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Out of all the addictive substances available to us- alcohol is the most commonly used. When drinking becomes severe the given medical diagnosis is “alcohol use disorder” or AUD. In the United States of America one in every 12 adults suffers from alcohol abuse or dependence. According to the World Health Organization 3.3 million people die from alcohol each year.

It is terribly difficult to overcome an addiction- our brains re-wire so that we seek our drug of choice. This makes it difficult to “say no” even after admitting to a problem. Our ability to “say no” is further compromised because our brain circuits that are involved in forming an addiction are heavily activated by signals in our environment and stress. This is partly why avoiding environmental signals (or cues) like going into a bar if you have AUD or limiting stress can be instrumental in not yielding to our brains’ need for the drug.

What if patients with addictions could get a little helping hand to ignore the cue and stress-driven need to seek out drugs and help those trying to quit or stay clean?

A family of receptors called metabotropic glutamate receptors (mGluRs), that are part of a wider class of receptors called G-protein coupled receptors, or GPCRs, have been of interest as a route to developing new treatments for a number of psychiatric and neurological disorders. Experimental data generated with earlier compounds which act on multiple members of the mGluR family (namely, mGluR2 and mGluR3) suggested these could reduce heroin, methamphetamine, nicotine and cocaine seeking but, perhaps due to their lack of selectivity, were associated with potential side-effects

In recent years, medicinal chemists have developed classes of compounds called positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs). These compounds are able to interact very specifically with an individual receptor type. It is hoped these specific interactions will lessen the risk of side-effects that are associated with the earlier compounds that affected multiple receptors. A novel drug developed by AstraZeneca, called AZD8529, is a PAM that selectively binds to mGluR2.

Why is targeting mGluR2 important in addiction? mGluR2 “listens” to a chemical in the brain called glutamate that activates brain cells. Glutamate is essential for making new connections in the brain, and is thus also instrumental in addiction formation. Enhanced amounts of glutamate in the brain have been associated with withdrawal and drug seeking behavior during withdrawal.

mGluR2 is positioned in such a place in the connections between brain cells that when it is activated by glutamate it can work to reduce glutamate release. AZD8529 binds to mGluR2 in a different place to the natural activator glutamate and therefore the receptor is activated more by the drug when there is also glutamate present. Therefore, when high levels of glutamate are present, AZD8529 works to enhance the mGluR2 ability to reduce levels of glutamate release. Reducing glutamate release at this point would lead to less activation of pre-wired addiction seeking pathways and make those cues to seek drugs easier to ignore.

A study published in Neuropsychopharmacology found that AZD8529 reduced cue-induced, but not stress-induced, alcohol and sugar consumption in rodents. The researchers further demonstrated the efficacy and selectivity of AZD8529 by trying it out in innately alcohol-abusing rats that lack the mGluR2 receptor. AZD8529 did not prevent these rats from seeking alcohol.

Addiction is a global health crisis. Therapies that can reinforce a desire to abstain would be hugely beneficial. Interestingly, AZD8529 helped rats combat seeking alcohol after seeing a cue (for someone with AUD it might be seeing a bar) but it did not help them as much when it was stress driving them to seek alcohol- suggesting that this drug therapy, in addition to stress management, could be key to helping those who want to get on the wagon, stay on the wagon.

GPCR modulation with positive and negative allosteric modulators is clearly an area that has great potential for the development of novel drug targets and therapies for CNS diseases. Developing assays of GPCRs is a speciality of Neurexpert.

To view the original paper discussed in this blog, The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats in Neuropsychopharmacology. 2016 Nov;41(12):2932-2940, please click here

The Blog was written by Carolyn Lacey, Scientific Outreach Manager at Neurexpert. To learn more about Carolyn and Neurexpert, please click here.