Scientists from the University of British Columbia have genetically engineered several mice that are resistant to cocaine addiction.
By increasing the levels of a protein called cadherin in the mice, the scientists essentially prevented the pleasurable memory of cocaine from forming in the mice and leading to addiction.
The cadherin protein helps bind cells together and, in the brain, helps to strengthen synapses between neurons.
This strengthening of synapses is integral to learning, including forming the memory of the pleasure induced by stimulants, and thus led to the belief that the mice with increased cadherin would in fact be more susceptible to addiction.
Shernaz Bamji, a professor in the Department of Cellular and Physiological Sciences, and her colleagues injected cocaine into mice over several days and immediately placed them in a distinctly decorated compartment in a three-room cage. The notion was that the mice would associate the cocaine rush with that compartment and gravitate towards it.
After the cocaine treatment days, the mice were put in the cage and allowed to go where they wished. It was found, to the researchers’ surprise, that while the normal mice would always head to the cocaine-associated compartment, the cadherin boosted mice would spend only half as much time there.
The results indicated that the engineered mice hadn’t formed the strong memories of the drug that would be expected and, following brain tissue analysis, it was found that extra cadherin prevents a type of neurochemical receptor from migrating from the cell’s interior to the synaptic membrane. Without said receptor, neurons find it harder to receive signals from adjoining neurons and the synaptic memory of cocaine’s high thus does not “stick”.
“Through genetic engineering, we hard-wired in place the synapses in the reward circuits of these mice,” said graduate student Andrea Globa, a co-lead author with former graduate student Fergil Mills. “By preventing the synapses from strengthening, we prevented the mutant mice from ‘learning’ the memory of cocaine, and thus prevented them from becoming addicted.”
The researchers’ findings go a long way towards explaining the findings of previous studies that showed people with substance abuse problems have more genetic mutations associated with cadherin and cell adhesion. Furthermore, the evidence that addiction is as much genetically predilected as a result of poor decision making could allow for prediction of vulnerability to drug abuse.
Unfortunately, there are still pitfalls ahead. While increasing cadherin in humans could help with a resistance to addiction, it could pose other risks. In many cases, it’s important to strengthen synapses – even in the reward circuit of the brain.
“For normal learning, we need to be able to both weaken and strengthen synapses,” Dr. Bamji says. “That plasticity allows for the pruning of some neural pathways and the formation of others, enabling the brain to adapt and to learn. Ideally, we would need to find a molecule that blocks formation of a memory of a drug-induced high, while not interfering with the ability to remember important things.”