First Study of Addiction Mechanisms Conducted on Human Cells
Scientists have demonstrated, for the first time, the loss of sensitivity of dopamine receptors in response to prolonged dopamine exposure using human cells. This research marks the first instance where such experiments have been conducted on human-derived cells.
Researchers from North Carolina State University (USA) showed that neuron-like cells derived from human stem cells can serve as a model for studying changes in the nervous system associated with addiction. This new work sheds light on how dopamine affects gene activity in neurons and provides a roadmap for future research in this field.
“It is extremely difficult to study how addiction changes the human brain at the cellular level—no one wants to experiment on someone’s brain,” said Albert Keung, corresponding author of the study and associate professor of chemical and biomolecular engineering at North Carolina State University. “What we’ve done shows that it’s possible to gain deep insight into key cellular responses using neuron-like cells derived from human stem cells.”
The research focuses on how cells in our nervous system respond to substances associated with psychoactive drug abuse and addiction. The body produces a neurotransmitter called dopamine, which is linked to feelings of pleasure 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 a sense of reward. This hormone makes people feel good, increases motivation, and elevates mood.
Many substances cause the body to produce higher levels of dopamine. This list includes various drugs—from socially acceptable ones like alcohol and nicotine to illegal substances such as opiates and cocaine.
In the new study, the authors exposed neuron-like cells derived from human stem cells to different levels of dopamine for varying periods. They found that when the cells were exposed to high levels of the neurotransmitter for a prolonged time, the corresponding “reward” genes became significantly less sensitive.
Translating this model to humans, it means that if a certain level of dopamine was once enough for motivation, now a higher level is required. Whether the body can produce more of this hormone out of nothing is a rhetorical question. It’s no surprise that addiction drives people to artificially increase dopamine levels.
The problem is that with regular reuptake of dopamine in doses higher than the body naturally produces, its reserves are simply depleted. Restoring dopamine levels in the body takes a long time. When a person stops using substances that inhibit dopamine receptors or its reuptake, they may experience a lack of motivation and a depressed mood for months—sometimes to the point of complete apathy and loss of will to live, all linked to low dopamine levels. This is what creates the nearly irresistible urge to return to substance use.
“Our work is the first experimental study to demonstrate the loss of gene sensitivity in human neuron-like cells, especially in response to dopamine,” noted Ryan Tam, the study’s first author and a graduate student at North Carolina State University. “We don’t have to speculate that this happens in human cells—we’ve shown how it happens in them.”
Many questions remain. For example, can higher dopamine levels cause loss of sensitivity in a shorter time? Or could lower levels provoke loss of sensitivity over longer periods? Are there threshold levels, or is it a linear relationship? How might the presence of other neurotransmitters or bioactive chemicals affect these reactions?
According to Keung, the model used in this research could eventually provide answers to all these questions.