Commonly used in medicine as an anesthetic, ketamine is also increasingly prescribed to relieve depressive symptoms. This very fast-acting psychotropic drug is particularly indicated for the treatment of patients resistant to conventional antidepressants. However, its prescription has been debated: some believe that it presents a high addictive risk. A team from the University of Geneva (UNIGE) studied this by administering the drug to mice. Although it triggers an increase in dopamine in their brain – like all drugs – it also inhibits a specific receptor that prevents progression to 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, particularly for pain relief and brief sedation. It is also used illicitly for recreational purposes, its dissociative effect inducing an altered notion of reality.
For the past ten years, ketamine has also been prescribed to treat the symptoms depression in people resistant to conventional treatments. Its action has the advantage of being very fast: its effect is felt a few hours after 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 high addictive risk if it is taken for a long time, others are not. The whole point of our research was to try to provide some answers”, explains Christian Lüscher, full professor in the Department of Fundamental Neurosciences of the UNIGE Faculty of Medicine and specialist in the mechanisms underlying the addiction.
Addiction versus addiction
Addiction is defined as the compulsive use of a substance despite its negative consequences (behavioral difficulty). Dependence, on the other hand, is characterized by the appearance of one or more withdrawal symptoms when consumption is suddenly stopped (physiological difficulty). Addiction, whose physical manifestations vary greatly depending on the drug, affects everyone. Addiction, on the other hand, only affects a minority of people and is not caused by all drugs.
In the case of cocaine, for example, only 20 % of users become dependent, even after prolonged exposure. For opiates, the rate is 30%. In its recent work, Christian Lüscher’s team sought to assess the risk of ketamine addiction.
Short stimulation of the reward system
UNIGE researchers used a device allowing 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”, explains Yue Li, postdoctoral researcher in the Department of Basic Neurosciences of the UNIGE Faculty of Medicine.
Scientists have discovered that the level of dopamine – also known as “ 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 the dopamine level decreased very quickly after taking the drug,” says Yue Li.
A drug that does not leave its “mark”
The research team wanted to understand this phenomenon. They found that ketamine triggered an increase in dopamine by inhibiting a molecule called the NMDA receptor in the reward center of rodent brains. 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 alter the communication between nerve cells that underlies behavioral 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 do addictive drugs and lingers in the brain after the substance wears off. It is this memorization of the product in the reward system – absent in the case of ketamine – which leads to repeated consumption, explains Christian Lüscher. Thus, the addictive risk of ketamine seems zero in rodents. Is this also the case in humans? Could this risk vary between individuals? Our study provides a solid framework for discussing access to its therapeutic use”, concludes Christian Lüscher.