BREAKING THE CHAINS OF ADDICTION
The cost of addiction is high. In 1992 the estimated cost of substance abuse in British Columbia was $2.2 billion, but that is just money. It is difficult to know the full cost of lives eroded away by addiction because addiction is more than an addict. The price of addiction is also paid by all the lives that are touched by an addict as well. In a way we are all chained to the networks in the brain that cause addiction. But, a group of scientists out of the University of British Columbia are examining the biological chains of addiction and have found a new way of breaking one of the links
Current treatment for addiction focuses on social outreach, counselling, and the management of withdrawal symptoms. While necessary and very useful, none of these approaches are focusing specifically on the rewiring in the brain that maintains the addiction. Counselling effects the rewiring, but in a more holistic sense. Medications manage the withdrawal symptoms and they focus on making drugs of abuse less effective. “They block the positive effects of drugs or provide disincentives,” says Dr. David Marsh, head of Addiction Services for Vancouver Health.
The treatments we have now are only able to target peripheral effects of addiction in hopes of being able to eventually strike at its core. But new research, published in a recent issue of the journal Science, aims directly for the root cause. The research is “taking a whole new approach,” says Dr. Karen Brebner, co-author of the paper and neuroscientist. “It is aimed at restoring the connections in the brain that may have existed before the exposure to the addictive substances.”
The brain is a huge network of interacting brain cells, called neurons. Connections between neurons are constantly changing and this rewiring is thought to be how memories are formed and behaviours, like addiction, are wired in. The UBC research team focused on the rewiring in the brain that causes addictive behaviour. “We found that blocking one type of rewiring in normal memory formation, also plays a role in the formation of rewiring in drug addiction,” says Dr. Tak Pan Wong, co-author and researcher at UBC’s Brain Research Centre. The memory formation process that Dr. Wong is referring to is called long-term depression or LTD. LTD looks like one way that addictions get hardwired into the brain.
In order to make long-term depression, the signal of the neurons needs to be depressed. This signal lowering occurs by decreasing the number of receptors on the neuron that pick up the signal. If you prevent the neuron from decreasing the number of receptors, then you prevent the signal from being lowered and you stop the LTD that helps wire in addiction. To stop the recycling of the receptors, the scientists made a small protein, or peptide, that jammed up the receptor recycling machinery.
The idea is a lot like breaking off a key in the lock of a door. The normal protein for LTD unlocks the door and starts the receptor-recycling machine. Whereas the peptide that Dr. Wong’s team made just sits in the lock and keeps the normal protein out and the receptors up. “It is like a competitor or interfering peptide,” says Dr. Wong. The end result is no weakening of signal, no LTD, and no rewiring.
With the jamming peptide in hand, the researchers were then able to block LTD in an area of the brain that is thought to be involved in addiction, the nucleus accumbens. The specific behaviour that the team looked at was behavioural sensitization in rats. Behavioural sensitization “is parallel to craving phenomena in human drug addicts,” says Dr. Wong, “it is a very commonly used animal model of addiction.”
When sensitized animals, that were repeatedly given amphetamine, were treated with the new peptide, “their behaviour looked like animals that were receiving the drug for the first time,” says Dr. Brebner.
“Sensitized animals which receive amphetamine for a long period of time show an enhanced responsiveness to amphetamine,” says Dr. Wong, “and giving this peptide abolished this enhanced responsiveness.” So with the depression of LTD on the circuit blocked, the rats that were on amphetamine acted like first time users. It was as if a chain of addiction broke and the animals returned to a state before addiction took hold.
This result is the first to directly link a specific rewiring mechanism to addiction, and it is moving addiction research into a new direction. “Now our understanding of normal learning and memory can also play a role in designing treatments for addiction,” says Dr. Wong. Before this research the study of memory and addiction could only touch, now they have the potential to merge. With the new peptide as a tool, the direct effects of LTD can be studied in many types of behaviour; the results of which will expand our understanding of all types of addiction.
The brain rewiring of LTD that the scientists have targeted could occur in all forms of addiction. “We’re hoping that we are taking a step back and looking at a mechanism that would underlie all types of addictive behaviour,” says Dr. Brebner, “but we can’t just draw that conclusion.” If this research has found a type of rewiring that occurs in all addiction, it could lead to better treatments for addiction. But there is a lot of work that needs to be done before any thought can be given to new medications.
Amphetamine, alcohol, crack, and heroin addictions all come from different sources, and the researchers are not ready to generalizing their finding. “We would have to go on and look at the other drugs individually because other addictive substances have very different effects on the brain,” says Dr. Brebner.
The researchers have also just found one piece of the puzzle. “In this study we only focused on the craving part of addiction,” says Dr. Wong, “so we would also like to see whether this peptide can play a role in the formation of addiction or the relapse of addiction.”
Before any drug development can occur, the effect the researchers found in amphetamine using rats needs to be replicated with other drugs, other addictive behaviours, and other animals. “We do not have the complete picture yet,” says Dr. Antonello Bonci, a neurologist at the University of California whose work on addiction and learning built the foundation for the UBC study. “It would be for me very comforting to know that the same synaptic phenomena is shared by a variety of addictive behaviours.” So that means a lot more work is needed.
Dr. Wong estimates that their research group will not be able to start thinking of drug development for another two to three years, and that is only if everything goes well. Science is often a very unpredictable endeavour. “From some observation in a lab to the creation of a drug can be 15 years,” says Dr. Sidney Katz, a pharmacologist and expert on drug development at UBC. Before you can develop a drug, “efficacy (does it work) and then toxicity are the two big issues that you look at.”
The UBC research team does have the future in mind and has performed a number of tests on rats given the new peptide. So far it is all good news, no side effects seen. “This peptide is very specific in targeting craving in drug addiction,” says Dr. Wong, “we don’t foresee that there are any major side effects.”
But even if the peptide is very specific for the rewiring process of LTD, scientists still do not know everything LTD does. Dr. Bonci says that the receptors effected by the peptide “are widely expressed throughout the central nervous system, they are essential receptors.” So unforeseen side effects are still very possible since LTD contributes to many different functions in the brain.
Currently the UBC research group is looking at the effects of their new peptide on other aspects of addiction and other drugs of abuse. Even though medications are a long way off, the UBC team’s promising new finding will further our understanding of addiction and the brain.