlling cancer induced mucositis, which is an inflammation in the digestive tract . Overall, the wide array of effects of capsaicin and its prevalence in nature makes it useful in both basic and clinical contexts.
Jacob Umans is an aspiring physician-scientist in the Stanford University Class of 2020. As a cofounder of the IYNA, he is passionate about science education and hopes to share his excitement about all subfields of neuroscience -- especially glial biology and neuroimmunity -- with students around the world. He hopes to go on to earn an MD/Ph.D. after graduating from Stanford and to use his clinical experience develop a research focused on developing a better understanding of and improved therapies for neurodegenerative diseases. Outside of neuroscience, Jacob is an avid fan of puns, table tennis, and reading.
This author has not yet uploaded a bio.
This author has not yet uploaded a bio.
This author has not yet uploaded a bio.