Beyond dopamine in Parkinson’s

For much of the last 50 years, Parkinson’s has been considered a condition based on dopamine signalling, but this simplistic view means today many of its symptoms are inadequately managed by the drugs available. So what is going on and what other chemicals are involved?

There are many different types of chemical messengers used all over our bodies. For instance, insulin released from the pancreas encourages cells to take up sugar from the blood, while adrenaline is produced by the adrenal glands to increase heart rate and get the body ready for the fight or flight response.

But signals don’t always involve a whole body response, individual cells communicate with each other by sending chemical messages as well. In fact, they do this all the time, sending out hundreds of different signals that relay a host of information about the status of the cell and its environment.

The brain uses lots of chemical messengers to orchestrate complex communications that allow us to think, feel, move, remember and much more. These chemical messengers are known as neurotransmitters ("neuro" meaning relating to nerves or the nervous system) and are used by individual parts of the brain, allowing them to carry out their function.

What is dopamine?

Dopamine is a neurotransmitter that is involved in how we move and learn, our memory and attention, and even responsible for addictive behaviours.

At the start of the 1950s, we knew almost nothing of the importance of dopamine in our daily lives. It was Dr Arvid Carlsson, a Nobel Prize-winning Swedish scientist, who first discovered how dopamine is involved in controlling movement. He showed that rabbits with lowered levels of dopamine lost their ability to move, and regained movement when given levodopa, a drug that can be turned into dopamine.

This discovery became the basis of how we treat Parkinson’s, a condition caused by the loss of dopamine-producing cells, and still underpins the gold standard drugs available today.

More than just dopamine

This year marks 20 years since Dr Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine alongside Paul Greengard and Eric Kandel in the field of "signal transduction in the nervous system". And our understanding of how brain cells communicate in Parkinson’s has come a long way in this time.

A number of other chemical signalling pathways are now known to be affected in the condition and may be responsible for many of the symptoms that are not improved by levodopa based medication.

Some of the neurotransmitters affected in Parkinson’s and possible associated symptoms include:

• acetylcholine — changes in thinking, concentration and memory as well as uncontrolled movements and the production of too much saliva
• norepinephrine — mood and sleep disturbances, and mild memory and thinking problems
• serotonin — changes in mood, fatigue and depression
• endocannabinoids — alterations in appetite, pain, and may play a role in psychosis symptoms such as hallucinations
• glutamate — may impact movement, learning and memory, pain, and mood
• GABA (gamma-aminobutyric acid) — alterations in movement, anxiety and vision.

Now researchers need to understand more about the balance of these chemicals and how they are causing symptoms in order to find better treatments. Here we discover more about the role of GABA and how researchers are targeting it in the pursuit of better treatments for Parkinson’s.

GABA: a traffic light for brain cells

GABA is considered an inhibitory neurotransmitter because it blocks, or inhibits, certain brain signals. Just like red and green lights are both needed to control traffic, a careful balance of excitatory and inhibitory neurotransmitters is needed for effective control of signalling within the brain.

For instance, in anxiety, where brain cells are over stimulated, GABA works to slow down signals to reduce the feeling of being overwhelmed.

A protective role for GABA involving calcium

Back in 2012, researchers found that dopamine-producing brain cells release GABA as well as dopamine. So in Parkinson’s when dopamine-producing cells are lost over time, as well as the depletion of dopamine, there is a decrease in the levels of GABA. Read the 2012 research paper in full on the ScienceDaily website.

This is significant as GABA has a role in controlling levels of calcium. You might be more familiar with the role calcium plays in keeping our bones strong and healthy. But calcium is also vital for brain cells.

In brain cells, calcium controls the release of dopamine, but too much calcium at the wrong time and place can kill cells. GABA works as an inhibitory signal, a stop light, to block calcium from entering cells. This has a protective effect on brain cells as it stops them from being overwhelmed with an influx of calcium which can result in death.

Most of the current drug treatments for Parkinson’s aim to boost or mimic dopamine in Parkinson’s to overcome the loss of this neurotransmitter. But now we know the important role that other neurotransmitters have, and that they may have protective effects, maybe we should turn our attention beyond dopamine.

By finding ways to mimic the action of GABA we might be able to reestablish the careful balance of neurotransmitters in the brain and develop better treatments.

Mimicking the protective effects of GABA

In 2014, Parkinson’s UK funded work to find out more about GABA and its links to dopamine. Today this research could see drugs that target GABA being repurposed for Parkinson’s.

Gabapentinoids are drugs, including gabapentin and pregabalin, which are currently used to treat epilepsy, restless leg syndrome, and neuropathic pain. These drugs copy the action of GABA.

Professor Stephanie Cragg and her team think that gabapentinoids will be able to protect brain cells by stopping too much calcium for entering cells just like GABA. They hope that preserving cells could help maintain dopamine levels and ultimately slow or prevent the progression of Parkinson’s.

What are the researchers doing?

In a pioneering new study, which started last year, Professor Cragg and her team are measuring the effects the drugs have on the levels of dopamine and calcium using a powerful technique called "fastscan cyclic voltammetry".

Using an extremely small electrode (we’re talking micrometers in size) inserted into the brain of a mouse model of Parkinson’s and brand new reporter dyes, the team is trying to understand how these drugs work. This technique is looking at how the calcium is moving into the cells, and will try to understand how the drugs boost dopamine, what kind of dose is required and which neurons are affected.

They will also look to see if these drugs can fix problems in already affected cells, like the build-up of toxic molecules such as alpha-synuclein.

Professor Cragg is working alongside people affected by Parkinson’s to help shape this research and engage with the local community. Two people with Parkinson’s are meeting with Professor Cragg and her team regularly over the course of the project. So far the group has discussed some of the challenges of repurposing drugs and how people affected by Parkinson’s can get more involved in lab-based studies. Find out how you can help shape research.

Drug repurposing

Gabapentinoids are already in use and are regularly being prescribed for people with a range of conditions. That means that we already know they are safe for humans to take. That puts us miles ahead. If they can do what we’re hoping they will then we will be able to start trialling them in people with Parkinson’s straight away. Repurposing existing drugs has the potential to shave years off the time it takes to bring those drugs to the people who need them.

However, we wouldn’t recommend that all people with Parkinson’s be prescribed this drug as there is still a lot to learn. In fact, recent research has suggested that the use of gabapentinoid drugs may actually be linked to Parkinsonism, a group of conditions that include Parkinson’s and share some of the same symptoms. This highlights the need for us to understand more about the role of GABA, and that a careful balance needs to be found when looking at targeting neurotransmitters in Parkinson’s.

Read more about the research linking gabapentinoid drugs and Parkinsonism on the International Parkinson and Movement Disorder Society's website.

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