Overloaded: How Every Aspect of Your Life is Influenced by Your Brain Chemicals

by Ginny Smith

In the 1930s, following in the footsteps of his mentor Oskar Heinroth, Lorenz began working on greylag geese, and a phenomenon he later called ‘imprinting’. When chicks hatch, many species need to rapidly learn to follow their mother, wherever she leads, to avoid getting lost. Heinroth noticed that the goslings of greylag geese would, if the conditions were right, begin following a human, rather than their mother. So his student Lorenz set about finding out how this happens. Through various experiments, Lorenz discovered that the goslings are born ready to form an attachment to the first large, conspicuous moving object they see. In the wild, this would be the mother, but in the lab the birds would imprint on models of other species, a ball, or even (most famously) Lorenz himself.

Take cocaine, for example.4 Normally, when dopamine is released into a synapse, it diffuses across to bind with receptors on the second neuron, changing how likely it is to send a signal. Meanwhile, any excess dopamine in the synapse is sucked back up by the first neuron, where it is recycled. This process is known as reuptake and is controlled by dopamine transporters in the membrane of the first neuron, which you can think of as the vacuum cleaners of the synapse. When someone takes cocaine, the drug enters the brain and blocks the dopamine transporters. This means that when dopamine is released into the synapse, it hangs around for longer, and at higher levels, than it normally would.

Because of this experiment, and the many that followed it, Schultz believed he had discovered a different role for dopamine, not reward as such, but prediction error. In every moment of our day we are predicting what will happen next, based on our past experiences. We aren’t experiencing the world as it really is, but based on those expectations. Dopamine’s role is to let us know when something is better than we expected, because unexpectedly good outcomes are worth remembering, to ensure we repeat them in the future.

One of the classes of drugs that causes the biggest dependence reaction, most rapidly, is opioids. When someone takes heroin or a related drug, the amount of opioids in their system is much higher than would ever happen naturally. The brain isn’t used to these huge doses of these chemicals, so it begins to fight back. The neurons that respond to opioids begin to become less sensitive, to counter their effects. This is known as tolerance, and means the brain can function more ‘normally’ when the drug is in the person’s system, but it also has two knock-on effects. First, it means that larger and larger doses are needed to produce the same feelings of pleasure. Second, it means that when the drug hasn’t been consumed, natural rewards (which cause a small amount of opioids to be released) are likely to have very little effect at all.

As well as activating these opioid receptors, heroin and related drugs have other effects. They cause the release of huge amounts of dopamine from the ventral tegmental area, and they suppress the release of noradrenaline in an area called the locus coeruleus. Noradrenaline is a hormone involved in the body’s fight-or-flight reflex, speeding up our heart rate and breathing to prepare us to tackle a threat (see Chapter 4). It also functions as a neurotransmitter in the brain. Here it helps us feel alert and focuses our attention, but can also produce feelings of anxiety. Suppressing this chemical leads to some of the symptoms of opioid intoxication, such as drowsiness, relaxation and slowed breathing.

Then, Rapport developed a multi-step process which, eventually, allowed him to isolate this vasoconstricting substance as pale yellow crystals – just a few milligrams from 900 litres of serum. In 1948, they published their findings, calling these precious crystals ‘serotonin’. A year later, now at Columbia University, Rapport identified the chemical structure of serotonin as 5-hydroxytryptamine, or 5-HT.

Around the same time, it was found that a tuberculosis drug also affected patients’ moods. Treated individuals regained their appetites, felt happier and less apathetic and even, sometimes, experienced euphoria. Of course, if you had a horrible illness and suddenly started feeling better, it wouldn’t be surprising if your mood improved too. But other side effects like drowsiness and a dry mouth suggested the drug might be having an impact on the nervous system. So the drug was tested in psychiatric patients, and soon evidence started to emerge that iproniazid (as it was called) might be effective in treating depression.

Just like reserpine, iproniazid had side effects that meant its popularity quickly declined, but its mechanism of action was a vital ingredient in the understanding of depression. In 1952, scientists found that the drug blocked an enzyme which usually breaks down the monoamines (a class of neurotransmitters including dopamine, noradrenaline, adrenaline and serotonin, amongst others), increasing levels of these chemicals in the neuron, ready for release into the synapse.

Pharmaceutical company Eli Lilly began to search for ways to boost serotonin in the brain without affecting other neurotransmitters. In 1974, they were successful, publishing a report on their first selective serotonin reuptake inhibitor (SSRI): fluoxetine. By 1988, fluoxetine had been approved by the FDA and released under the trade name Prozac®.

The mechanism of SSRIs sounds, on the surface at least, relatively simple. Just like cocaine does for dopamine (see Chapter 3), SSRIs block the serotonin transporter. This prevents excess serotonin being sucked back up into the neuron that released it, meaning it hangs around in the synapse a lot longer after it is released. This, in theory at least, produces an antidepressant effect.

this world, you wake up at dawn. Soon, the sun is high in the sky, producing lots of light. This light signals the SCN and we feel awake. In the evening, the light gets dimmer as the sun sinks down towards the horizon. This, along with the time that has passed since you first saw the bright light, signals the SCN to release a hormone called melatonin, making you feel sleepy. But there is another element to this process: the colour of the light. Morning light has a large blue component,3 and blue light, with its short wavelength, is particularly good at resetting the circadian rhythm by delaying the release of melatonin.

It seems pretty obvious that the longer you have been awake, the sleepier you feel. This is known as ‘sleep pressure’ and is driven by a chemical called adenosine. This tiny molecule is a by-product of the metabolic processes our cells undergo all the time when we are awake, so it builds up throughout the day. The more of it there is sloshing around in an area of the brain called the basal forebrain, the higher our ‘sleep pressure’ and the more likely we are to drop off.

It is the adenosine system that so many of us trick with our daily dose of caffeine. When adenosine levels are low, acetylcholine is released in the basal forebrain. As we saw in Chapter 2, acetylcholine guides our attention towards external stimuli, making us feel awake and alert. Adenosine prevents the release of acetylcholine, so we feel sleepy. But caffeine blocks the receptors that are normally triggered by adenosine, making it seem to our brains that the concentration is lower than it actually is. This, in turn, means more acetylcholine is released, activating neurons in the cortex and making us feel more alert.10

The fact that it isn’t precisely 24 hours is actually where the term circadian came from – it’s a combination of the Latin words circa (approximately) and diem (day).

Ghrelin is the only ‘hunger hormone’ we have found so far, but it has a dramatic effect. If people are given extra ghrelin, they will eat around 30 per cent more.

The hypothalamus is probably the most important brain region for controlling our appetite, and it is well positioned to be an ‘eating centre’. It has connections with various other brain areas, and with the pituitary gland, meaning it can control the release of hormones. Unusually for a brain region, part of the hypothalamus is outside the blood–brain barrier, meaning it has access to your main blood supply, and can detect the levels of circulating glucose, for example. It also monitors the workings of your immune system.

Now scientists had discovered the missing satiety signal, the idea of the hypothalamus as a regulator of body weight gained momentum. This discovery provided weight3 to the set-point theory. The hypothalamus helps animals to maintain a steady weight by detecting leptin, which tells it how much energy we have stored in fat reserves.

A quick caveat here: BMI (body mass index) is commonly used to calculate whether someone is a healthy weight. Unfortunately, it is a poor measure of health, because it uses only height and weight to make the assessment. As muscle weighs more than fat, very muscular people can come out as obese. Measuring body fat percentage would be better, but even this isn’t perfect as where your fat is stored is important. Visceral fat, which is stored around your organs, is much worse for your health, so people who store fat on their thighs or buttocks are at lower risk for diseases like diabetes and heart disease than those who store it around their middles. In fact, someone may be a normal weight and appear slim, but still have unhealthy levels of visceral fat.

There is currently only one really effective treatment for obesity: bariatric (or weight loss) surgery. This can take a number of forms, but all aim to reduce the capacity of the stomach, so people feel full more quickly. This can be done by placing a silicone band around the stomach to squeeze it closed at the top (gastric band); putting a balloon inside to take up space; or cutting away part of the stomach (gastric bypass or gastric sleeve). After surgery, patients will feel full when eating very small amounts of food, restricting their intake and causing weight loss. But this isn’t the full story. People and rats who have had the surgery could just eat more often to overcome their smaller stomach – but they don’t. This seems to be because rearranging the digestive tracts changes the release of hormones. After surgery, there is an increase in satiating chemicals like peptide YY, which activate the ‘don’t eat’ network in the hypothalamus, and a decrease in the hunger hormone ghrelin. These changes work together to help people feel full and therefore eat less. Studies have also found that gastric bypass increases the calories burned by rats, meaning they need 40 per cent more food than control animals to maintain the same body weight. We don’t yet understand how this happens, but again, it might be linked to those neurons in the hypothalamus. The surgery seems to reset the set point of the animal, so its body then does everything it can to reach and maintain its new, lower...

There is certainly evidence, though, that our brains respond in a different way to foods containing a mix of fat and sugar than to either nutrient alone.

Tasty food is highly rewarding, and we saw in Chapter 3 that over time, dopamine release can be transferred to anything that predicts a reward. In the real world, this means the logo of your favourite restaurant, or the smell of freshly baked cookies. Experiencing these cues could drive you to seek the food as a habit, overriding any notion of whether you ‘need’ the food (how hungry you are) or whether you ‘like’ it.

Here is another gambling game: I have a fair coin, and I’m going to flip it. To start with, I’ll put £2 in the pot, but every time I flip a head, the amount in the pot doubles. The first time I flip tails, the game is over, and you get whatever is in the pot. So if I flipped tails the first time, you would get £2. If it’s the second flip, it would be £4, and so on. How much would you pay to play that game? This is called the St Petersburg Paradox and it was initially devised by mathematician Daniel Bernoulli in the eighteenth century. If you work out the expected value, it is infinite.2 But people won’t pay an infinite amount to play. In fact, they won’t pay much at all, which is why it was called a paradox – the theory just didn’t match up with real life.

Another idea is that we ignore the fact that the payoff is supposedly infinite, because we know that no one has infinite money. If we work out the expected value of playing this game against Bill Gates, where the maximum we could win is his 2020 wealth of $111.8 billion, the expected value is around $37 – no wonder people won’t pay much to play.

Many of the areas in the brain network vital for decision-making are found in our frontal lobe. As we have seen in previous chapters, this area is known for controlling our most ‘high-level’ functions, such as reasoning, planning and cognitive control. So it isn’t surprising it is important for making decisions. Damasio and his colleagues were interested in the ventromedial prefrontal cortex because of the difficulties faced by people with damage here, particularly a patient known as EVR. By the time he was 35, EVR was married with two children and had worked his way up to be responsible for all the accounting operations of a home-building firm. He was active in the church and his four younger siblings said he was someone they had always looked up to. But then things began to change. He had problems with his vision, and he began to act differently. It turned out EVR had a brain tumour in both of his frontal lobes, so surgery was scheduled to remove it. After the operation, he seemed to recover well, and was discharged from hospital two weeks later. When it came to follow-up appointments, however, it was clear that all was not well.

These messages were travelling down A-delta fibres, which are large, and coated in insulating myelin, meaning their signals travel rapidly. They detect mechanical damage over a certain threshold (and possibly heat damage as well in some cases) and the pain they produce is described as sharp, stinging or pricking. It is also easy to localise. You know almost immediately exactly where that drawing pin you stepped on has embedded itself in your foot! But as she sat there, with the cuff blocking the blood flow, her arm began to go numb. The large A-delta fibres, which need a lot of energy, were some of the first to stop working. The next time we pricked her, she didn’t respond right away.

And she wasn’t sure exactly where on her hand it was coming from. This was because she was no longer receiving signals from her A-delta fibres; instead, the sensation was coming from another type of nerve, known as C-fibres. These are smaller, and unmyelinated, so transmit their pain signals more slowly, and the pain they produce is duller, more of an ache or a burn, and harder to localise. These fibres, being smaller, don’t use as much energy, so can survive longer without blood flow. C-fibres have endings that respond to a range of different potentially dangerous stimuli. Some respond to mechanical injury, like cutting your finger or stubbing your toe.

It is here that some of the over-the-counter painkillers you can buy work their magic. Aspirin and related compounds, for example, block the production of prostaglandins, reducing this sensitisation. This is why these painkillers are also effective at reducing inflammation. However, they only work on this secondary mechanism, and do nothing to block the pain signals caused by the initial injury, so they don’t inhibit pain entirely.

Around the beginning of the 1900s, a theory emerged that all drugs must have a corresponding receptor. By binding to these specialised sites on cells, and either activating or blocking them, they could directly change the function of the cells, or influence how our body’s natural chemicals affect them. It took until the 1960s, however, when the first drugs were developed to block receptors (beta-blockers, which affect one of the adrenaline receptors), for this theory to be accepted by the mainstream scientific community. Excitement began to grow for the idea that all sorts of drugs might have their own receptors.

But just in case the signal does make it up the second neuron to the brain, opioids have another role to play. As well as the ascending pathway, which takes pain information to the brain, there is another pathway, going in the opposite direction, which interacts with it. Opioids act on a region of the brain called the periaqueductal gray (PAG), to activate this descending pathway. Once activated, the descending pathway releases chemicals including GABA, serotonin, noradrenaline and more opioids into the synapse between the sensory neurons and the neuron that would carry the signal up the spinal cord.

Imagine your pain signals as tiny ambulances, travelling along the road which is your ascending pain pathway, and your descending pain control pathway as a river, held back by a sluice gate. When released, the river will flow down the hill and flood the road, stopping any traffic from getting through. Close the sluice gate again, and the water will dissipate, allowing the ambulances to resume their journey. So opioids, by releasing the river of descending pain control, can have huge knock-on effects.