Ketamine, commonly used medically as an anesthetic, is also increasingly being prescribed to relieve symptoms of depression. This very fast-acting psychotropic is particularly indicated for the treatment of patients resistant to conventional antidepressants. However, its prescription has been the subject of debate: some believe it poses a strong risk of addiction. A team from the University of Geneva (UNIGE) investigated this by injecting the drug into mice. While it causes an increase in dopamine in their brain – like all drugs – it also inhibits a specific receptor that prevents addiction. These results can be found in the journal Nature.
Discovered in 1962 by American chemist Calvin Lee Stevens, ketamine is a synthetic drug derived from phencyclidine with powerful anesthetic properties. It is commonly used in human and veterinary medicine, especially for pain relief and short-term sedation. It is also used illegally for recreational purposes, its dissociative effect causing an altered perception of reality.
Over the past decade or so, ketamine has also been prescribed to treat symptoms of depression in people resistant to conventional treatments. Its action has the advantage of being very fast: its effect is felt within hours after the first dose, while traditional antidepressants take several weeks. Although his prescriptions for this type of treatment are increasing, this substance is still widely debated in the scientific community.
”Some people believe that ketamine poses a strong risk of addiction with long-term use, others do not. The whole point of our study was to try to provide some answers – explains Christian Lüscher, Professor of the Department of Basic Neurosciences of the UNIGE Faculty of Medicine and specialist in the mechanisms underlying addiction.
Addiction vs Addiction
Addiction is defined as the compulsive use of a substance despite its negative consequences (disordered behavior). Addiction, on the other hand, is characterized by the appearance of one or more withdrawal symptoms upon abrupt cessation of use (a physiological disorder). Addiction – the physical manifestations of which vary greatly depending on the drug – affects everyone. Drug addiction, on the other hand, affects only a minority of people and is not caused by all drugs.
In the case of cocaine, for example, only 20% of users become addicted, even after prolonged exposure. For opiates, the rate is 30%. In their recent work, Christian Lüscher’s team sought to assess the risk of addiction to ketamine.
Brief stimulation of the reward system
UNIGE researchers used a device that allowed mice to self-administer doses of ketamine. The drugs intensely stimulate the reward system in the brain, leading to an increase in dopamine levels. The first step was to observe whether this mechanism also works when ketamine is taken,” explains Yue Li, PhD student at the Department of Basic Neuroscience, Faculty of Medicine, UNIGE.
The scientists found that levels of dopamine – also known as the “pleasure molecule” – increased with each dose and induced positive reinforcement in the mice, motivating them to repeat the self-administration. “However, unlike cocaine, for example, we found that dopamine levels drop very quickly after taking the drug,” says Yue Li.
A drug that leaves no “trace”
The research team wanted to understand this phenomenon. They found that ketamine causes an increase in dopamine by inhibiting a molecule called the NMDA receptor in the reward center of the rodent brain. Dopamine then binds to another receptor (called the D2 receptor), which acts as a quick brake to increase dopamine. The researchers also confirmed that the action of the NMDA receptor is necessary to change the communication between nerve cells that underlie the change in behavior that leads to addiction. Inhibition of the NMDA receptor by ketamine makes this modification impossible.
“A consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do, which persists in the brain after the substance wears off. It is this memorization of the product in the reward system – which is absent in the case of ketamine – that leads to repeated consumption, explains Christian Lüscher. Therefore, the risk of addiction to ketamine in rodents is zero. Does this also happen in humans? Could this risk vary from person to person? Our study provides a solid basis for the discussion of access to its therapeutic use, concludes Christian Lüscher.