Addiction to fentanyl is built from two complementary brain mechanisms: the feeling of pleasure when taking the drug (positive reinforcement), and the withdrawal syndrome when trying to stop taking it (negative reinforcement). Both processes are carried out by the same molecule, a neuron receptor called mu opioid, but they take place in different regions of the brain, according to a study in mice published this Wednesday in the journal Nature.
The research, carried out by Swiss and French scientists, is still preliminary, but the results are encouraging: by blocking the receptors in each brain region, positive and negative reinforcement, that is, addictive mechanisms, decline. The finding may contribute to developing treatments for addiction to fentanyl, an opioid 50 times more powerful than heroin, and the main cause of the more than 100,000 overdose deaths recorded each of the last three years in the United States.
The key fact is that each type of reinforcement follows different neural pathways. Until now, it was believed that both the sensation of pleasure and the withdrawal syndrome were related to dopamine, better known as the happiness hormone. The idea was that the use of fentanyl triggers the production of this neurotransmitter, and that the levels drop sharply when you stop taking it, causing withdrawal symptoms.
A team of researchers led by Christian Lüscher, a neuroscientist expert in addictions at the University of Geneva, has validated the first part of the hypothesis (the release of dopamine resulting from the use of the drug), but proposes a new scenario for the second. “Our findings suggest moving from a model where negative reinforcement was led by a deficient state of dopamine to a model with a different version of the circuit that originates in the amygdala,” he explains in an email to La Vanguardia.
This opens the door to treating withdrawal syndrome without fueling the pleasure associated with fentanyl consumption. “It seems possible to develop a replacement medication that mitigates the aversive component without activating the positive reinforcement circuit each time,” describes Lüscher. The expert draws with his words a hypothetical substitute drug for the opiate, which can bind to the mu receptor, and which does so only in the neurons of the amygdala.
The University of Geneva researcher is, however, careful with extrapolation and excessive optimism of his findings. “Our study has been carried out only in mice and represents primarily a gain in knowledge,” he reasons, “translation [to humans] must begin with functional magnetic resonance imaging in patients suffering from opioid use disorder.”
In the experiment, scientists measured the brain activity of a group of mice after injecting them with fentanyl in increasing doses for five days. They have seen that the most active region of the brain during administration is the ventral tegmental area (VTA), where dopamine is produced. The drug “wakes up” the neurons responsible for producing it and makes the mice more active.
Instead, by pausing administration and forcing abstinence, neuronal activity moves to the central amygdala, a region that plays a key role in anxiety disorder. In response, the mice become virtually immobile. They only make small jumps, like spasms, as a result of the lack of the drug in their body.
By blocking the mu opioid receptors in each region, both brain activity and behavioral changes in the mice are drastically reduced, which for the researchers is an unequivocal sign that the VTA and the central amygdala are key regions of positive reinforcement and negative, respectively. Still, Lüscher acknowledges, it is likely that there are other systems involved that reinforce the role of each region and, therefore, the addiction mechanism.
