Scientists were able to demonstrate a loss of dopamine receptor sensitivity in response to prolonged exposure to dopamine. This study was the first in which such experiments were conducted on human cells.
Researchers from North Carolina State University (USA) have shown that neuro-like cells derived from human stem cells, can serve as a model for studying changes in the nervous system associated with addiction. The new work sheds light on the effects of dopamine on gene activity in neurons and suggests a plan for further research in this area.
“It’s extremely difficult to study how addiction changes the human brain at the cellular level: no one wants to experiment on someone else’s brain,” says Albert Keung, corresponding author of the study and associate professor of chemical and biomolecular engineering at the University of North Carolina. – “What we’ve done shows that you can get a deep understanding of key cellular responses by using neuro-like cells from human stem cells.
It’s about how cells in our nervous system respond to drugs that are associated with substance abuse and addiction. The body produces a neurotransmitter called dopamine, which is associated with feelings of satisfaction and is responsible for motivation and reward functions. When neurons in the brain’s “reward pathway” are exposed to dopamine, the cells activate a specific set of genes that trigger feelings of reward. Thus, this hormone makes people feel good, makes them want to do something and boosts their mood.
Many substances cause the body to produce higher levels of dopamine. The list ranges from socially acceptable alcohol and nicotine to illegal opiates and cocaine.
The authors of the new work exposed neuro-like cells derived from human stem cells to different levels of dopamine for different periods of time. As it turned out, when the cells were exposed to high levels of the neurotransmitter for long periods of time, the corresponding “reward” genes became significantly less sensitive.
Transferring this model to humans, one could say that if previously one level of dopamine was required to feel motivated, now higher levels would be needed. Whether the body is able to produce more of this hormone out of nothing is a rhetorical question. Not surprisingly, addiction forces one to increase dopamine levels artificially.
The problem is that when dopamine is regularly reuptaken in greater doses than the body produces, its stores are simply depleted. It takes a long time for dopamine levels in the body to recover. When withdrawing from substances that inhibit dopamine receptors or dopamine reuptake, the addict may feel for months the lack of motivation and mood deterioration, in extreme cases turning into complete apathy and unwillingness to live, which is associated with lowered dopamine levels. This leads to a virtually irresistible desire to return to use.
“Our work is the first experimental study to demonstrate a loss of gene sensitivity in human neuro-like cells, especially in response to dopamine,” said Ryan Tam, the study’s first author and a graduate student at the University of North Carolina. – “We don’t need to speculate that this happens in human cells: we’ve shown how it happens in them.
Many questions remain open. For example, could higher levels of dopamine cause loss of sensitivity in a shorter period of time? Or, could its lower levels be capable of provoking loss of sensitivity on longer time scales? Are there threshold levels or is there some kind of linear relationship? How might the presence of other neurotransmitters or bioactive chemicals affect these responses?
According to Keung, the model on which the study is based has the potential to answer all of these questions in the future.