The commonly used anaesthetic ketamine, which is also increasingly prescribed for the relief of depression symptoms, has created concern over whether it poses an addiction risk.
University of Geneva (UNIGE) researchers found that ketamine triggers an increase in dopamine in mice’s brains, and that it also inhibits a specific receptor that precludes the progression to addiction. These results can be found in the journal Nature.
For the past ten years or so, ketamine has also been prescribed to treat the depressive symptoms of people who are resistant to conventional treatments. Its action has the advantage of a swift onset, acting within hours of the first dose, whereas traditional antidepressants take several weeks to act. Although its prescription is increasing for this type of treatment, this substance is still widely debated within the scientific community.
”Some people believe that ketamine presents a strong addictive risk if taken for a long time, others do not. The whole point of our research was to try to provide some answers,” explained Professor Christian Lüscher.
Brief reward system stimulation
The UNIGE researchers allowed mice to self-administer doses of ketamine. ”The drugs intensely stimulate the reward system in the brain, which leads to an increase in dopamine levels. The first step was to observe whether this mechanism was also at work when taking ketamine,” explained Yue Li, a Postdoctoral Scholar in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine.
The scientists found that dopamine levels increased with each dose and induced a positive reinforcement in the mice, which motivated them to repeat the self-administration. ”However, unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug,” said Dr Li.
A drug that leaves no ‘mark’
Probing the mechanism behind this phenomenon, the researchers discovered that ketamine triggered an increase in dopamine by inhibiting a molecule called NMDA receptor in the reward centre of the rodent brain. Dopamine then binds to another receptor (called the D2 receptor), which acts as a rapid brake on the increase in dopamine. The researchers also confirmed that the action of the NMDA receptor is necessary to modify the communication between the nerve cells that underlie the behavioural change leading to addiction. Ketamine’s inhibition of the NMDA receptor makes this modification impossible.
”The consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do and that persists in the brain after the substance has worn off. It is this memorization of the product in the reward system – absent in the case of ketamine – that drives the repetition of consumption,” explained Prof Lüscher. “Therefore, the addictive risk of ketamine appears to be zero in rodents. Is this also the case in humans? Could this risk vary according to the individual? Our study provides a solid framework for debating access to its therapeutic use,” concludes Christian Lüscher.
Source: Université de Genève