Good news! We are learning more how addiction works!
"... The study in mice, reported May 22 in Nature, suggests two distinct brain pathways are in play. ...
Researchers have known that dopamine-releasing neurons in an area of the midbrain called the ventral tegmental area, or VTA, mediate feelings like euphoria. But the circuits driving withdrawal symptoms were less clear. Such symptoms include nausea, pain, irritability and an inability to feel pleasure. ...
Looking at these neurons in more detail revealed that they possessed the main receptor known to respond to fentanyl and other opioids. To the team’s surprise, removing this receptor in the VTA of mice eliminated the rewarding effects of the drug but not the withdrawal behaviors. But when the team knocked out the receptor in the central amygdala, the mice jumped less, suggesting this distinct pathway is involved in withdrawal, the team says.
The researchers took the study one step further, genetically engineering mice so that the neurons in the central amygdala could be turned on and off with light. These mice eventually learned to press a lever to get the neurons to turn off, presumably seeking to avoid the associated negative feelings. This further suggests these neurons have a role in the drug’s withdrawal effects. ..."
"... The article shows that fentanyl acts, through the same cellular receptor, on two distinct populations of neurons projecting to two different regions of the brain and thus causes a euphoric effect in one case and intense discomfort during withdrawal. in the other. This would explain both the dual dependence of individuals on fentanyl, namely the search for the well-being that this substance provides as well as the avoidance of withdrawal that follows, and why opioids are more addictive than other drugs. ..."
From the abstract:
"Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs. Among the opioid receptors, µ-opioid receptors have a key role, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation."
Le double pouvoir addictif du fentanyl Une étude montre comment le fentanyl active, via un même type de récepteurs, deux populations distinctes de neurones, entraînant l’effet euphorisant pour l’une et le malaise lors du sevrage pour l’autre.
Fig. 1: Cellular determinant of fentanyl reward and aversion.
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