The protein with the potential to rewire the alcohol-addicted brain

During FebFast (no alcohol all this month, raising money for charity), it’s sobering to realise that one in six Australians drink enough booze to put them at lifetime risk of alcohol-related disease.

The Australian Institute of Health and Welfare (AIHW) also has data showing a quarter of the population aged more than 14 drink at a risky level at least once a month.

One in six Australians drink enough booze to put them at lifetime risk of alcohol-related disease.

Misuse of alcohol costs the country more than $14 billion a year. It’s a huge public health problem, yet for those addicted, apart from counselling, there are only three medications available – Campral, Naltrexone, and Antabuse. Experts consider these medicines only partly effective, because they don’t fix the neurological causes of addiction and relapse.

Identifying the path forward

A new discovery by Monash’s Institute of Pharmaceutical Sciences (MIPS), with The Florey Institute of Neuroscience and Mental Health, has the potential to change all that. The team is deep into a ground-breaking scientific journey to eventually make a drug that stops habitual drinking, and decreases the chance of relapse by reprogramming a tiny part of the brain.

“A lot of people drink voluntarily, and are fine with it,” says MIPS’ Dr Chris Langmead, who co-led the team. “But then there's a subset of people in which it goes from voluntary behaviour to habitual behaviour. This is a transition in the brain. They keep going even when they know they've had enough.

“Addiction means you carry on even though you know it’s bad for you,” he says. “You lose the control. Also, this group of people are vulnerable to relapse if they stop. Both environment and stress can trigger them to start drinking again.”

Late last year, the team published its findings in the journal Biological Psychiatry, identifying a particular protein in the brain – the M4 muscarinic receptor, which is activated by a neurotransmitter called acetylcholine – as a new therapeutic target for modulating problem drinking and relapse behaviours.

The team utilised genomic sequencing to make the initial discovery in post-mortem human brains (from heavy drinkers), and then followed up with pharmacology and other very complex biology to confirm these results in pre-clinical animal models, thus identifying a path forward for testing new drugs.

Read more: Risky drinking among men: Alcohol's role in social interaction

The ultimate goal, after further drug development, is to progress to clinical trials of M4 receptor-targeting medicines in humans. Which – as these things go – could be a while off, but the team is excited at the prospects.

“It's incumbent on us to improve the human condition in such major areas of unmet medical need,” says Professor Arthur Christopoulos, the Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, and also a research team member.

“We have a unique convergence of innovative approaches and highly committed people here at MIPS. All the pieces of the jigsaw are in place to see this through.”

The next steps

Key fields of science for the next steps in this promising journey are structural biology and pharmacology. The technology being used at MIPS is the relatively new cryo-electron microscopy, which visualises protein structures at atomic-level resolution. A team from Cambridge University in the UK won the Nobel Prize for Chemistry in 2017 for its work developing this technique.

Earlier, in 2012, two eminent researchers from the United States (one of whom, Nobel Laureate Professor Brian Kobilka, has an adjunct appointment from Monash) won the prize for their work on the same family of cell receptors now under examination by Dr Langmead’s team, thus highlighting the therapeutic relevance of targeting these particular types of proteins.

Dr Langmead and Professor Christopoulos have both been studying the M4 receptor in question for a long time – since they were students, in fact.

Although this particular protein is activated by acetylcholine, it's part of a broader family of receptors that mediate important physiological functions of other neurochemicals and hormones, such as adrenaline, dopamine and serotonin.

Many existing psychiatric medicines are targeted at these receptors, but the relationship with alcohol addiction was unexpected.

Taking greater control

“We’ve been using other drugs for alcohol use disorder that are patchwork approaches,” says Dr Langmead, “treating symptoms only. We started in this case with patients’ brains. We knew from other studies that there are regions of the brain that are responsible for what we call ‘goal-directed’ and ‘habitual’ behaviours.

"So we asked ourselves, what would happen if we look across the whole genome [all the DNA in a cell]? Are there genes that are changed in these regions in patients that chronically drank alcohol compared to those who died of natural causes? With the power of genome sequencing now, we can look at everything; at the top of the tree were the receptors that we were interested in.”

The team found these receptors were significantly changed in the addicted drinkers. They then tried the same trick in pre-clinical animal models and got the same result.

“One of the things we’re interested in is revitalising neuropsychiatric medicines research.”

“Alongside that,” says Professor Christopoulos, “we were able to couple this finding to the other big thing that we had previously discovered, which is a totally different way of targeting these proteins with high selectivity. That’s the other part of the story – the ‘dimmer switch'.

“Most medicines on the market targeting these proteins simply activate or block them, much like an 'on/off' switch,” he says.

“What we discovered is a completely different region on these proteins, akin to a dimmer switch. You can literally design drugs that dial protein activity up or down to a predefined level!

“Not only does this make your drug more selective, but you can also titrate the effect to the specific disease, giving you more control. For instance, now that we know the M4 receptor is reduced in alcohol addiction, we can use our dimmer-switch approach to design medicines that dial its activity back up.”

Pre-clinical models can be used for testing

Another important finding of the study with relevance to medicines development is that the pre-clinical models used by the researchers can also now be used to test potential drugs, because of the link between the human and animal results identified by the team.

This is very important because, in the past, the lack of such predictive capability of animal models contributed to many clinical trial failures of psychiatric drugs; despite the huge market, psychiatric drugs are notoriously expensive to develop.

Indeed, in a commentary alongside the published paper in Biological Psychiatry, two University of Cambridge psychology researchers, while calling the Monash research a “landmark study”, wrote that “few blockbuster treatments have emerged from the ‘receptor revolution’ in neuropsychiatry”.

To Professor Christopoulos, this is an opportunity rather than an impediment.

“One of the things we’re interested in is revitalising neuropsychiatric medicines research,” he says. “Every psychiatric drug on the market is based on 50-year-old science.

"Here at Monash we have an engine of innovation that can break this bottleneck. Although we are world leaders in this new type of pharmacology, we also know that getting a medicine to market is a monumental and highly collaborative task. Fortunately, we partner frequently and we partner well, so we're excited about where this can take us next.”