Cocaine is a popular recreational drug that makes users energetic, confident and talkative. It’s also highly addictive and dependence-producing. Australians rank fourth in the world in cocaine abuse rates.
We have a drug that could be used to treat opioid abuse and dependence, (+)-naloxone. This works differently to the classic Narcan (aka (-)-naloxone), instead preventing the immune system’s response to the opioids, which blocks the rewarding properties of drugs such as morphine and heroin.
Research my colleagues and I published today in the Nature journal Molecular Psychiatry shows we’re a step closer to developing an equivalent drug to block the reward properties of cocaine and other drugs of addiction.
To explain how, we need to take a couple of steps back.
How does cocaine work?
Drugs of abuse change a complex array of brain functions, but central to their actions are their ability to increase the quantity of one or two of these key neurotransmitters in very specialised brain regions. These changes in neurotransmitter availability produce the reinforcing (reward and withdrawal) effects of cocaine.
Cocaine blocks the re-uptake transporters of both dopamine and serotonin. These transporters normally remove the excess of dopamine and serotonin after they have done their job. This means that when cocaine enters the brain it causes a very rapid increase in the available dopamine and serotonin.
The dopamine increases are a very important and common property of the reinforcing actions of multiple drugs of abuse, ranging from cocaine to opioids to methamphetamine.
This is the traditional “neuro” science explanation of drug abuse.
Enter the immune system
The brain is full of cells called glia. These immune-like cells are critical to the health and well-being of our brains. They help translate the immune messages that tell our brain we are sick or something is wrong.
These glia are also influenced by the presence of addictive drugs. Dopamine is still the key reward neurotransmitter of the brain. But the immune system that surrounds the dopamine systems of the brain also seem to be very sensitive to drugs of abuse.
In fact, we’re now realising that addictive drugs generate multiple immune-like signals within the brain. These immune-like events are not solely bystander responses of the brain; they’re critical to creating the rewarding properties of a number drugs of abuse, such as alcohol, opioids, methamphetamine and, as our research reveals, cocaine.
As such, the solely “neuro” science view of drugs of abuse is giving way to the “neuro-immune” hypothesis of how drugs become addictive.
The immune system’s role in drug abuse
Our research team studied the role of the immune receptor known as Toll-Like receptor 4 (TLR4), which is responsible for amplifying addiction to opioid drugs such as morphine.
We found that TLR4 is also critical to cocaine’s reinforcing actions.
The fascinating thing about TLR4 is that, as one of the evolutionarily oldest parts of our innate immune system, it has evolved to detect a diverse array of structural patterns. This is very different from the “single lock and key” concept that is commonly applied to the actions of drugs in the brain.
Instead, the immunology of the brain sees cocaine and some other drugs of abuse as foreign and dangerous, and responds appropriately with the release of immune signals.
This immune response appears to act as an addictive drug linchpin, allowing the classical reinforcing neurotransmitters to create the behavioural responses of addictive drugs, including cocaine.
How we did it
The research journey began over eight years ago when we proposed that the brain’s immune-like signals were involved in the responses to drugs of abuse.
We started with a computer simulation of the cocaine molecule docking with TLR4 and its associated protein partners. This experiment revealed that, like morphine, cocaine preferred to dock to the same pocket that a fragment of bacterial cell walls (endotoxin) binds to.
We then ran a series of molecular and cellular studies to establish that cocaine binds directly to a critical TLR4 partner protein called MD2.
From here, the team found that cocaine caused the same immune signals to increase in the brains of rats. We used two TLR4-targeted drugs to stop the cocaine-induced brain immune signals and shut down the reinforcing behaviours in rats. These TLR4-targeted drugs even stopped the rats pressing a bar to get cocaine.
So what now?
The “neuroimmune” hypothesis of drug abuse suggests that the rewarding, and possibly addictive, effects of some drugs require stimulation of both neuronal and immune-like cell functioning.
Collectively, this work suggests that some addictive drugs are viewed by the brain’s immunology as foreign, very much like when we are sick. This could help explain both the initial stages of drug use driven by the rewarding effects of drugs and the drug-induced changes in the brain associated with chronic use.
Our discovery of drugs that are able to block some of cocaine’s action in the brain may pave the way to an immune-targeted treatment for a number of addictive drugs. We are partnering collaborators from the United States to move these promising drug candidates from the bench to the bedside.
The research also has wide-reaching implications for diseases affecting dopamine systems, which could guide the development of drugs aiming to treat these diseases.