A special molecular switch influences addictive (dependent) behavior and determines the strength of the body's response to addictive drugs.
A group of researchers from Heidelberg and Sorbonne Universities (Paris) came to this conclusion during experiments on mice (cocaine was used as a drug). The researchers, led by Professor Hilmar Bading (Heidelberg) and Professor Peter Vanhout (Paris) have demonstrated that the protein Npas4 regulates the structure and function of nerve cells, which are responsible for dependent behavior in mice. When the amount of Npas4 was reduced during the experiment, the animals' response to cocaine was significantly weaker.
According to the lead author of the study, Thomas Lissek, in an animal model Npas4 acts as a molecular regulator of sensitivity to drugs that cause addictive behavior and abuse. The authors hope that the results of this work will lead to a better understanding of the nature of addiction in humans and could have clinical applications. As a physician and scientist, he is conducting research for his doctoral dissertation on molecular signaling mechanisms linking neuronal activity to gene transcription at the Interdisciplinary Center for Neuroscience (IZN) at Heidelberg University. The researcher also believes that the results confirm the existence of a biological basis for addictive behavior, similar to the development of diabetes or cardiovascular disease.
The Npas4 protein is a so-called transcription factor. Thomas Lissek explains that we can consider Npas4 as a conductor that coordinates how many and which molecules will be produced in the cell. The molecules that Npas4 primarily acts on regulate patterns of electrical activity and nerve cell structure, as well as affecting the number of synapses between them. When the amount of Npas4 was experimentally decreased, the number of intercellular contacts between neurons also decreased. Subsequently, mice showed a weaker response to cocaine than when the number of Npas4 proteins was higher.
Also, the results of this work by scientists from Heidelberg and Paris demonstrate that Npas4 is controlled by specific regulatory mechanisms. Induction of expression of this protein occurs only through signals that induce an increase in calcium concentration in neuronal nuclei. For example, activation of dopamine receptors (which is the most discussed mechanism of addiction) does not increase Npas4. The research teams of Hilmar Bading and Peter Vanhout were also able to confirm this feature using the example of neurons derived from human stem cells.
The unusual mechanism of regulation of Npas4 expression is of interest both for basic biological research and for the development of clinical therapies for addiction. Professor Bading (director of the neurobiology department of the IZN) adds that exposure to Npas4 and the associated signaling pathway for controlling addictive behavior are promising therapies.
The study was conducted as part of a German-French collaborative project and was funded by the German Research Foundation (DFG) and the National Research Agency (ANR, France), among others. The results were published in the journal EMBO Reports.