Ever Wondered How Alcohol Affects the Nervous System?

Not only in the UK, but all around the world, alcohol is enjoyed by many - drinking is indeed a popular pastime. However, when individuals over-indulge, it can lead to serious health problems including addition even though this is not very common. Nevertheless, in the UK, the NHS estimates that '9% of men and 4% of women show signs of alcohol dependence' (Source: DrinkAware). Over the decades, interest has increased around the effects of alcohol, not only on the physical but also on the mental state. In medicine, researchers will endeavour to find a physiological mechanism to a unexplained mental or behavioural phenomenon. A perfect example of this is the effect of various drugs, illegal and legal, on human behaviour. Quite a few of these substances cause imbalances in the amount of neurotransmitter released from pre-synaptic vesicles into the synaptic cleft in particular areas of the brain. In turn, the frequency of electrical impulses transmitted can fluctuate which can ultimately influence behaviour. To understand this better, it is beneficial to look back in history when the basic physiology and chemistry were uncovered.

Above: Scanning electron micrograph of neurotransmitter-containing vesicles (orange and blue) being released from a pre-synaptic neuron (Source: AnatomyBox)

Pre-1930s, there were noticeable disagreements between academics on how exactly neurons communicate their signals to one another. Was it electrical or was it chemical? It wasn't until 1936, when Sir Henry Dale and Otto Loewi received the Nobel Prize in Physiology or Medicine, that it became clear that these signals were indeed due to chemical transmission. This is possible through the action of neurotransmitters - chemicals which are released into the space between neuron, the synaptic cleft. Some scientists prior to this award did suggest that chemicals were involved, through observing the similarities in nerve stimulation in plants and animals (Source: NobelPrize.org) Loewi managed to illustrate the importance of these chemicals in an elegant way using experiments on frogs. His papers were published in 1921 - these showed that nerve impulses affected the heart using chemical transmission. Firstly, Loewi stimulated the vagus nerve fibres of an isolated frog's heart that had been connected on the other side to a ringer solution. Soon after this, he observed that the strength and frequency of the heartbeat decreased. The fluid remaining was used to surround another frog heart - the vagus nerves were not electrically stimulated. This time, the heart changed it's activity as if it had been electrically stimulated (Source: AnimalResearch.info) It seemed that the fluid has caused this change. Dale's discovery of the action of acteylcholine was inline with Loewi's results and so after subsequent years of research, Dale and Loewi were awarded the Nobel Prize in Physiology or Medicine. 

Chemical transmission is an important concept to understand when we consider how an impulse is able to transmit from neuron to neuron in the brain. It can be understood as a cascade of events beginning with the arrival of an action potential at the axon terminal of the pre-synaptic neuron. The depolarisation stimulates calcium ion channels to open, causing an influx of Ca²⁺ into the axon. This in turn stimulates vesicles filled with neurotransmitter to migrate to the end of the axon. The vesicles are then able to fuse with the lipid bi-layer membrane to release the neurotransmitter (e.g. acetylcholine) into the synaptic cleft. When these neurotransmitters bind to ligand-gated sodium channels on the post-synaptic neuron, this triggers another action potential to fire. To prevent constant firing of action potentials, a neurotransmitter such as acetylcholine is broken down by an enzyme (in this case, acetylcholinesterase), and the inactive products are reabsorbed by the pre-synaptic neuron through re-uptake transporters. These events will become important when we look at the effect of alcohol on the nervous system.

Above: Schematic diagram showing the transmission of an action potential  (Source: Biological Sciences Review Volume 26, Number 2).

Now, alcohol is one of the few substances than can cross what is referred to in anatomy as the blood-brain barrier (BBB). This is largely a fatty barrier than surrounds the blood vessels in the brain. In medical research, this barrier has been notoriously difficult to overcome when delivering drugs or attempting to treat an array of brain-related diseases, for example Alzheimer's. Until very recently, this has caused problems, however scientists have now found a way of delivering cancer-fighting drugs to targets by breaching the blood-brain barrier. A research team in Canada used 'tiny gas-filled bubbles, injected into the bloodstream of a patient, to punch temporary holes in the blood-brain barrier'. Following this, ultrasound was used to make the bubbles 'vibrate and push their way through, along with chemotherapy drugs' (Source: BBC) This has been a significant breakthrough - I encourage you to read more on the subject here.

The reason that alcohol is able to cross this barrier is that it is lipid soluble. Once alcohol crosses the barrier, it is able to affect the action of neurotransmitters. Before looking at how alcohol comes into play, it is useful to consider the different types of neurotransmitter that exist in the nervous system, and their different modes of action.

Neurotransmitters can either be excitatory (increases the likelihood of an action potential being fired on the post-synaptic neuron) or inhibitory (decreases the likelihood). Examples of excitatory neurotransmitters are glutamate, dopamine and acetylcholine. Glutamate is the most common kind of neurotransmitter in the brain and is thought to be involved in memory and learning. The well-known neurotransmitter dopamine is involved in the mechanisms of motivation and reward. It follows that many addictive drugs utilise the 'feel good' sensation that dopamine causes. And finally, acetylcholine is most commonly used in the contraction of involuntary muscle - it can be released at the site of a neuromuscular junction. A good example of an inhibitory neurotransmitter is gamma-amino butyric acid (GABA) - it's action is known to reduce stress. In fact, about a third of all brain synapses use GABA, and anti-anxiety drugs such as Valium enhance it's action. Another example of an inhibitory neurotransmitter is the amino acid glycine, however this is used mainly in the spinal cord, and is involved in about half of all synapses there, the rest using GABA. (Source: Principles of Anatomy and Physiology 13th edition - G.J. Tortora and B. Derrickson)

Above: The structure of common neurotransmitters (Source: CompoundChem). See source link for larger image.

Alcohol is widely known as a depressant drug. It is able to decrease excitatory action, and increase inhibitory action. Here, we can look at how alcohol affects the release of GABA. Ethanol increases the amount of GABA neurotransmitter released from pre-synaptic neuron in the brain, by increasing the likelihood that GABA containing vesicles fuse with the bi-layer membrane. To further induce an effect, ethanol encourages GABA to bind more easily to it's corresponding ligand-gated ion channels on the post-synaptic neuron. Subsequently, chloride ions flood into post-synaptic neuron cytoplasm, decreasing the chance that an action potential will fire. In parallel with this effect on GABA transmission, alcohol also affects the action of the excitatory neurotransmitter, glutamate. Ethanol decreases glutamate's excitatory activity, and this effect is quite dramatic considering that glutamate is used in 90% of synapses! (Source: Biological Sciences Review Volume 26, Number 2) The binding of glutamate to it's receptors on the post-synaptic neuron is blocked, thus an action potential cannot be triggered. Since glutamate is used in routes in the brain associated with learning and memory, it is common that people will suffer memory loss after a booze-fuelled night.

The imbalances between inhibitory and excitatory activity do explain the drowsiness, slow reactions and sometimes poor memory people have when drinking a significant amount of alcohol. However one observation we may have forgotten is that to many, drinking alcohol can make them feel good. From research, we know that the reward centre and the pathways associated with it are located in an area of the brain called the striatum. So far, there has been no clear link between alcohol and an effect on the action of the neurotransmitter dopamine. Recall that dopamine is involved in motivation and reward. Where is the link? Well, it is thought that the reward feedback system is usually 'kept in check by GABA inhibition. When this inhibition is suppressed, the reward system becomes more active'. Remember that alcohol does cause suppression of GABA inhibition as it encourages more GABA to bind to the post-synpatic neuron!

Above: Schematic of the brain showing the location of the striatum (yellow-orange region) (Source: Biological Sciences Review Volume 26, Number 2)

To conclude, we can see that in order to understand how alcohol can affect the nervous system, it is important to appreciate the biological cascade of events that occur during chemical transmission at the synapse. Although alcohol can be enjoyed in moderation, the public must be aware of the potential health complications associated, including liver disease, weight gain and sleep disruption. The incidence of liver disease particularly, is rising in the UK. Bear in mind that this disease not only affect adults, but also the young as well. Let us not forget also of the societal problems that can arise due to alcohol abuse, which include antisocial behaviour and violence in extreme cases.

Even today, alcohol still presents unsolved mysteries to researchers. However with continuous advances in technology, medicine, and neuroscience, how the brain is affected by substances is becoming clearer and clearer.


Additional credit: Oliver Freeman is a writer for the Biological Sciences Review and is also studying for a PhD in neuroscience.
 - Michelle Roberts, for her article published on the BBC website, 'Scientists breach brain barrier to treat sick patient'. Read more on the subject here.

Revolutionary Platinum-based Chemistry: A New Hopeful for Cancer Therapy

As many would agree, one of the most well-known treatments that cancer patients undergo is chemotherapy. Today, it is not unusual for platinum compounds to be used in chemotherapy - cisplatin is a notable example.

Above: False-colour electron micrograph of cancer cells (Source: Wellcome Collection)

In medicine, particularly pharmacology, the shape of molecules are extremely important. In cisplatin, the oxidation state of platinum is +2 and the molecule is said to be square planar. This means that all of the atoms lie in the same plane, forming a square if you were to join up the atoms with imaginary lines. Each of the groups, Cl^- (Chloride - with an oxidation state of -1) and NH₃ are called ligands, and because each of the different groups are on the same side of the molecule, the platinum compound is said to have a cis structure. In the body, cisplatin's basic chemistry works as follows:

Since, in the bloodstream there is a high concentration of chloride ions, none of the ligands on the molecule are substituted (NH₃ groups are more resistant to this substitution). However, once inside the cell the environment is very different. In fact, there is a much lower concentration of chloride ions, and the chloride ligands are replaced by water molecules. Now the cisplatin compound is activated. This is a perfect illustration of Le Chatelier's principle:

"If a dynamic equilibrium is disturbed by changing the conditions, the position of equilibrium moves to counteract the change"

(Source: Chemguide)

Above: Displayed formula of cisplatin

Although cisplatin  has proved effective, over the years, several similar drugs such as carboplatin have been produced to maximise efficiency and potency. The drug works by disrupting cell replication, thus leading to cell apoptosis (death). The mechanism for this relies on the substitution of those chloride ligands for water molecules once inside the (cancer) cell. From this point, nitrogen atoms from the nucleotides forming DNA substitute the water molecules. Water molecules tend to be easily replaced. In this situation, cisplatin  is effectively bound to the DNA, causing the nucleotide chain to bend due to formation of a 'kink'. In DNA replication, the shape of DNA is very important and many checks are made by feedback mechanisms to make sure the cell has proceed to divide by mitosis. Once cisplatin is bound, mitosis can no longer take place - cell death results.

However, current research into the field of photoactive compounds has proved promising - the research could be a step to producing cancer drugs that can be activated at the tumour site using lasar technology. Firstly, let us consider the properties of platinum. It has a silverly coloured surface (without tarnish) and is used in catalysis - catalytic converters in road vehicles is an example. So why does this metal prove useful in the body? Platinum is considered a relatively safe, it is said to be biologically compatible due to it's inability to react with body tissue. However, in medicine, what we are more concerned about is whether we can use platinum compounds. In fact, these compounds are used but scientists are aware of the toxicity of such substances. Platinum ions that are bonded to several ligands help to channel potential toxicity in a useful way, often to produce life-saving drugs.

The challenge now is to produce treatments that are even more localised to the cancer cells. This is inevitably the subject of research in universities and pharmaceutical corporations across the globe. Existing cancer drugs work well simply because cancer cells are subject to more damage than normal body cells - cancer cells proliferate at a faster rate. Note however that normal body cells can still become affected. As many may have experienced, the side effects of chemotherapy can be quite extensive, nausea and kidney damage to name a couple. The human body is simply trying to reject the foreign substance introduced, and this is what drives scientists to look for new solutions. 

The key fact to know is that whilst cisplatin and other similar drugs are not tumour specific, how they are activated can be controlled. Platinum, like many other transition metals, have multiple oxidation states. Platinum(IV), Pt⁴⁺ complexes 'have been proven to be inactive and non-toxic inside cells, but only in the dark' (Source; Chemistry Review Volume 24, Number 4). One reason for this is to do with the shape of these platinum(IV) complexes. With an oxidation state of +4, platinum is able to form 6 bonds to ligands in an octahedral arrangement. Remember than a platinum(II) compound can only form 4 bonds with ligands in a square planar structure. This higher oxidation state enables the molecule to be less reactive and therefore ligands tend to be become replaced. This is very relevant, recall that cisplatin has it's chloride ion ligands replaced by water molecules once inside the cell. However, it is important to remember that the reduced reactivity in the case of platinum(IV) compounds is true in the dark. These compounds can be photo-activated - light enables the configuration of the molecule to change. This process is irreversible:

Above: The photo-activation of a platinum complex - X and Y denote alternative ligands (Source: Chemistry Review Volume 24, Number 4)

This reaction is able to occur to due to the phenomenon of electron transition. An election which absorbs light energy is able to be promoted to a higher energy state, and therefore a higher energy orbital with an atom. In transition metal chemistry, it is common knowledge that when ligands bond to the central metal ion, this causes the d-orbitals of the metal ion to split. The orbitals are split into two levels, one with a higher energy level than the other. The very fact that these complexes can absorb light energy means that transition metal complexes are often colourful. During the above reaction, electrons in the central metal ion 'jump' to a higher energy level. Any remaining light that is not absorbed is reflected back. These electron transitions can cause multiple changes, such as a change in oxidation state of the central ion, or substitution of ligands. Controlling this activation could indeed be a useful tool in cancer therapy, it could potentially have wider applications in medicine. After activation, the cisplatin-like compound can then perform it's anti-cancer wonders. 

Above: Diagram showing that the energy of a particular wavelength of light is equal to the energy required to promote an election to a higher energy level (Source: Chemguide)

Using these platinum compounds does leave room for flexibility. For example, scientists would be able to change the ligands to vary the amount of light energy absorbed (to cause d-orbitals to split). However, getting this energy quota just right is a challenge, and is still the subject of research. 

So what are the applications in cancer treatment? Any treatments should be as safe as possible, so it is important what type of light should be used to activate the platinum complexes inside the body. Now, most complexes tend to be activated by blue or even UV light, however these frequencies of light do not penetrate tissue as well as red light does. Bear in mind that UV can damage tissue - red light seems a relatively safe option. A compromise must be made as red light would mean that it is less likely that a complex would be activated. Nonetheless, 'some promising Pt⁴⁺ complexes have been made, which are non-toxic in the dark but once activated have a high toxicity towards cancer cells'. After all, it is completely dark inside the body, therefore a laser would need to be used to activate the chosen drug. A laser would be a suitable choice due to it's precision - it would be much less likely that a healthy body cell would be affected (Source: Chemistry Review Volume 24, Number 4). 

As with any new treatment, this new concept would need to be subject to vigorous testing through a series of clinical trials. Safety and effectiveness are two crucial criteria that will need to be evaluated during the course of these trials in future. 

Additional credit: Louise Tear who wrote an article in the Chemistry Review, which was inspired by an undergraduate research project completed under the guidance of Professor Peter Sadler.

Further credit: Professor Sadler who wrote a short piece for theInformationDaily.com, 'Using precious metals to fight cancer', following research at The University of Warwick. 

Further reading: BBC, 'Chemists create new way to fight drug resistant cancer'.

Macmillan Cancer Support - 'Cisplatin - Cancer Information'

Has This Been Humanity's Deadliest Threat to Date?

Over the course of centuries, humans have witnessed the wrath of many deadly endemic, epidemic and pandemic diseases. Some notable examples include the uprising of small pox and the Bubonic plague. The number of deaths worldwide that have resulted are alarming. However, what is more profound is how fast the pathogens of these diseases spread in a population. In later years, the impact of these epidemics often become the subject of academic study in Medicine, in particular, epidemiology. In addition to these giants of infectious disease, there is another worth mentioning, which could be debated as 'the greatest medical holocaust in history' - the Spanish Flu of 1918.

Above: A Spanish flu ward at Fort Riley, Kansas, in 1918. (Source: The Guardian)

Caused by the H1N1 Influenza virus, the Spanish Flu was capable of rapid transmission, which resulted in it's success - 500 million people infected worldwide (one fifth of the world's population at that time (Source: Census.gov)). The fact that the infection numbers were indeed astronomically large, in the years post-pandemic, it was difficult to make an estimate of the mortality rate. Another reason is that many different countries around the world were affected by a preceding war, and different countries were affected to different extents. However, most sources indicate that the number of deaths ranged between 10-20% of those infected, i.e 50-100 million (Source: Archives.gov - The Deadly Virus). To put this into comparison, just over 17 million were killed over the duration of the Great War (Source: BBC). Despite the magnitude of destruction that the Spanish Flu inflicted, it has become a subject of lesser interest over the years. Looking back at these events, what could we learn to move ourselves forward in the medical field?


One of the great mysteries surrounding the Spanish Flu pandemic is that of the origin of the virus. Some of the latest media report that this virus is likely to have originated from the Far East, in particular, China. However, previous suggestions for the origin location range from Midwest America to France! It is generally accepted that the virus later mutated, causing the most destruction. According to the National Geographic, "new research is placing the flu's emergence in a forgotten episode of WW1: the shipment of Chinese labourers across Canada in sealed train cars." During the War, there was an increasing demand for labour, especially behind the British and French lines.

Above: Public notice for influenza in 1918 (Source: Wikipedia)

Unfortunately those that were infected often suffered unpleasant symptoms: bleeding from the nose and ears was common as well as (after autopsy) swollen hearts and lungs that had become solidified. Some figures showed that some lungs after autopsy measured up to six times their normal weight. The explanation for this is the build up of fluids (oedema) during the course of infection. This accumulation of fluid would have been a significant obstruction and gas exchange would have become increasingly difficult. It follows that as a result of this, many of those infected would die of asphyxiation. One of the physicians working at a military camp near Boston, Massachusetts in September 1918 describes the symptoms of asphyxiation one would typically have in vivid detail:

"Two hours after admission they have mahogany spots all over the cheek bones, and a few hours later you begin to see the cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the coloured men from the white. It is only a matter of a few hours then until death comes and is is a struggle for air until they suffocate. It is horrible. One can stand it to see one, two or twenty men, but to see these poor devils dropping like flies sort of gets on your nerves." 
                                                 
                                                                         - A physician stationed at Fort Devens, Boston, September 1918 (Source: Voices of the Pandemic) 

As well as these conditions that resulted from infection of the virus, often, many others would become ill from secondary infections such as pneumonia - a bacterial infection. The influenza virus is able to penetrate the respiratory system and damage the cilia and epithelial cells lining the lungs. The immunity of the infected is weakened due to the cells of the immune system losing their function. Thus, one becomes increasingly susceptible to pneumonia. 

(Above: Orginal photograph of the H1N1 virus, taken in the CDC Influenza Laboratory) 

As we know, the Spanish flu was caused by the H1N1 virus. What does this mean? Any virus that contain the letters H and N each followed by a number indicates that the virus is type A influenza. The letters H and N refer to haemagglutinin and neuraminidase respectively, the distinctive membrane proteins on the virus. Haemagglutinin binds to receptors on host cells. This causes fusion of the two membranes and deadly infiltration of the viral content. Neuraminidase acts at the end of the viral replication cycle - it 'cleaves' the new virus from the host cell. Now, the cycle is able to occur again and again, and other neighbouring cells become infected. Moreover, the proteins can actually prove very useful - they are extracted from circulating strains, purified, and use in a flu jab vaccine that is given every year.

However, what made H1N1 in 1918 such a big problem was the concept of genetic drift. This became apparent in 2005, when a group of American scientists sequenced the genome of the 1918 flu virus. The tissue sample came from a female patient who was buried in an Alaskan permafrost. The shift was gradual, initially being carried in an avian host. The H1N1 was able to mutate during the course of the pandemic, making it's infection very potent. A mutation in the genome would have caused the subsequent virus to produce subtly different variations of haemagglutinin and neuraminidase. As a consequence, antibodies produced by the host will no longer be able to bind to these proteins. The virus evades the immune response.

Above: The pathogenesis of an influenza A type virus (Source: Biological Sciences Review Volume 27, Number 4)

You might argue that perhaps only the most vulnerable would have been at risk. However the virus was evidently very potent and not discriminatory it would seem. The flu was prevalent in rural as well as urban areas - even the most remote parts of Alaska were affected! Usually, young adults tend to be the least affected when it comes these types of infectious diseases - their immune systems are generally well developed. However, for the Spanish flu, it was the exact opposite. This group tended to be severely affected, along with the vulnerable groups (elderly and young children). One astonishing statistic is that the average life expectancy of the USA dropped by twelve years during one year of the pandemic alone. (Source: Archives.gov)

Above: Age profile of deaths from Spanish flu (Source: Data from Centers for Disease Control and Prevention)

In the graph above, we can compare the deaths for each age group during the period 1911-1917 to the year 1918 - the year of the Spanish flu. What is unusual is the spike in deaths in the age group for young adults. Over the years, this has intrigued epidemiologists - however one theory that does exist to explain this oddity of flu epidemics is the 'cytokine storm'. This relates to the idea that the young and healthy have the most powerful and effective immune systems. However, during an infection with flu, the immune response can too excessive, becoming detrimental to health. Cytokines are chemical released by cells of the immune system during an infection to provide a means of cell communication. Some cytokines accelerate chemical processes, whilst others inhibit them. They also cause increased inflammation, swelling, and vasopermiability (the blood vessels become more permeable). Usually, this would help to fight the infection, however sometimes this response can come at the expense of an organ that has an oedema (and reduced blood supply). A consequence of this is tissue scarring, and then multiple organ failure. So, in the case of Spanish flu, an 'overreaction' of the immune system can indeed prove fatal (Source: Biological Sciences Review Volume 27, Number 4).

What could be done in the future? According to the World Health Organisation, the next pandemic 'will kill between 2 and 7.4 million people'. H5N1 (bird flu) is considered the most dangerous currently. In future, epidemiologists will need to keep watch for emerging epidemics that could potentially become catastrophic pandemics. In the field of infectious diseases, emphasis is being placed on prevention, more than ever before.

In addition to the reference provided above, credit should be given to Bethany Butcher who wrote an article on Spanish flu for the Biological Sciences Review April issue, 2015.

Additional credit: BBC - Viewpoint: The deadly disease that killed more people than WW1

Extra reading:

World Health Organisation - Influenza

Flu - NHS Choices