New drug relieves rats of cocaine addiction
Sergey Vasiliev, Naked Science
Drug addiction is not just a disorder of the will, but the result of an intricate complex of psychological, physiological and social factors. Addiction and its symptoms are described by headings F10-F19 of the current edition of the International Classification of Diseases (ICD-10). Such conditions are extremely difficult to treat and require a complex, comprehensive approach that takes into account both psychology, physiology, and social aspects of addiction.
And while narcologists are developing more and more effective therapies, physiologists are looking for drugs that can "undo" the serious changes that long-term drug use causes in the body. A notable breakthrough in this direction is described by an article published in the Journal of Neuroscience (Verheij et al., Systematic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex). According to the authors, they managed to "remove" the experimental rats from cocaine addiction.
Like other drugs, cocaine acts on the dopaminergic system, which normally provides positive reinforcement for actions that promote survival and reproduction. Drugs not only stimulate it, but eventually lead to disruption of work, not allowing it to function as before. In particular, it is known that cocaine leads to an increase in the level of brain-Derived Neurotrophic Factor (BDNF), a protein that normally supports the growth and development of neurons and the formation of connections between them.
Increased amounts of BDNF affect tyrosine kinase TrkB receptors in the nucleus accumbens – a key element of the brain where the synthesis of emotional and sensory information occurs – causing its abnormal activity. Therefore, one of the approaches to creating drugs against cocaine addiction is to block TrkB receptors, and scientists have previously demonstrated that this really leads to the disappearance of addiction syndromes in experimental rats.
However, cocaine affects the prefrontal cortex of the large hemispheres in exactly the opposite way. Under its influence, the amount of BDNF protein decreases here, the activity of TrkB receptors also decreases – and in order to cancel dependence, they need to be returned to normal here as well. But, unlike the nucleus accumbens, in the prefrontal cortex, TrkB needs, on the contrary, to be stimulated.
However, the Dutch physiologist Michel Verheij and his colleagues from the USA and Europe went the third way and decided to try to completely disable the work of BDNF factors throughout the brain. Substances capable of binding firmly to TrkB receptors and preventing them from being triggered by BDNF are unable to cross the blood-brain barrier on their own and end up in brain tissues. Therefore, the authors combined one such molecule (cyclotraxin-B) with a fragment of a protein isolated from HIV (tat), showing that it successfully penetrates the brain.
According to the authors, the effect of injections of such a substance on laboratory rats who had developed an addiction to cocaine led "to a significant decrease in dependent behavior." The animals were less likely to prefer the drug to the usual delicious sweet water and showed less interest in the new dose, which they could get by pressing the lever.
After studying the physiology of this effect, the scientists found that their drug leads to a decrease and complete normalization of the activity of TrkB receptors in the nucleus accumbens. Unexpectedly, it also normalized in the prefrontal cortex – that is, it increased to the usual level, despite the fact that the injected substance is a TrkB inhibitor. This paradox has yet to be explained.
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29.08.2016