Researchers Discover of a New Therapeutic Target to Treat Drug Addiction

When someone is addicted to one or more drugs, their only obsession is to get their next fix, regardless of the consequences. Currently, no drug treatment with real long-term efficacy is available. The rate of relapse after abstinence is often high. But research is making progress and recently a new therapeutic target for addiction has been discovered.

Drug Addiction

Drug Addiction

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All addictive drugs have the distinction of increasing dopamine levels in the striatum, an area of the brain involved in the neuronal reward circuitry. This increase in dopamine alters the release of glutamate and exacerbates its excitatory effects. The dopaminergic-glutamatergic balance is disturbed, and this permanently alters the behavior of the drug consumer. A better understanding of the underlying molecular mechanisms has led to the identification of a new therapeutic target.

A new treatment that works in mice

Mice were injected with cocaine several times a day, long enough to become addicted to the substance. The mice were then killed and then their brains were examined under a microscope. The dopamine receptor and the glutamate receptor are physically close to each other in the brain and are both located in the striatum. Using traceable antibodies, the authors were able to demonstrate the formation of a complex between the two receptors. This complex is called a heterodimer.

As a result, a treatment has been developed that can prevent heterodimerization of the receptors. This does not change the individual functions of each of the receptors. In the same way as before, new mice were made dependent on cocaine. One group received saline (control), while the other group received the treatment that prevents heterodimerization.

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In the treated group, the glutamate-dopamine balance was not disturbed by cocaine intake! Tests were also done to verify that the treatment did not alter the natural behavior of the mice.

Interesting results in humans

Further studies were conducted on humans. Human brain samples were recovered after death. Selected patients had used psychostimulants in the past and psychostimulants were found in their blood at the time of death. Control samples were also available.

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Dopamine receptor expression was lower in the addicted group, whereas glutamate receptor expression was identical between the two groups. Using labeled antibodies, the glutamate-dopamine receptor heterodimer could also be detected in higher amounts in the brains of drug-addicted patients, despite the decrease in dopamine receptor expression. Even more interesting: subjects with the lowest concentrations of dopamine receptors had the highest concentrations of heterodimers!

These findings in humans confirm that the dopamine heterodimer of the glutamate receptor is a relevant pharmacological target in the treatment of addiction. This work also opens interesting perspectives for the treatment of other psychiatric disorders that depend on glutamate-dopamine balance, such as schizophrenia, autism, or attention deficit disorders.

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References

Disrupting D2-NMDA receptor heteromerization blocks the rewarding effects of cocaine but preserves natural reward processing

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