Addiction Research: Cowboys coke quicker

22. February 2012

For smokers, the threshold for resisting cocaine is much lower, because nicotine changes the nerves in the reward center of the brain. Agents which intervene in gene regulation in this area could be a means to address the addiction.

The “golden shot” defines the end of a path on drugs. Could this have been prevented, or is the victim so impelled toward dependence, because the tendency to addiction simply resides within his chromosomes? The genetic code delivers about half the outcome for their carrier, as to whether drugs or alcohol present a particular risk. How the risk genes look exactly, however, is still unknown.

Nicotine incites cocaine-addicted mice

Since Autumn 2011 we have nevertheless known that regular ‘sucking on the fags’ greatly facilitates the transition to the ‘syringe full of cocaine’. Nicotine enacts high gene activity in the reward center of the brain, in the striatum, by reacting with histones, DNA-binding proteins, there.

The research group working under Nobel laureate Eric Kandel of New York’s Columbia University simulated with mice as a substitute for the puff on a cigarette the addition of nicotine to drinking water for a day or a week. If cocaine came in after this, behavioural sensitisation increased in the animals by almost one hundred percent. The animals became hyperactive when the expected reward took place. Compared with other members not given nicotine treatment, they preferred a lot more often (78 percent of the time) to stay in a place within the cage, where the stimulus was received.

Even with remodeling of synapses in cocaine-addicted mice, the authors of the article in Science Translational Medicine observed variations which were dependent on the history of the animal. Nicotine caused in the nucleus accumbens a further reduction in cocaine-induced long-term potentiation. This in turn causes a local release of dopamine and thus created the reward effect.

Histone modification: addiction using a feed-back loop

Looking at the genes in the striatum, the DNA analysts recorded increased output of the FosB gene product. This transcription factor is an old and familiar object among addiction research experts. Almost all drugs induce its continued secretion, which in turn is closely related to changes of a behavioral nature in those addicted. In the experiments of the New York researchers however, a prior nicotine treatment was responsible for a further increase in FosB production. The tobacco poison also changes the activity of enzymes, which acetylise DNA-binding histones (H3 and H4), and inhibits the deacetylases involved. Histones with acetic acid residues however do not bind as effectively to the DNA strand. As a result, many genes are read more, including those for FosB which, after cocaine has been enjoyed, see to it that the craving for the drug is not lost.

The researchers were also able to simulate with a synthetic histone deacetylase inhibitor the effects of nicotine. Possibly, the authors hope, this could be a clue that points to possibilities of medical intervention, in cases where one sampling of the drug has led to dependency. One thing seems already to be certain: those who try to get away from long-term smoking with nicotine patches or e-cigarette are perhaps doing good for their lungs, but are probably not reducing the desire for an ever new bit of satisfaction.

Particularly at risk: stressed female teenagers

A number of factors help in accounting for a desire turning into an addiction. Especially with young people, stress supports this unhealthy transformation in the large interneurons of our reward center. Once set in motion, changes in gene expression are extremely stable. Therefore, even those who have banished the substance of their desire for years are at risk of relapse. Women carry a higher risk than men. For them, the reward center responds to stimulae with higher dopamine levels than in men.

In the recent issue of the journal PNAS researchers showed with laboratory rats that adolescents are particularly vulnerable. Gratification, as measured by the activity in the nucleus accumbens, was the same in adult and adolescent animals, but the drive among the “teen-rats” toward the behavior connected to it was significantly larger.

The researchers led by Eric Kandel did not let research on nicotine acting as a gateway drug to cocaine simply stop with experiments on mice – they also tested their hypotheses in the drug scene in New York. An investigation of a previous study of over a thousand high school students shows that three out of four cocaine addicts started their illicit drug path by smoking. Alcohol is another drug that is often present at the beginning of the downfall of addicts. Can beer and schnapps accomplish the same thing which cigarettes do by switching on the reward center in the brain? What about marijuana? These are questions that the team in the Department of Neuroscience at Columbia University wants to address.

Future drug therapy: press “reset” on the synapses?

In Nature earlier this year an article by Christian Lüscher and his colleagues from the University of Geneva appeared, which shows how addicts could be helped to find a way out of this vicious circle. At least in mice, the researchers succeeded in switching off addictive behavior – ie. the habituation to the stimulus and its correspondent behavior. Using optogenetic methods they made reversing changes at the synapses, which where involved in regular use of cocaine. After that, the previously-addicted mice behaved normally. Although the method from the animal experiments cannot be extrapolated to humans directly, Lüscher and other experts attach great hopes to the use of physical methods such as transcranial magnetic stimulation or deep brain wave stimulation in influencing, and thus putting a clamp on, the overwhelming demand coming from within addicts for ‘supplies’.

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