Cocaine addiction is a significant issue in the United States and other parts of the world, with deaths from the drug growing by 42 % between 2001-2014. Now, investigators may have identified a way to reverse the problem.
A new research – led by investigators from The Scripps Research Institute (TSRI), explains how targeting and preventing the activity of a brain receptor known as TrkB decreased cocaine-seeking behavior in mice, providing the way to a possible therapy for cocaine addiction.
Senior author Candice Contet and colleagues recently presented their results in The Journal of Neuroscience.
Cocaine is an unlawful drug that originates from the leaves of the Erythroxylum coca bush, native to the Andean region of South America.
Cocaine a highly effective stimulant and extremely addictive. It triggers the reward pathway in the brain – well-known as the mesocorticolimbic reward system – developing a sense of euphoria and pleasure, making consumers desire more of the drug.
In accordance to the National Institute on Drug Abuse (NIDA), in 2014, about 913,000 individuals in the U.S. met the criteria for cocaine addiction, and of the nearly 1.3 million emergency department visits for drug abuse in 2012, cocaine was engaged in over 500,000.
At the moment, there are no drugs to treat cocaine addiction; behavioral interventions – like as contingency management, where individuals with cocaine use disorders are provided with motivational incentives to quit using the drug – are the major type of treatment.
The new research from Contet and colleagues, however, recommends a pharmacological therapy for cocaine addiction may well be in the cards.
Focusing on TrkB to combat cocaine addiction
Earlier research in rat models of cocaine addiction has revealed that repeated visibility to the drug results in long-term modifications in two significant areas of the mesocorticolimbic reward system: the nucleus accumbens and the medial prefrontal cortex.
Scientists identified such modifications are partly activated by changes to the production of brain-derived neurotrophic factor (BDNF) – a protein that triggers TrkB receptors – and injecting BDNF directly into the nucleus accumbens of rats improves cocaine-seeking behavior.
However, research have identified that inhibiting BDNF production or BDNF/TrkB signaling in the nucleus accumbens decreases signs of drug dependency in rats.
As such, investigators have seemed to focusing on and blocking TrkB as a way to combat addiction to cocaine and other drugs, but this has not been without its difficulties.
For instance, Contet and colleagues observe that in the medial prefrontal cortex, BDNF decreases dependency behaviors – as confirmed in rat studies. On the other hand, blocking BDNF/TrkB signaling in this region raises such behaviors.
“Based on these earlier results, we were very enthusiastic to investigate whether preventing TrkB receptors throughout the brain would be advantageous or detrimental in assisting to decrease the motivation to take cocaine,” says study co-author Michel M.M. Verheij, who was a research associate at TSRI when the research was performed.
TrkB inhibitor decreased cocaine dependency in rats
For their research, the team examined the effects of a recently developed compound known as cyclotraxin-B – which can move from the bloodstream to the brain to stop TrkB receptors – on rats that had learned to press a lever to be able to self-administer cocaine.
This led the rats to use considerably less cocaine and press the lever less times. In addition, the treated rats were less probably to start using the drug again following a period of withdrawal. All of these aspects signify a reduction in cocaine dependency.
What is more, the investigators identified that cyclotraxin-B resulted in more normal TrkB signaling activity in the nucleus accumbens.
Curiously, therapy with the the TrkB inhibitor also led to signs of more normal TrkB signaling activity in the medial prefrontal cortex.
“We believe that the antagonist has its main action in the nucleus accumbens, where it’s logical that it would avoid the activation that is activated by cocaine,” describes Contet, “while what occurs in the prefrontal cortex is most likely a downstream impact, instead of a direct effect of the TrkB antagonist in that region.”
One essential observation, the team notices, is that cyclotraxin-B did not reduced the rodents’ appetite for a tasty glucose solution. “That’s good because it demonstrates that the TrkB antagonist doesn’t work by resulting in a general suppression of appetite or activity, but particularly decreases the sense of reward and motivation for cocaine,” says Contet.
Overall, the team states that these results indicate that targeting and blocking TrkB receptors in the brain has the possibilities to curb cocaine abuse.
“Entirely, our data demonstrate that systemic administration of a brain-penetrant TrkB antagonist results in brain region-specific effects and could be a possible pharmacological strategy for the therapy of cocaine addiction.”