Double-action mechanism found that makes ketamine less addictive

Fast-acting psychotropic drug ketamine is increasingly used as an anesthetic, as well as to rapidly relieve depression. University of Geneva researchers have studied its effects on the dopamine system and a mechanism that may make it less addictive.

Ketamine has found a variety of uses in medicine, and its ability to alter a person’s perception of reality has made it a popular recreational drug as well, if an illegal one in most jurisdictions. Generally, it’s not considered a dangerously addictive drug, although the science in this area is relatively new and unsettled and there’s still some debate.

The Swiss team started out by examining ketamine’s effect on the pleasurable “reward” molecule dopamine. Many drugs heavily stimulate the brain’s reward pathways, causing a rush of this neurotransmitter, and this can play a key role in addiction.

In particular, when dopamine accumulates in a brain region called the nucleus accumbens, it facilitates a kind of neuroplasticity that can lead to behavior changes, habit formation and eventually compulsion. From an evolutionary standpoint, this is very helpful; dopamine tends to be naturally released in the brain when we do things that will help us survive, compete, or reproduce, so this mechanism helps us form good habits. Clearly, it’s much less helpful when it’s triggered by drugs.

The researchers set up a device that allowed mice to self-administer doses of ketamine, and first sought to confirm whether ketamine actually does trigger a rush of dopamine in the brain. Indeed, they found it did. The mice were quickly motivated to keep giving themselves more of the drug.

But they found something different as compared to other drugs of addiction. “Unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug,’’ said Yue Li, a postdoctral scholar in the Department of Basic Neuroscience. The mice wanted more ketamine, but they never reached the point of “uncontrolled self-administration.”

Looking closer, the researchers found a mechanism that could explain why. One of ketamine’s known effects in the brain is to block a protein receptor called N-methyl-D-aspartate, or NDMA. This triggers an increase in dopamine, which then binds to another receptor called the D2 receptor, and this D2 receptor triggers a rapid brake on the increase in dopamine.

The researchers found that with the NMDA system blocked, the state of deep-brain plasticity leading to behavioral change can’t occur. ‘‘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,” said Christian Lüscher, a Professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and a specialist in the mechanisms underlying addiction.

“It is this memorization of the product in the reward system – absent in the case of ketamine – that drives the repetition of consumption,” he continued. “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.”

The research is published in the journal Nature.

Source: Universite de Geneve

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