MedicalResearch.com Interview with:
Andrea K. Globa, Ph.D. Candidate
Graduate Program in Neuroscience
Life Sciences Institute
University of British Columbia
Vancouver, BC, Canada
MedicalResearch.com: What is the background for this study?
Response: Addiction is a complex disease, characterized by continued substance use despite serious negative consequences, increased drug tolerance, and withdrawal. In fact, the statistics show that over 40 million Americans abuse or are addicted to nicotine, alcohol or other drugs. This is a huge public health issue, so naturally, scientists are interested in figuring out why people get addicted, and in particular why certain people are more prone to addiction than others.
Studies examining genetic differences in addicted populations have shown that there are many mutations in genes that are important for brain function. One group of genes affected encode proteins that act as ‘glue’ to hold cells together. These proteins are called cadherins. In the brain, cadherins are important for holding brain cells together at spots where they communicate with one another – and these points where brain cells talk to one another are called synapses.
Many neuroscientists believe that addiction is actually a type of “pathological” learning, where there are changes at synapses in a brain circuit involved in reward and motivation. So we decided to examine the molecular mechanisms that are important for the strengthening of synapses in this brain circuit.
To put it very simply, to learn something you have to make your synapses stronger, and this involves adding more cadherin or ‘glue’ to the synapse. We wanted to see if these same rules held true in addiction.
MedicalResearch.com: What are the main findings?
Response: We asked ourselves what would happen if we add more cadherin to synapses within the brain circuit involved in addiction. We genetically engineered mice to have lots of cadherin ‘glue’ at these synapses. We thought – more glue – stronger synapses – more learning – more addiction.
But we actually saw the opposite effect! We used an experiment called conditioned place preference to test this. Using a cage with 3 very distinct chambers in it, we give each mouse cocaine, and let it associate the cocaine “high” with one of the 3 chambers. We trained each mouse this way for a number of days until it learned to associated the rewarding effects of the drug with one chamber. To test their drug preference, we allowed each mouse to freely move between the chambers. Normal mice always gravitated towards the chamber where they received the drug, which indicated it’s preference for the drug ‘high’. However, the mice that had too much cadherin ‘glue’ at synapses didn’t behave this way. In fact, they spent half as much time in the cocaine chamber, and were just as happy to explore all the chambers equally.
This was fascinating to us. Why did this happen? What was going on at the cellular level to make these mice almost “resistant” to seeking out the cocaine high?
Other researchers have examined the neurotransmitter receptors at these synapses after drug exposure. (Neurotransmitter receptors receive signals from other neurons, and when enough input is received the cell will pass the signal on to the next neuron in the circuit.) These previous studies found that to strengthen synapses in the reward circuit, you have to remove a certain type of neurotransmitter receptor from the synapse, to allow a much more sensitive receptor to get inserted at the synapse.
As there is only so much space available at the synaptic surface, when you have too much cadherin ‘glue’, the less sensitive receptors are held too strongly in place. As a result, there is no room for the more sensitive receptors to reach the synapse. To summarize, when we increased cadherin at these synapses, we blocked synapse strengthening, which resulted in reduced addiction in these mice.
MedicalResearch.com: What should readers take away from your report?
Response: Readers should know that addiction is a form of learning that happens in a particular part of the brain. Learning involves the strengthening of synaptic connections in the brain. Proteins that regulate the strength of synapses, like the cadherin protein we were studying, can regulate learning and can regulate addiction.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Given that we’ve shown that manipulating cadherins can influence drug learning, we naturally would like to find a way to use this knowledge to create therapeutics to reduce the negative effects of drug addiction in humans. However, cadherin proteins are important for normal synapse function in many regions of the brain, not just the reward circuitry. So targeting the cadherin protein directly might have negative effects on learning and memory, and this doesn’t seem like a good tradeoff.
For this reason, we are interested in finding other proteins that act on cadherin, some of which might be more specific to the reward circuit. This is why basic science research is so important – it allows us to flesh out our understanding of the brain, and can lead to unexpected applications in medicine.
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Fergil Mills, Andrea K Globa, Shuai Liu, Catherine M Cowan, Mahsan Mobasser, Anthony G Phillips, Stephanie L Borgland, Shernaz X Bamji. Cadherins mediate cocaine-induced synaptic plasticity and behavioral conditioning. Nature Neuroscience, 2017; DOI: 10.1038/nn.4503
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